Acta Tropica 231 (2022) 106432

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Acta Tropica
journal homepage: www.elsevier.com/locate/actatropica

Toxoplasmosis in Human and Animals Around the World. Diagnosis and

Perspectives in the One Health Approach
Rosangela Aparecida Müller de Barros a, b, 1, Ana Claudia Torrecilhas c, 2,
Maria Aparecida Moraes Marciano d, 3, Monica Leszkowicz Mazuz f, 4,
Vera Lucia Pereira-Chioccola e, 5, **, Blima Fux a, b, 6, *
a
Unidade de Medicina Tropical, Departamento de Patologia, Universidade Federal do Espirito Santo, Vitoria, ES, Brazil.
b
Programa em Doenças Infecciosas, Centro de Doenças Infecciosas, Universidade Federal do Espirito Santo, Vitoria, ES, Brazil.
c
Laboratório de Imunologia Celular e Bioquímica de Fungos e Protozoários, Departamento de Ciências Farmacêuticas, Universidade Federal de São Paulo (UNIFESP),
Campus Diadema, Sao Paulo, SP, Brazil.
d
Núcleo de Morfologia e Microscopia, Instituto Adolfo Lutz, Sao Paulo, SP, Brazil.
e
Centro de Parasitologia e Micologia, Instituto Adolfo Lutz, Sao Paulo, SP, Brazil.
f
Parasitology Division, Kimron Veterinary Institute, Israeli Veterinary Service and Animal Health, Ministry of Agriculture and Rural Development Beit Dagan, 5025000,
Israel.

A R T I C L E I N F O A B S T R A C T

Key-words: Toxoplasmosis is a unique health disease that significantly affects the health of humans, domestic animals,
Toxoplasma gondii wildlife and is present in ecosystems, including water, soil and food. Toxoplasma gondii is one of the best-adapted
Toxoplasmosis parasites in the word. This parasite is able to persist for long periods in its hosts, in different geographic regions
Laboratorial diagnosis
of the word. This review summarizes the current literature of these themes, focusing on: (1) toxoplasmosis, a
One health approach
Extracellular vesicles
zoonotic infection; (2) One health approach and toxoplasmosis; (3) human toxoplasmosis; (4) animal toxo­
plasmosis; (5) toxoplasmosis diagnosis, as immunological, parasitological and molecular diagnosis; (6) T. gondii
outbreaks caused by infected meat, milk and dairy products, as well as, vegetables and water consume; (7)
studies in experimental models; (8) genetic characterization of T. gondii strains; (9) extracellular vesicles and
miRNA; and (10) future perspectives on T. gondii and toxoplasmosis. The vast prevalence of toxoplasmosis in
both humans and animals and the dispersion and resistence of T. gondii parasites in environment highlight the
importance of the one health approach in diagnostic and control of the disease. Here the different aspects of the
one health approach are presented and discussed.

1. Toxoplasmosis, a Zoonotic Infection
Toxoplasma gondii is an obligate intracellular parasitic protozoan,
causative agent of toxoplasmosis that is widely distributed (Ybañez
et al., 2020). According to recent studies T. gondii was originated in
South American felines with relative expansion through migratory birds.
Probably, the transatlantic slave trade promoted the migration of do­
mestic cats, rats and mice (Lehmann et al., 2006).
T. gondii is one of the best adapted parasites, being able to infect
innumerous species of animals and different types of cells. Thus, these

* Corresponding author at: Unidade de Medicina Tropical, Departamento de Patologia, Universidade Federal do Espirito Santo, Av. Marechal Campos, 1468,
Vitória, ES, CEP 29043-900, Brazil.
** Corresponding author at: Centro de Parasitologia e Micologia, Instituto Adolfo Lutz, Sao Paulo, SP, Brazil.
E-mail addresses: ramuller.es@gmail.com (R.A.M. de Barros), ana.torrecilhas@unifesp.br (A.C. Torrecilhas), maria.marciano@ial.sp.gov.br (M.A.M. Marciano),
monical@moag.gov.il (M.L. Mazuz), pchioccola@gmail.com (V.L. Pereira-Chioccola), blima.fux@ufes.br (B. Fux).
1
ORCID: 0000-0001-5924-8789
2
ORCID: 0000-0001-5724-2199
3
ORCID: 0000-0002-6720-736X
4
ORCID: 0000-0001-5357-0136
5
ORCID: 0000-0003-3317-195X
6
ORCID: 0000-0002-5038-3551

https://doi.org/10.1016/j.actatropica.2022.106432
Received 25 January 2022; Received in revised form 25 March 2022; Accepted 27 March 2022
Available online 4 April 2022
0001-706X/© 2022 Elsevier B.V. All rights reserved.
R.A.M. de Barros et al.
parasites are able to persist for long periods in their hosts, probably for a
lifetime. The course of the infection and pathogenicity depends on the
doses of inoculated parasites, parasite genetic background, host genetics
and immunological status (Suzuki et al., 1996; Habegger de Sorrentino
et al, 2005; Hunter and Sibley 2012).
T. gondii is a tissue cyst forming coccidia thus having the ability to
encyst within host tissue cells. In a failure of the host immune system,
parasites are converted back to their proliferative stage. This is an
evaluative shift, circumventing the need of parasites to go through their
sexual stage to be transmitted to new hosts. This property gives to
T. gondii a second route of transmission and the ability to clonally spread
through intermediate hosts, especially in immunocompromised animals
or during pregnancy (Sullivan and Jeffers, 2012).
Felids are the definitive hosts of T. gondii and are responsible for the
production and shedding the environmentally resistant oocyst. Human
and animal infections are mostly acquired by ingesting food or water
contaminated with sporulated oocysts or undercooked meat infected
with latent cysts. Other ways of infection include congenital trans­
mission (during pregnancy), blood transfusion and organ trans­
plantation (Montoya and Liesenfeld, 2004).
The infection occurs in the different geographic regions. The prev­
alence is higher in area with warm, humid climates and lower altitudes.
The oocysts are resistant and survive better in humid environments
(Weiss and Kim, 2020).
Estimates of human infection in Central America, South America and
Continental Europe range from 30 to 90% (Dubey and Jones, 2008;
Jones and Dubey, 2010; Dubey, 2010a; Minbaeva et al., 2013; Wilking
et al., 2016). Epidemiological studies carried out in different countries
revealed that the prevalence in Germany was around 55% (Wilking
et al., 2016; Lassen et al., 2016); in China, from 3.4% to 17.5% (Liu
et al., 2017, Pan et al., 2017); in the United States of America, around
11.4% (Jones et al., 2001; Jones et al., 2009; Jones and Dubey, 2014); in
Brazil, the prevalence ranging from 52.6% to 72.3% (Costa et al., 2018).
Studies conducted in Israel showed a wide variation of seropositivity,
ranging from 9.8% to 54.9% in different ethnic populations (Markovich
et al., 2014).
2. One Health Approach and Toxoplasmosis
One Health recognizes the interconnectedness of human, animal,
plant and environmental health at the local and global levels. One
Health still employs an interdisciplinary approach encouraging and
expanding collaborations in integrative research, capacity building,
clinical practice, policy and communication across diverse fields
(Aguirre and Wilcox, 2008; Aguirre et al., 2019). This approach can
cross bureaucratic boundaries and represents an opportunity for new
partnerships focused on solutions to complex problems (Zinsstag, 2012).
Toxoplasmosis as a zoonotic infection, significantly affects the health
of humans, domestic and wildlife animals. T. gondii is able to infect
animals in all ecosystems, including water, soil and food (Crozier and
Schulte-Hostedde, 2014; Jenkins et al. 2015). Due to its ability to suc­
cessfully spread throughout the ecosystem and on diverse hosts, T. gondii
is one of the most successful parasites. Studies estimate that T. gondii
already infected more than a third of the global human population
(Montoya and Liesenfeld, 2004). Thus, toxoplasmosis is considerate as a
global health hazard since its global seroprevalence is high. However,
this seroprevalence varies widely from one region to another due to
differences in climate, diet, hygiene, habits and host susceptibility
(Flegr et al., 2014; Nogareda et al., 2014).
As disease burden, toxoplasmosis is ranked among one of the highest
infections (Suijkerbuijk et al., 2018; Smith et al., 2021). The toxoplas­
mosis burden can be identified as years of life lost and years lived in less
health. The aggregate of both measures determines quantification of
years of healthy life lost due to a particular disease or infection. This
equation is known as "Disability Adjusted Life Years" (Mangen et al.,
2015).
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Acta Tropica 231 (2022) 106432
In recent years, toxoplasmosis has become the subject of numerous
studies. There is solid knowledge of T. gondii genome, life cycle, trans­
mission routes and epidemiology. Furthermore, T. gondii strains are
easily maintained and manipulated in the laboratory, making it a model
organism for studying many aspects of its biology (Boothroyd, 2009).
Studies also evaluated the high and less virulent strains, susceptibility
based on genetic characteristics (Carme et al., 2009; Ngô et al., 2019).
The infection is subclinical in the vast majority of cases, and this char­
acteristic makes difficult the effective control of toxoplasmosis.
Despite advances in the knowledge of T. gondii biology and the
development of new diagnostic methods, there is still no efficient
parasite control. The development of a vaccine for use in humans is still
a global challenge, as it is considered a neglected disease. Therefore, in
the absence of an effective vaccine the control of the human infection
should be based on the one health control approaches such as hygienic
measures, reduction of infection in animals, reduction of contamination
of the environment and water, and others. To date, there is only one
commercially available vaccine that is licensed for use in sheep against
abortion (Innes et al., 2019).
The zoonotic potential and pathogenicity of atypical strains of
T. gondii common in wildlife are often unknown (Thompson, 2013).
Virulence varies between different genotypes (Dardé, 2008; Costa Vie­
gas de Lima et al, 2019). There is evidence of abnormally high levels of
human exposure to T. gondii in some regions of the Canadian Arctic.
Transmission of T. gondii is complex and enigmatic in the Arctic, where
definitive feline hosts are scarce. Possible routes of transmission include
oocysts shed in feline feces driven by marine and freshwater routes from
subarctic regions and (Lindsay et al., 2003; Simon et al., 2013) trophic
and vertical routes of transmission.
A better understanding of the contamination of the environment by
oocysts and the actual epidemiology of the cases are critical to deter­
mine actions to control the disease. Studies indicate that large regions of
terrestrial, aquatic and marine environments may be contaminated (Du
et al., 2012; Vanwormer et al., 2013; Gao et al., 2016). Although
different studies, additional research is needed to elucidate environ­
mental conditions responsible for oocyst survival and resistance, extent
of environmental contamination, and tissue cyst survival or infectivity
after host death VanWormer et al., 2013; VanWormer et al., 2013a).
The first strategy to reduce the burden of toxoplasmosis in humans
would be the knowledge of prevalence, in selected areas, of the human
toxoplasmosis Next, the intervention of animal reservoirs. These actions
would require close collaboration of different disciplines, such as med­
icine, public health, veterinary, food safety, biology, genetics, environ­
mental and water science and water science (Patz and Hahn, 2013).
Collaboration between professionals from different fields as well as,
organizations and institutions from various countries would aid the
understanding of the ecological interactions. As summarized in Fig. 1,
such actions would facilitate a clearer understanding the impacts of this
zoonotic disease on animal and human health, as well as, in
environmental.
3. Human Toxoplasmosis
Toxoplasmosis prevalence in humans is highly variable since it is
influenced by socioeconomic and environmental conditions, as well as,
cultural habits (Dubey et al., 2012; Mareze et al., 2019). The three main
routes of T. gondii transmission include vertical transmission from
mother to fetus, ingestion of tissue cysts from infected animal tissues,
and ingestion of oocysts from contaminated water, soil or food (Tenter
et al., 2000; Montoya and Liesenfeld, 2004).
The infection is normally asymptomatic or sub-clinical however
primary infection during pregnancy can cause damage to fetus and even
abortion. In addition, primary infection or recrudescence of parasitemia
in immunocompromised humans and animals lead to severe neurolog­
ical clinical signs causing significant impacts on public health and ani­
mal production (Dubey and Jones, 2008; Dubey et al., 2020).
R.A.M. de Barros et al. Acta Tropica 231 (2022) 106432

Fig. 1. One Health an interdisciplinary approach for toxoplasmosis control. T. gondii lives in ecosystems, as water, soil and food. Due to it successfully ability to
spread throughout the ecosystem and on many hosts, T. gondii has become one of the most successful parasites on the planet. Successful public health interventions
require the cooperation of partners working with human and animal health, as well as, the environmental actions. The One Health concept proposes collaborative
multi-sectorial and interdisciplinary approaches with the goal of achieving optimal health outcomes. Efforts to better understand toxoplasmosis and its real
epidemiology are crucial for controlling of this infection. The collaboration between professionals from different areas, such human health professionals (physicians,
nurses, biologists, epidemiologists and others), animal health (veterinarians, pet owners, paraprofessionals, agricultural workers), environment (biologists, ecolo­
gists, educators, wildlife specialists), and other areas of expertise need to communicate, collaborate and coordinate activities to better understand the ecological
interactions and impacts of this zoonotic disease. Other relevant actors include policy makers, farmers and different communities.

In the beginning of infection, T. gondii can spread to mesenteric
lymph nodes and then to distant organs by invasion of lymphatic vessels
and blood and can multiply in virtually any cell in the body. Like many
obligate intracellular microbial pathogens, T. gondii infection induces a
type 1 polarized immune response, engaging both innate and adaptive
immune systems. It is clear that the major mechanism of host resistance
to toxoplasmosis is mediated by production of pro-inflammatory cyto­
kines (Habegger de Sorrentino et al, 2005; Bogitsh et al., 2018).
The chronic infection appears after two-three weeks of infection,
when the production of cytokines and antibodies against many T. gondii
proteins begin. Extracellular tachyzoites are cleared from host tissues
and intracellular parasites differentiate into latent bradyzoite forms,
which are surrounded by the parasitophorous vacuole that is enclosed in
a cyst wall. In this clinical phase, cysts preferentially reside in neural and
muscular tissues and are periodically ruptured. However, the majority of
them persist indefinitely in the brain and muscles, developing life-long
protective immunity against reinfection, since bradyzoites released are
normally destroyed by the host immune response (Suzuki et al., 1989;
Gazzinelli e al, 1992; Schlüter et al., 1997; Schlüter et al., 2003; Dubey
et al., 2008; Pereira-Chioccola et al., 2009). The ability of bradyzoites to
escape the host immune response and persist in a quiescent form within
the host is another event in the T. gondii life cycle.
If parasite multiplication is not controlled by the immune system, it
causes a generalized toxoplasmosis, which is always fatal (Vidal and
Pereira-Chioccola, 2021). Host T-cell-mediated immune responses play
an important role in suppression of tachyzoite replication and resistance
to T. gondii, resulting in chronic infection or possibly clearance of the
parasites (Montoya and Liesenfeld, 2004; Melo et al., 2020). Although
the infection is usually asymptomatic, in immunocompetent individuals,
multiple clinical manifestations in chronic infection are widely
described as in inflammation, usually following necrosis (Holland Gary,
2004; Bogitsh et al., 2018). Around 10-20% of the infected immuno­
competent individuals, during the chronic infection are reactive by the
rupture of a tissue cyst in eyes, brain or muscles causing local necrosis
accompanied by inflammation. Hypersensitivity plays a major role in
such reactions. However, when infection collapses the eyes establishe
the tachyzoite multiplication (Montoya and Liesenfeld, 2004; Vidal and
Pereira-Chioccola, 2021).
Ocular toxoplasmosis usually manifests as recurrent attacks of
necrotizing retinal inflammation with subsequent scarring (Bala­
sundaram et al., 2010; Kianersi et al., 2012). The clinical manifestations
of ocular toxoplasmosis partly reflect the parasite infection and partly
the host immune response, which often involves exuberant inflamma­
tion, is recognized as a leading cause of blindness in many parts of the
world.
Ocular lesions may result from congenital or after birth-acquired
infections. The lesion is often necrotic, destroying the architecture of
the neural retina and sometimes involving the choroid (retinochor­
oiditis), the most common lesion caused by infection with this proto­
zoan. Typical findings of toxoplasmic retinochoroiditis include white
focal lesions with an intense overlaying and vitreal inflammatory reac­
tion (Montoya and Remington, 1996; Klaren and Kijlstra, 2002; Vallochi
et al., 2005; Arevalo et al., 2010). Alternatively, retinochoroiditis might
result from a hypersensitivity reaction triggered by unknown causes
(Commodaro et al., 2009), resulting in irreversible damage to the retina
involved, whose consequences may be severe visual morbidity (Previato
et al, 2015).
Toxoplasmic retinochoroiditis has been reported as more severe in

3
R.A.M. de Barros et al.
Brazil than in Europe. Brazilian mothers received later prenatal treat­
ment. Consequently, seroconvertion determination is detected later in
pregnancy. European mothers received early prenatal treatment
reducing the risk of fetuses with ocular disease (Gilbert et al., 2008).
Another point that favors the frequency and severity of ocular disease in
Brazil compared with Europe is due to exposure to more virulent strains
of T.gondii in Brazil. Type 1 and atypical strains appear to be associated
with more severe ocular disease, compared with type II strains, which
predominate in Europe and North America (Vallochi et al., 2005; Kan
et al., 2006). These data favor understanding differences in the risk of
retinochoroiditis in Brazil and Europe (Gilbert et al., 2008).
Despite that, the diagnosis of ocular toxoplasmosis is typically clin­
ical; laboratory testing normally provides a definitive diagnosis. The
presence of anti T. gondii IgG antibodies do not confirm a toxoplasmic
etiology, but such antibodies can often persist at high titers for years
after acute infection, and a negative result generally contradicts the
diagnosis. T. gondii DNA has been identified in ocular tissue sections and
vitreous fluid and blood (Grigg et al., 2001; Rothova et al., 2008, Mattos
et al., 2011; Ferreira et al., 2014).
The reactivation of latent infection in asymptomatic individuals can
be caused by some immunodeficiency. Thus, bradyzoites convert into
active and rapidly replicating tachyzoites that may result in clinical
toxoplasmosis and even cause fatal tissue injury. As the cysts have a
predilection for neural and muscle tissue as well as the eye, most cases of
reactivation disease presenting, more frequently, cerebral toxoplasmosis
that is a life-threatening condition (Pereira-Chioccola et al., 2009;
Bogitsh et al., 2018). Cerebral toxoplasmosis is usually the most com­
mon cerebral opportunistic disease in both developed and developing
countries. The disease reactivation caused by immunosuppression cau­
ses a serious neurological disease. Usually, immunosuppression is
caused by the use of immunosuppressed drugs such as transplant
recipient patients, patients with lymph-proliferative diseases or HIV
infection (Vidal et al., 2003; Pereira-Chioccola et al., 2009; Vidal et al.,
2011; Vidal and Oliveira, 2013; Vidal and Pereira-Chioccola, 2021).
Globally, T. gondii causes the most common focal brain lesion in
HIV-infected patients (Manzardo et al., 2005; Vidal et al., 2005; Vidal
et al., 2008).
In congenital infection, tachyzoites cross the placenta and reach the
fetus. Women acutely infected for the first-time during pregnancy may
cause severe damage to the fetus with high morbidity and mortality in
congenitally infected infants. Infections acquired during the first
trimester are more severe for the fetus than those acquired in the second
and third trimesters (Desmonts and Remington 1980; Remington et al.,
1995; Dubey et al., 2021).
The clinical signs can be stillbirth, premature birth, intrauterine
growth retardation, fever, pneumonia, hepatosplenomegaly, thrombo­
cytopenia involvement in eyes and brain (McAuley et al., 1994; Peyron
et al., 2016). However, a great part of the congenitally infected new­
borns presents no clinical signs, but they are at risk of developing ocular
lesions in childhood or adolescence (Remington et al., 2001; Dubey
et al., 2021).
4. Animal Toxoplasmosis
T. gondii is found in all habitats and regions, from the Arctic to the
tropics in terrestrial, aquatic and marine environments, affecting a wide
range of hosts (Sibley 2003; Dubey and Jones 2008; Dubey, 2010).
Theoretically all warm-blooded animals can be infected and at least 350
host species have been described to date (Zhao and Ewald, 2020).
Toxoplasmosis causes important clinical infection in small ruminants
being a major cause of abortion (Anderson et al., 1994; Oliveira et al.,
2018; Lindsay and Dubey, 2020). In addition, T. gondii infection is
considered an important cause of reproductive disorders in goats (Cal­
deira et al., 2011; Unzaga et al., 2014). Abortion cases in goats have
been described in different regions of the world such as Spain, (Moreno
et al., 2012), Argentina, (Unzaga et al., 2014) and Brazil (Caldeira et al.,
4
Acta Tropica 231 (2022) 106432
2011; Oliveira et al., 2018).
T. gondii cause acute and fatal disseminated toxoplasmosis in wild
animals with macropodidae, monkeys and meerkats being highly sus­
ceptible for infection (Cunningham et al., 1992; Juan-Sallés et al., 1997;
Portas, 2010). Due to its great importance as a causative agent of a
zoonosis, T. gondii has been studied more intensively among coccidian
(Tenter et al., 2000).
The environmental contamination occurs by oocysts that are shed by
domestic cats and other wild felids (Frenkel et al., 1970; Dubey, 2008;
Dubey, 2009). The oocyst stage has a resistant wall that protects para­
sites from severe environmental conditions until their ingestion by the
host (Dumètre et al., 2013). Different T. gondii biological parameters are
not totally known, as the environmental conditions that cause the oocyst
long survival and resistance. (Dubey, 2010a). Despite the important role
of epidemiology, environmental transmission remains the least studied
(Shahet al, 2019). Even with epidemiological progress about T. gondii
infecting humans and animals, the environmental contamination and
the factors that contribute to the survival of oocysts in the environment
are not totally established (Maleki et al., 2021; Oliveira et al., 2021).
Domestic and wild felids are the only known definitive hosts capable
of releasing environmentally resistant oocysts into their feces (Hutch­
ison et al., 1969; Jewell et al., 1972; Dubey et al., 2008; Miller et al.,
2018). Young cats can release greater numbers of oocysts than adult
domestic cats. Interest in the evaluation of T. gondii infection has focused
on domestic animals that cohabit or serve as food for humans, as these
animals can act as reservoirs for human infections (Sogorb et al., 1977;
Ruiz and Frenkel 1980; Dubey and Beattie, 1988).
T. gondii infects a variety of domestic animals, including dogs
(Machado et al., 2019; Dubey et al., 2020a; Arruda et al., 2021); sheep
and goats (Bártová et al, 2009; Chikweto et al, 2011; Gharekhani et al.,
2018; Moskwa et al., 2018); pigs (Saavedra and Ortega, 2004; Guo
et al., 2015; Flores et al., 2021); chickens (Mahami-Oskouei et al., 2017;
Ferreira et al., 2018; Dubey et al., 2021a; Lachkhem et al., 2021); ducks
(Lv et al., 2021); cattle (Moore et al., 2008; Jokelainen et al., 2017;
Gomes et al., 2020; Shariatzadeh et al., 2021); horses (Li et al., 2020);
rabbits (Almería et al., 2021); wild boar (Rostami et al., 2017; Laforet
et al., 2019); camels (Maspi et al., 2021); among others. In sheep and
goats, congenital infection is a major cause of stillbirth. Those who
survive generally grow normally, but still pose a public health risk if
their infected meat is consumed (Dubey, 2009; Oliveira et al., 2018).
Sheep and pigs are the most susceptible to toxoplasmosis. Cattle and
equines are easily infected, but resistant to acute disease, which makes
them important reservoirs for transmission to humans and other ani­
mals. Chickens are also resistant to T. gondii infection, but studies have
shown a high frequency of T. gondii in free-range chicken (Dubey et al.,
2005; Dubey and Jones, 2014; Magalhães et al., 2016).
Several wildlife species play an important role in the transmission
and maintenance of T. gondii in the environment (Yai et al., 2009; Dubey
et al, 2010; Pena et al., 2011; Cabral et al., 2013; Cañón-Franco et al.,
2013). Detection in apparently healthy and free-living wild animals
suggests that asymptomatic or subclinical infections may occur. Wildlife
routes of infection include consumption of infected felines, predation or
elimination of infected intermediate hosts, direct ingestion of oocysts in
contaminated environments, or congenital transmission.
T. gondii infections were shown in a wide range of wild species,
including freshwater mammals (Santos et al., 2011; Ribas et al., 2018);
marine mammals (Fayer et al., 2004; Jensen et al., 2012; Rengifo-­
Herrera et al., 2012; Miller et al., 2018); non-human primates
(Catão-Dias et al., 2013; Cano-Terriza et al., 2019; Paula et al., 2020);
birds (Frenkel et al., 1995; Dubey, 2002; Dubey, 2010a; Darwich et al.,
2012; Barroso et al., 2020; Ammar et al., 2021; Dubey et al., 2021a);
ungulates (Dubey et al., 2014; Almería et al., 2018); polar, brown and
black bears (Chomel et al., 1995; Oksanen et al., 2009); terrestrial
herbivores (Ballash et al., 2015); among others.
Aquatic invertebrates can significantly influence the aquatic trans­
port of T. gondii by ingestion, which can transmit the infectious stage to
R.A.M. de Barros et al.
susceptible hosts, including marine mammals and humans (Shapiro
et al., 2014). Although cold-blooded animals may not serve true inter­
mediate hosts, T. gondii oocysts can be ingested and retained by fish
(Massie et al., 2010); bivalves (Arkush et al., 2003; Lindsay et al., 2003)
and marine snails (Krusor et al., 2015; Schott et al., 2016). Ingestion of
these invertebrates has been epidemiologically associated with an
increased risk of T. gondii infections in marine mammals or people who
consume seafood (Jones et al., 2009).
When cats have free access to a farm premises and, principally, to
pastures, the other domestic or farm animals are very exposured to
T. gondii infection (Guo et al., 2015). The exposure to contaminated soil
with oocysts is the main transmission route to these animals that are
intermediate hosts and will be food to humans (Gilot-Fromont et al.,
2012).
5. Diagnosis of Toxoplasmosis
The diagnosis is crucial for the surveillance, prevention and control
of toxoplasmosis. Traditional approaches to the laboratorial diagnosis
include etiological, immunological, molecular and histopathological/
immunohistochemical methodologies. Currently, two biological ap­
proaches are used: (i) indirect detection through immunological assays
and (ii) direct detection as parasitological methods using microscopy to
parasite detection. The other is the molecular methodology that detects
the parasite DNA in suspected samples (Table 1).
5.1. Indirect Methodologies: Immunological and Imunohistochemical
Diagnosis
A wide range of serological tests for T. gondii detection is available
with various methodologies and antigens that can detect different
immunoglobulin isotypes. Most are not Rapid Diagnostic Test (RDT) and
are aimed at laboratories with good infrastructure and qualified
personnel. Immunological techniques are relatively inexpensive, require
a small sample volume, and can be used on live animals (Elmore et al.,
2016; Cakir-Koc, 2016). Assays include the Sabin-Feldman (DT) dye test,
based on tachyzoite stains under microscopy; enzyme-linked immuno­
sorbent assay (ELISA), immunosorbent agglutination assay (ISAGA),
indirect hemagglutination assay (IHA), indirect fluorescent antibody
test (IFAT), modified agglutination test (MAT), Latex Agglutination Test
(LAT) and Western blot (WB) (Liu et al., 2015; Sun et al., 2015; Dard
et al., 2016).
Humans present a lifelong persistence of anti-T. gondii IgG antibodies
and, in many geographical areas, toxoplasmosis prevalence is high.
Thus, in many cases, the serological titers do not reflect a recent infec­
tion. In this way, it is often the lack of reliability in discriminating recent
from old infection by detection of anti-T. gondii IgM, IgA, or IgE. This
situation is very common in congenital toxoplasmosis diagnosis (Per­
eira-Chioccola et al. 2009). In the case of cerebral toxoplasmosis, the
identification of a positive serology is less useful in settings where the
Table 1
Strategies for T. gondii diagnostic in samples from humans, animals and environmental.
Methods for diagnostic of T. gondii infection/contamination
Indirected detection Serology Sabin –Feldman (DT)
ISAGA/IHA
ELISA/Avidity ELISA
MAT/LAT
IFAT/ WB
Biopsy/ Necropsy/authopsy Pathology (histology)
Immunohistochemical
Direct detection Microscopic examination
Electron microscopy
Molecular detection
Isolation (bioassays and culture)
*
Detection of T. gondii oocysts in environmental samples (soil, water, feed) is technically difficult. Normally samples are concentrated (filtrated) and prepared with
the combination of several techniques.
5
Acta Tropica 231 (2022) 106432
seroprevalence for T. gondii in the general population is very high. In
Brazil, most AIDS patients with any focal brain lesion also show positive
serological diagnosis for toxoplasmosis However, the identification of a
negative serological result presents a high negative predictive value
(Vidal et al., 2008; Vidal and Pereira-Chioccola, 2021).
MAT is a sensitive serological method to detect T. gondii IgG anti­
bodies in herds and wild animals. MAT primarily detects antibodies from
animal tissue fluid, serum or plasma (Al-Adhami, 2016). It is the most
widely used method for diagnosis, the most economical and the simplest
among many methods available to detect T. gondii infection, and there is
no need for specific equipment (Hill et al., 2006, Dubey, 2010a). In most
laboratories, the development of MAT is performed with the aid of
tachyzoites collected by traditional propagation performed in murine
peritoneal cavity in vitro culture (Bachand et al, 2019). Among the
advantages of this method is that it can be used for birds and mammals
with easy interpretation of results, its high sensitivity and specificity, as
well as its ease of execution, with no need for specific equipment
(Desmonts and Remington, 1980). The antigen is stable at 4◦ C for many
months and does not need species-specific reagents (Langoni et al.,
2007; Macrì et al, 2009).
ELISA has been used as the most reliable, practical, economical and
widely used for detecting exposure to T. gondii in hosts (Titilincu et al.,
2009; Tumurjav et al, 2010). Only a small sample volume is needed, and
the assay can be semi-automatic, making it suitable for large-scale
screening (Felin et al., 2017). Furthermore, different ELISAs can
differentiate between immunoglobulin classes. Therefore, it is useful for
determining the infection stage (Lind et al., 1997). Different method­
ologies for ELISA were standardized using various antigens (native, re­
combinant, chimeric), secondary antibodies and antibody binding
reagents (Ferra et al., 2015). However, the choice of components can
significantly influence test performance. Commercial ELISA kits for the
detection of T. gondii antibodies in domesticated animals are available,
making large-scale and routine screening feasible.
IFAT is a simple test that detects IgG and IgM antibodies and has been
widely used in the detection of antibodies against T. gondii in humans
and animals (Miller et al., 2002). Fluorescence-labeled antibodies to a
variety of species are commercially available. However, a fluorescence
microscope is required for the test and the results are read with the
naked eye, and individual variation may occur. Some species-specific
conjugates can be difficult to find, and there is a risk of possible
cross-reactivity with rheumatoid factor and antinuclear antibodies
(Filice et al., 1983).
Immunohistochemical diagnosis is frequently used for determination
of fetal brain damage in early abortions of ovine toxoplasmosis
(Gutiérrez-Expósito et al, 2020), necropsies of wild and marine mam­
mals as cetaceans (Sanots et al., 2018; Costa-Silva et al., 2019), and
autopsies for undefined death investigation (Bastos da Silva et al, 2016;
Hippólito et al., 2019).
In addition bioassays in mice and cats can be used for T. gondii
isolation, infection confirmation. This method is considered gold
Humans Animals *Environment
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R.A.M. de Barros et al.
standard for detecting viable tissue cysts (Dubey et al., 2016). In tissues
of chronically infected animals the number of parasites is low therefore
bioassays can be of great importance. Bioassay in cats is considered a
highly sensitive method of detecting T. gondii bradyzoites in tissues. Cats
experiment fed with as few as one bradyzoite may excrete large numbers
of oocysts in their feces (Dubey et al., 1995).
5.2. Direct T. gondii Detection: Parasitological and Molecular Diagnosis
T. gondii detection in feces, water, environmental and tissue samples
has been traditionally performed using microscopy. However, the
identification based on this method is less sensitive and unreliable (Liu
et al., 2015).
Oocysts in feces, water and environment can be previously stained,
which helps to distinguish the parasites from the host cells. Giemsa/
Hematoxylin/Eosin (HE) staining is simple and economical and
commonly used for this purpose (Silva et al., 2010). Electron microscopy
is also used to detect tissue cysts in the brain of mice and oocysts in the
small intestine of infected cats, but it is difficult to apply for routine use
(Sims et al., 1989).
According to molecular diagnosis, the methodology used to detect
T. gondii DNA in clinical, veterinary and environment samples is poly­
merase chain reaction (PCR). This methodology is considered highly
specific and highly sensitive (Belaz et al., 2015). The test sensitivity can
be influenced by different factors such as variation in tissue predilection
by T. gondii in host, heterogeneous distribution of bradyzoite cysts
within tissues, tissue selection and tissue quantity (Hill et al., 2006). PCR
can be used in situations where sera are not available or antibody
preservation is compromised, for example, in wildlife studies when the
eliminated carcasses are the most readily available set of samples. In
addition, PCR-based techniques can be expanded to allow for
sequencing and typing of strains, which can be important in detailed
epidemiological studies.
In humans, PCR have allowed the sensitive detection of T. gondii DNA
in clinical specimens such amniotic fluid, aqueous humor, cerebrospinal
fluid (CSF), bone marrow, and blood (Colombo et al., 2005, Contini
et al., 2005; Edvinsson et al., 2008; Mattos et al., 2011; Camilo et al.,
2017). PCR is appropriate for AIDS patients, since this method is not
affected by the immunological status and has shown to be rapid, sensi­
tive and specific, avoiding invasive and expensive brain biopsy pro­
cedures. As an alternative approach, PCR in CSF and peripheral blood
samples has also been used with several reported sensitivities (Pelloux
et al., 1997; Priya et al., 2002; Contini et al. 2005; Colombo et al., 2005).
The development of the Real-time PCR (qPCR) has revolutionized
molecular diagnosis by adding reliability and speed, representing
considerable progress (Robert-Gangneux et al., 2010). Many reports
tend to generalize the idea that qPCR in general has an improved
sensitivity compared with conventional PCR (Lin et. al., 2000; Mesquita
et al., 2010; Camilo et al., 2017).
Subsequently, varieties of PCR sensitivity and specificity depend also
on factors including the standardization of reagents and protocols for
DNA extraction, the inadequate storage of the clinical sample and the
time elapsing between the start of specific therapy and collection (blood
or CSF) which often affects PCR reproducibility and makes comparison
of results difficult. The use of a second reaction using parallel amplifi­
cation of a marker that amplifies a human sequence as the β-globulin
gene in case of human samples guarantees the quality of the DNA
extraction and PCR inhibitors, avoiding false results (Camilo et al.,
2017).
Several DNA targets for PCR were evaluated and have been used
regularly in the different laboratories to determine the diagnosis of
congenital, ocular, disseminated or cerebral toxoplasmosis. Targets such
as bradyzoite genes encoding for specific antigens, B1 gene; P30, ribo­
somal DNA genes and 529-bp sequence have been frequently used
(Chabbert et al., 2004; Contini et al., 2005; Mesquita et al., 2010;
Camilo et al., 2017), or to detect and quantify parasite DNA load and its
6
Acta Tropica 231 (2022) 106432
levels in different moments of infection, as during the course of therapy
(Contini et al., 2005). Among them, two are more frequently used by the
great sensitivity and specificity. One is the 529-bp sequence, which has
200-300 copies in the genome of T. gondii. The other is the B1 gene that
has 35 copies in the genome and is conserved in different parasite strains
(Costa and Bretagne 2012; Robert-Gangneux et al., 2010). The sensi­
tivity and accuracy of the targets 529-bp sequence, B1 gene and the
comparison of both were analyzed in conventional PCR and qPCR
(Holman et al., 2000; Belaz et al., 2015; Camilo et al., 2017). They have
shown markers to 529 bp repeat region that were more sensitive than
those from B1 gene.
6. T. gondii Outbreaks
6.1. Meat products
One of the major public health problems in the world is the food-
borne diseases, since they cause several infections in the population,
with significant economic losses. Protozoa as T. gondii, which is trans­
mitted by water and food, cause to severe clinical involvements. The
consumption of raw or undercooked meat and its by-products, mainly,
those from pigs and sheep, is one of the main risk factors for acquiring
toxoplasmosis (Kijlstra and Jongert, 2009; Belluco et al., 2018; Tenter
et al., 2000; Smith et al., 2021). The cyst number found in meat is
generally slight (around one cyst/100g of meat). The cyst localization in
musculature and/or viscera may vary from host to host. Cysts in tissues
from swine, sheep and goats are found more frequently (Hill and Dubey,
2002; Djokic et al., 2016; Sroka et al., 2020). On the other hand, cysts
are less frequent in tissues of chickens, rabbits, horses and, rarely found
in tissues of infected cattle and buffaloes (Tenter et al., 2000; Tenter,
2009).
Toxoplasmosis control by “Sanitary Inspection Services” is unfeasi­
ble, since T. gondii cysts are microscopic and cannot be visualized with
the naked eye. Therefore, the sanitary control of T. gondii is a challenge
for regulatory surveillance services and science (Kijlstra and Jongert,
2009). The strategies adopted include prevention measures, as hygienic
and sanitary guidelines on care in the correct meat cooking and its
products as well as, the proper handling of cooking utensils (Germano
and Germano, 2011; CDC, 2021). One third of the human population
already had contact with T. gondii by ingestion of contaminated water or
food, mainly in places where sanitary conditions are precarious (Kijlstra
and Jongert 2008; Almeria and Dubey, 2021; CDC, 2021).
Strategies to reduce the occurrence risk of tissue cysts in meat
products are considered preventive measures in T. gondii transmission
that can be by monitoring of fresh meat or cyst inactivation by pro­
cessing the contaminated meat (Berger-Schoch et al., 2011). The inac­
tivation of T. gondii cysts in meat products can be carried out by heating
homogeneously, at temperature above 67◦ C or by freezing at -13◦ C
(Sommer et al., 1965; Dubey et al., 1990; Kotula et al., 1991; Kijlstra and
Jongert, 2009). Cured process in some meat products causes unviable
cysts. However, they depend on the salt concentration and storage
temperature. Experimentally, cysts were inactivated in 6% NaCl solu­
tion at 4◦ C to 20◦ C, but they were resistant for weeks in 0.85 to 3.3%
NaCl solutions at the same temperatures (Dubey, 1998). The salting of
fresh-type homemade pork sausages does not inactivate cysts. The
inactivation occurs only at high NaCl concentrations. However, the
consumption is unfeasible, mainly due to changes in organoleptic
characteristics (Jamra et al., 1991; Navarro et al., 1992). Cultural habits
are relevant in the prevalence of T. gondii infection (Kijlstra and Jongert,
2009). Studies report that most infections in humans in the US are likely
the result of ingesting cysts contained in undercooked meat. In France,
the habit of eating raw or undercooked meat products also increases the
infection prevalence. Around 84% of pregnant women present anti­
bodies anti-T. gondii (Hill et al., 2005; Rodrigues et al., 2018).
Case-control studies developed in Europe have shown that meat is the
main risk factor for infection in pregnant women. Small toxoplasmosis
R.A.M. de Barros et al.
outbreaks have also been associated with raw meat consumption in
Korea, USA, France, French Guiana, and New Zealand (Choi et al., 1997;
Ross et al., 2001; Carme et al., 2002; Lake et al., 2020). It is important to
emphasize the management meat from hunting animals, since epide­
miological studies and reports of outbreaks have pointed to the man­
agement and consumption of raw or undercooked meat as a source of
toxoplasmosis (Cook et al., 2000; Ross et al., 2001; Carme et al., 2002;
Dubey and Jones, 2008; England et al, 2019; Gaulin et al., 2020).
In recent years, various parasitological and molecular methods have
been developed to detect T. gondii cysts in meat from different animal
species. These methodologies aimed to improve toxoplasmosis control
and prevention measures (Tenter et al., 2000; Hill and Dubey, 2002).
Alternative approaches were developed to employ meat exudate as
biological material for antibody detection in rabbit meat, fresh and
cured bovine meat (Mecca et al., 2011; Marciano et al., 2018). This
alternative approach was, also, tested in exudates from cattle, swine,
sheep and poultry retailed in Scotland. The authors obtained a good
positivity in swine and sheep exudates (Plaza et al., 2020). Schares et al.
(2018) compared the ELISA results of serum and meat exudate from
different bovine organs and muscles. They concluded that samples from
the heart had high immunoglobulin levels. These alternative approaches
are interesting for use in quality control and safety of meat products,
since they constitute a promising tool for Public Health Laboratories,
allowing the monitoring and elucidation of T. gondii outbreaks.
6.2. Milk and Dairy Products
Normally, milk and its products are industrialized and pasteurized,
therefore, the ingestion of milk or dairy products is considered low to the
risk of toxoplasmosis transmission. Occasional reports related the
occurrence of small outbreaks (Sacks et al., 1982; Jones et al., 2009;
Dubey and Jones, 2014; Dubey et al., 2014; Bezerra et al., 2015). Thus,
dairy products cannot be excluded as a potential source of transmission,
since they may represent a risk to human health, especially when they
are manipulated by informal producers that use unpasteurized milk, in
the production of dairy products intended for consumption by children,
elderly and immunocompromised individuals (Riemann et al., 1975;
Skinner et al., 1990; Bezerra et al., 2015). This evidence was tested by
Hiramoto et al. (2001). A sample of bovine milk previously contami­
nated with T. gondii (ME-49 strain) was used to prepare fresh cheese.
Next, this cheese was used in bioassay to infect two mice, which
developed an expressive infection after inoculation.
Studies related the presence of tachyzoites and cysts in milk from
sheep, goats, cattle and mice (Remington et al., 2004, Ragozo et al.,
2009; Camossi et al., 2011; Tavassoli et al., 2013). However, most of
them were related with small outbreaks and indicated that transmissions
were caused by ingestion of unpasteurized and raw goat milk (Riemann
et al., 1975; Chiari and Neves, 1984; Skinner et al., 1990; Dubey et al.,
2014; Silva, 2015). Recently, T. gondii DNA was detected in milk of 42
seropositive sheep in Santa Catarina State, Brazil. These DNA samples
were sequenced and results showed around 97% of identity with the
membrane antigen of T. gondii P22 gene. Besides the risk of human
infection by consumption of milk and/or dairy products, the lactogenic
transmission to lambs is possible (Ossani et al., 2017).
The importance of adopting measures for sanitary management of
herds was shown in a study that IgG antibodies or DNA were determined
in 15.78% in samples of raw milk from goats and sheep analyzed in
northern Italy (Gazzonis et al., 2019). Equality, a study in Poland
showed that milk was associated as a potential risk factor for T. gondii
transmission in humans. In Sudan a study showed a high seropositivity
(67%) for T. gondii in camels. These data represent public health sig­
nificance since nomads consume raw milk from camels (Elamin et al.,
1992). These studies show the importance of preventive measures,
health education and development of new research are essential to curb
the high toxoplasmosis incidence via food.
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Acta Tropica 231 (2022) 106432
6.3. Water Consume
Studies reporting the detection of T. gondii oocysts in water samples
are scarce when compared to those from Cryptosporidium spp. and
Giardia spp. Vieira et al. (2015) studied the vulnerability of groundwater
associated with toxoplasmosis prevalence in humans and discussed the
importance of oocysts in aquatic environments. However, waterborne
outbreaks have been described in different regions of the world (Franco,
2007; Jones and Dubey, 2010). An epidemiological study associated the
high toxoplasmosis prevalence to oocysts in contaminated food, irriga­
tion water, fresh fruits and vegetables. The authors highlighted water as
an efficient carrier source of T. gondii due to of its great dispersal ca­
pacity, its wide use and for being of fundamental consumption for the
maintenance of life (Hussain et al., 2017).
The largest epidemic outbreak of human toxoplasmosis reported in
the literature occurred in Santa Isabel do Ivaí city, Paraná state, Brazil
due to water transmission. Oocyst dissemination occurred in a water
treatment plant (Moura et al., 2006). In October/2018, 2,000 cases were
notified in Santa Maria city, Rio Grande do Sul state, Brazil (Minuzzi
et al., 2020; Minuzzi et al., 2020a). The main suspicion was water
transmission. Other studies have also linked toxoplasmosis outbreaks to
oocyst contamination in drinking water in the United States and Canada
(Bowie et al., 1997; Dubey, 2004). These studies suggested the envi­
ronmental contamination occur via oocysts, which are more restricted in
places with high feline concentration (Afonso et al., 2008). Less than
0.9% of cats actively excrete oocysts in feces and this may still be an
overestimation as it is difficult to distinguish T. gondii oocysts from
Hammondia hammondi oocysts by microscopic analysis (Schares et al.,
2008).
Investigations of T. gondii oocysts in water bring a series of scientific
and technological challenges, since internationally recognized meth­
odologies are of high complexity, combined with difficulties in detection
and possible presence of interfering in the matrices. Although different
studies have been carried out to investigate the infectivity of parasites in
soil and water, the viability of T. gondii oocysts in water is poorly re­
ported. Therefore, parasite viability is an important tool for the effective
monitoring of drinking water quality (Dubey, 1998; Dubey, 2009).
Recently, Marciano et al., (2020) evaluated the viability of T. gondii
oocysts by real-time PCR in samples treated or not with phorbol 12-myr­
istate 13-acetate (PMA), a DNA intercalant. In intact oocysts, the
intercalant did not bind to the DNA. In contrast, in non-viable oocysts,
an intercalation by PMA occurred in the DNA, allowing the differenti­
ation between them. The implementation of specific methodologies for
detecting this pathogen allows preventing or elucidating epidemic out­
breaks, as well as monitoring the quality of water available to the
population.
6.4. Vegetables
In the daily diet, vegetables are essential to gain vitamins and min­
erals. However, the consumption of raw vegetables, without proper
hygiene, can represent a health risk if they are contaminated by any
pathogen. Vegetable contamination can occur during irrigation, storage,
transport and inadequate handling (Soares, 2006; Fernandes et al.,
2015; Gois et al., 2018).The investigation of T. gondii oocysts in vege­
tables is appropriate, since they are widely consumed by the population.
However, the oocysts removal is hampered by intrinsic conditions of the
parasite including adherence to surfaces and resistance to environment
(Bekele et al., 2017).
Different T. gondii outbreaks related to consumption of raw vegeta­
bles were reported in epidemiological studies (Ekman et al., 2012;
Hohweyer et al., 2016; Lalonde and Gajadhar, 2016). However, oocyst
isolation and detection in these matrices are still a challenge (Lass et al.,
2012). A toxoplasmosis outbreak in 2016, in Para state, Brazil reported
73 cases. The contamination was correlated with the consumption of
acai juice, sold in three sale points of the product. The epidemiological
R.A.M. de Barros et al.
data pointed to food origin and the probable failure of good practices in
production of acai juice (Morais et al., 2016). For transmission reduction
is essential the adoption of good practices, such as correct vegetable
sanitizing before consumption in order to remove the oocysts.
7. Studies in Experimental Models
Toxoplasma gondii is a protozoan intensively studied and used as a
model organism for the study of other clinically relevant human and
veterinary parasites due to its ease of in vitro culture and genetic
manipulation.
Experimental models have largely contributed to a better under­
standing of the pathogenesis of toxoplasmosis in different experimental
approaches and applications, such as the pathophysiology of infection,
drug efficacy, treatment and prevention. However, these models do not
always reflect the natural dynamics of the infection, so it is important to
choose the most appropriate model for each scientific question.
Basically, all warm-blooded animals can be infected with T. gondii.
However, different animal species differ markedly in their resistance to
infection (Zenner et al., 1998; Gao et al., 2014; Dubey et al., 2016). The
outcome of infection depends not only on the animal species, but also on
the parasite strain (McLeod et al., 1984; Brown et al., 1995). Genetically,
the T. gondii strains are all relatively similar, differing only by about
1-2% at the nucleotide level (Fujii et al., 1983; Zenner et al., 1998).
Despite their genetic similarity, they induce strong phenotypic differ­
ences in the experimental models (Sibley et al., 2009).
T. gondii is capable of infecting most laboratory animals, although,
rat is partially resistant. The use of these animals has been useful for
understanding the mechanisms of resistance and immunity induction
(Benedetto et al, 1993; Darcy and Zener, 1993).
Mice, rats, rabbits, pigs and non-human primates are commonly used
to study the efficacy of drugs against T. gondii infection. Mice have been
used as a model to assess therapeutic assessment (Fux et al., 2000; Oz
and Tobin, 2012; Dunay et al., 2018), pathogenic mechanisms and, more
recently, for vaccine approaches (Ismael et al., 2006). Among the
experimental models, the most economical and widely used is the mouse
(Buxton, 1998; Que et al., 2004). Although murine models have many
advantages, extrapolation of results to other species must be done with
care (Dunay et al., 2018).
Animal models of congenital toxoplasmosis were effectively used to
evaluate efficacy of treatment and vaccines and to simulate fetal damage
and vertical transmission of human according to different doses and
time of pregnancies in a different dose and time of pregnancy (Var­
gas-Villavicencio, et al., 2016).
In recent years, the development of new technology of staining
(signaling) and genetic engineering of parasites has provided an addi­
tional alternative for experimental models of infection permitting real-
time analyses of infection with reduction of the number of animals
(Avci et al, 2018; Ribeiro-Andrade et al., 2019). The use of transfected
T. gondii parasites make it possible to evaluate progression of infection
and immune response to the parasite including the maintenance of
T. gondii tissue cysts and tachyzoites (Subauste, 2012; Ribeiro-Andrade
et al., 2019).
Other animal models can be used, such as sheep, rats, guinea pigs,
hamsters or (Santos et al., 2016; Freyre et al., 2012). Rats and sheep are
widely used in studies that address the efficacy of drugs for T. gondii
(Dunay et al., 2018). Rats have placental development and hemochorial
placentation identical to humans (Fonseca et al., 2012). In sheep,
congenital toxoplasmosis is very similar to that which occurs in humans.
Thus, sheep are an appropriate animal model for the study of congenital
toxoplasmosis, not only because they share important aspects of human
infection, but also because they directly contribute to the study of new
disease control measures in livestock, also severely affected by T. gondii.
There are well-established models of toxoplasmosis in pregnant ewes
that provide a starting point for the preparation and testing of new
vaccines (Innes et al., 2019).
8
Acta Tropica 231 (2022) 106432
Several animal models have been suggested as a model for toxo­
plasmosis, but they have never been widely used. Most studies were
conducted with rodents, due to the nature of their placenta and also for
practical reasons, due to the ease of maintenance and handling in the
laboratory (Araujo and Remington, 1974; Dubey and Shen, 1991; Fux
et al., 2000; Freyre et al., 2001; Oz and Tobin, 2012). However, studies
involving a detailed anatomical analysis and assessment of fetal infec­
tion often require larger animals such as rabbits, pigs, sheep or primates
(Schoondermark-van de Ven et al, 1994; Jungersen et al., 2001; Nau
et al., 2017).
An ideal animal model for congenital toxoplasmosis, for drug studies,
as well as for immunological and vaccine studies would be one that
mimics the conditions of infection in the human host (Weiss and Kim,
2020). To date, no animal model has been able to mimic all clinical
symptoms and signs developed by humans in response to T. gondii
infection (Munoz et al., 2011).
8. Genetic Characterization of T. gondii Strains
Extensive research regarding the genotyping of T. gondii in humans
and in different animals worldwide has been done in the last years (Fux
et al 2003). Investigation of the genotypes of T. gondii infection in ani­
mals aims to ascertain the correlation between the specific variant and
its biological properties and to epidemiologically track the relation of
the particular isolate with diseases outcome, outbreaks and pathoge­
nicity (Dardé 2008; Xiao and Yolken, 2015).
Genotyping of T. gondii isolates from different geographical places
showed several T. gondii subpopulations. Howe and Sibley (1995) sug­
gest that the genetic structure of T. gondii are from three widespread
clonal lineages named type I, II and III isolates from both wild and do­
mestic animals in diverse regions of North America has revealed greater
genetic diversity than previously described and a fourth clonal lineage
have been proposed (Khan et al., 2011). Yet, some isolates from animals
and humans are different from the known clonal lineage (I, II, III) and
therefore classified as atypical or exotic genotypes (Ajzenberg et al.,
2004).
For better understanding of the epidemiological population of
T. gondii worldwide an integrated approach using PCR-RFLP of 10
different genetic markers has been proposed by Su and collaborates in
2009 (Su et al, 2012). The use of this integrated approach revealed
several new major genotypes (Su et al., 2012). In order to standardize
the nomenclature of T. gondii genotypes, each identified genotype is
designated as a specific genotype number at ToxoDB–PCR-RFLP geno­
types (http://ToxoDB.org) database (Gajriaet al, 2008). Nowadays at
least, 278 variations have been described using PCR-RFLP (Su and
Dubey, 2020). Geographical analyses of 1457 samples revealed 189
ToxoDB genotypes by the PCR-RFLP method with few genotypes present
in the northern hemisphere, whereas hundreds of genotypes coexist in
the southern hemisphere (Su and Dubey, 2020).
In North America, Europe, Asia, Africa, most isolates belong to the
clonal type I, II, and III lineages, and there is no host boundary for
different genotypes (Sibley and Boothroyd, 1992; Howe and Sibley,
1995; Lindstrom et al., 2006; Zakimi et al., 2006). The three lineages are
highly similar at DNA sequence level. As the differences were less than
1% on average, it was suggested that I, II and III lineages were expanded
globally in the past 10,000 years (Su et al., 2003; Sibley and Ajioka,
2008).
Human toxoplasmosis has been most often associated with strains of
a type II genotype (Howe and Sibley, 1995; Hosseini et al., 2019).
Concerning virulence type I lineage is highly virulent compared to types
II and III (Dardé 2008; Robert-Gangneux and Dardé., 2012; Hosseini
et al., 2019).
Studies on T. gondii strains in South America have shown a high
genetic variability with distinct genotypes not identified in North
America, Europe, Asia and Africa (Fux et al 2003, Dubey et al., 2005;
Lehmann et al., 2006; Pena et al., 2008; Dubey et al., 2008). These
R.A.M. de Barros et al.
analyses were performed in isolates collected from clinical samples
(pregnant women with congenital infection, patients with ocular and
cerebral forms) (Ferreira et al., 2011; Bastos da Silva et al, 2016; Cunha
et al., 2016) and a great variety of isolates from domestic animals. The
investigations revealed more than 50 genotypes and they were consid­
ered to be the common clonal lineages in Brazil (Ferreira et al 2018, Yai
et al., 2009; Pena et al, 2011; Cabral et al, 2013; Cañón-Franco et al.,
2013). However, various isolates from different Brazilian regions had
atypical genotypes (Blaizot al., 2019). This genotype diversity suggests
the constant emergence of new or atypical genotypes. In addition,
T. gondii strains in South America have a high rate of transmission and
out-crossing (Ajzenberg et al., 2004; Lehmann, et al., 2006; Pereir­
a-Chioccola et al., 2009). The genetic exchange could occur when the
definitive host ingests different types of parasites from their interme­
diate hosts at nearly the same time, or the intermediate host has mixed
infection of different strains. T. gondii isolates in South America seem to
be different in physiological characteristics since in some cases, are
highly pathogenic in immunocompetent individuals (Ferreira et al.,
2011; Bastos da Silva et al, 2016). Atypical genotypes have also been
associated with human outbreak toxoplasmosis as in Santa Maria, Brazil
with 809 confirmed cases (Minuzzi et al., 2020; Paraboni et al., 2020;
Costa et al., 2020). In North America atypical genotypes have been
frequently identified and associated with severe ocular and systemic
disease in humans (Pomares et al., 2018).
Genotyping studies on T. gondii in wildlife showed extended genetic
diversity and evidence for recombination present in wildlife samples
thus it has been suggested that atypical strains are not insignificant
anomalies in the population structure, but significantly demonstrate
gene pool generated by the vast host range utilized by this parasite
(Wendte et al., 2011).
In ruminants (goat, sheep and cattle), type II strains and atypical
genotypes were predominant, with a high diversity of genotypes present
in sheep (Sharif et al., 2017). High prevalence of atypical genotypes was
observed in isolates from lambs, chickens, beef and pigs destined for
human consumption (Dubey et al., 2020a; Santos Silva, et al., 2020;
Frazão-Teixeira et al., 2011 Berger-Schoch et al., 2011a).
A study conducted in the Midwestern Brazil (Mato Grosso do Sul)
described a high genetic diversity of T. gondii among isolates from do­
mestic animals, wildlife, and humans. Among wildlife, an ocelot, two
crab-eating foxes, one Azara’s agouti and one roadside hawk were
infected with BrIII strain, as well as, the environment where they
circulate. This Brazilian clonal lineage was the most frequent among
wild animals in this region. Other reports indicated diverse genotypes in
Brazilian wildlife in various regions of the country (Yai et al., 2009;
Pena et al., 2011; Cañón-Franco et al., 2013, Witter et al., 2020).
9. Extracellular Vesicles and miRNA
The interaction parasite-host modulating the immune system and
precise mechanisms of delivery and functions of cargo excreted by
T. gondii are a little known and must be answered for higher control
toxoplasmosis, principally in outbreaks. The release of different T. gondii
antigens is essential to modulate the host immune system. Many articles
about T. gondii host interactions have been great advances in the past
years.
In the last decades, different studies have focused on extracellular
vesicles (EVs) released from prokaryotic or eukaryotic cells (Schwab
et al., 2015; Théry et al., 2018). EVs participate of cell-cell communi­
cation for transfer of proteins, lipids, nucleic acids, biomarkers of dis­
eases, bio reactive macromolecules and others (Cocucci et al., 2009;
Akers et al., 2013; Schwab et al., 2015; Tkach and Théry, 2016; Théry
et al., 2018). EVs comprise a variety of membrane-limited vesicles and
are released by cells. EVs are classified into three subclasses of particles
and based on their origin, markers and size. The subclass “apoptotic
bodies”, released as blebs from undergoing programmed death cells.
They represent the largest EVs with size ranging from 1,000 to 5,000
9
Acta Tropica 231 (2022) 106432
nm. The “microvesicles” vary in size between 100 to 1,000 nm. Micro­
vesicles are produced by external budding from plasma membrane
(Delabranch et al., 2012, Lagana et al., 2013; Akers et al., 2013; Théry
et al., 2018). These nanoparticles carry proteins, RNA, DNA, and act as
messengers between cells. Patients and experimental mice developing
symptomatic toxoplasmosis release EVs in blood when compared with
those without toxoplasmosis infection (Cruz et al., 2020; Maia et al.,
2021; Maia et al., 2021a). The subclass “exosomes” are the smallest EVs
(size 30 to 100 nm). Exosomes do not originate from plasma membrane.
These particles are derived from internal budding of vesicles in the
lumen of early endosome (Cocucci et al., 2009; Akers et al., 2013;
Fleming et al., 2014; Kowal et al., 2014; Coakley et al., 2015). These
intracellular multivesicular bodies fuse with the plasma membrane and
are released to the extracellular medium (Théry et al., 2009). As the
microvesicles, they also contain bioactive proteins, mRNA, micro-RNA
(miRNA) and other small non-coding RNA species (Delabranch et al.,
2012; Coakley et al., 2015; Schwab et al., 2015; Tkach and Théry, 2016;
Théry et al., 2018).
Protozoan parasites also release the three EVs subclasses that can be
generated by endocytic pathways or are directly released from the
plasma membrane (Trocoli Torrecilhas et al, 2009; Torrecilhas et al.,
2012; Marcilla et al., 2014; Montaner et al., 2014; Twu and Johnson,
2014; Campos et al., 2015; Torrecilhas et al., 2020). These bioactive
molecules have functions as host-parasite interaction, modulation of
host immune system and inflammatory response via TLR2 (Nogueira
et al., 2015). EVs released by protozoan parasites provide a mechanism
for inserting the parasite cargo into host cells, as virulence factors
(Torrecilhas et al., 2012; Mantel and Marti, 2014).
The effect of EVs excreted by T. gondii in immune host response and
physiological environment are not totally established. However, the
host-T gondii interactions certainly occur, also, via EVs. The first in­
vestigations of EVs and T. gondii were reported in 2004 (Aline et al.,
2004). The authors described the participation of exosomes excreted by
dendritic cells infected with T. gondii in protective immune response
against T. gondii infection. Later, Kim et al. (2016) confirmed these re­
sults reporting that treatment of exosomes isolated from
T. gondii-infected cells attenuated the cell proliferation and altered the
host cell cycle. The capacity of exosomes excreted by infected host cells
proceeded as an effective non-cellular vaccine with adjuvant properties
for immunization. The experiments were performed in an experimental
model with mice and, during the pregnancy (Beauvillain et al., 2007;
Beauvillain et al., 2009). These studies also demonstrated that exosomes
secreted from infected cells with T. gondii alter the cell proliferation
mechanisms causing changes in neighboring cells (Kim et al., 2016).
Subsequent studies were correlated with the specific characteriza­
tion of EVs (microvesicles and exosomes) secreted/excreted by T. gondii.
Studies using scanning (SEM) and transmission electron microscopy
(TEM) demonstrated the morphology of these EVs inside of tachyzoites
and at the moment to be released by plasma membrane (Silva et al.,
2018; Ramírez-Flores et al., 2019; Quiarim et al., 2021). In addition,
these studies showed that T. gondii derived EVs carry virulent factors.
Virulent strains, as RH secreted high concentration of EVs, when
compared as those non-virulent strains (VEG and ME49) (Quiarim et al.,
2021).
T. gondii EVs carry a high concentration of proteins. In the proteomic
profile of exosomes includes a wide range of proteins as the secretory
proteins used by tachyzoites for invasion and posterior replication
within host cells (Pope and Lasser, 2013; Wowk et al., 2017; Silva et al.,
2018; Quiarim et al., 2021). These EV-derived proteins inducing the
production of IL-10, IL-12, IFN-α, TNF-α and iNOS in host cells (Pope
and Lasser, 2013; Silva et al., 2018; Li et al., 2018; Maia et al, 2021,
Maia et al., 2021a; Quiarim et al., 2021). EVs purified of T. gondii used as
vaccine in experimental mice were able to stimulate the protective im­
mune response. Immunized mice developed high levels of IgG1, IFN-γ,
IL-10, IL-17 and TNF-α. When they were challenged with RH strain
(virulent), they presented reduced parasitemia and increased survival of
R.A.M. de Barros et al.
mice (Maia et al, 2020).
Studies on investigations of host-produced EVs collected from human
and murine sera showed that the concentration and not size was able to
distinguish infected and non-infected hosts. Serum-derived EVs from
patients with symptomatic toxoplasmosis (cerebral and gestational) had
more EVs when compared with those purified from non-infected in­
dividuals. Equality infected and immunized mice had more concentra­
tion of EVs in sera than non-infected ones (Cruz et al., 2020, Maia et al.,
2021a). Sera from chronically infected humans or mice recognized
distinct electrophoretic patterns in immunoblotting of EV proteins
produced by RH strain. However, these sera are poorly reactive to
EV-derived proteins of ME-49 and VEG strains (Silva et al., 2018; Maia
et al, 2021; Maia et al., 2021a; Quiarim et al., 2021). Fig. 2 shows a
scheme of the interaction T. gondii/host cells by EVs contribution.
T. gondii EVs carry mRNA and small-RNAs, including microRNAs
(miRNAs) and these molecules participate in the modulation of host
immune response against T gondii infection (Silva et al., 2018). The
numerous small-RNAs participate in biological processes such as cell
differentiation, proliferation, apoptosis and post-transcriptional gene
regulation in cell development and pathological processes. Among
small-RNAs, miRNAs are regulatory elements that can modulate gene
expression at the post-transcriptional level. These small single-strand
RNA molecules, with lengths of 18–25 nt do not encode proteins. They
act as negative regulators of the host response by the miRNA-induced
silencing complex (Bartel, 2004; Schorey et al., 2015).
T. gondii has complete machinery for generation of small-RNA and its
gene regulation. The exosomal miRNAs produced by T. gondii control the
regulation of target genes related to cell proliferation. Probably, EVs
released by T. gondii transport miRNA to the host cells (Braun et al.,
2010; Pope and Lasser, 2013; Kowal et al., 2014; Kim et al., 2016; Silva
et al., 2018; Faria Junior et al, 2021). However, there is a fine-tuning
mechanism of miRNA biogenesis in distinct strains of T. gondii, since
each strain has different miRNA species (Wang et al., 2012; Li et al.,
2019; Li et al., 2020). miRNAs can be imbalanced in mice and humans
during T. gondii infection. Different studies related that T. gondii infec­
tion modifies the levels of miRNAs in host cells by modulating the innate
and adaptive immune responses.
Human macrophages infected with T. gondii trigger a cluster of
miRNAs (miRNA-30c-1, miRNA-125b-2, miRNA-23b-27b-24-1 and
miRNA-17~92) that bind to the STAT3 promoter of macrophages,
which cause an increased apoptosis of these cells. Mice recently infected
expressed three miRNAs (mmu-miR-712-3p, mmu-miR-511-5p and
mmu-miR-217-5p) that were up-expressed in RH and ME49 strains (Cai
et al., 2013; Cai et al., 2014). Infected and immunized mice expressed
the same miRNAs (miR-155-5p, miR-125b-5p and miR-29c-3p) than
expressed by T. gondii strains (RH, ME-49 and VEG) (Quiarim et al.,
2021; Maia et al., 2021a).
Analyses of miRNA species in plasma collected of patients with
toxoplasmosis showed an up-expression of the miR-21-5p and miR-
146a-5p in patients with co-infection cerebral toxoplasmosis/AIDS.
Patients with ocular toxoplasmosis had up-expression of the miR-155-5p
10
Acta Tropica 231 (2022) 106432
and miR-29c-3p. The unbalance of miRNAs production in toxoplasmosis
is correlated with the unbalance of immune response as elevation of
TNF-α, IL-6 and down-regulation of IFN-γ in cerebral and ocular toxo­
plasmosis forms (Pereira et al., 2020; Meira-Strejevitch et al., 2020;
Cruz et al.; 2020).
10. T gondii and Toxoplasmosis Studies: Future Perspectives
The overall knowledge of T. gondii biology in it different aspects
involving humans, animals and environment are essential for the control
of toxoplasmosis worldwide. In the last few decades, significant research
efforts have led to the development of several studies with promising
results. Despite such knowledge as parasite-host interactions, other
cellular and molecular mechanisms underlying to such interactions are
not completely understood. Thus, a significant level of academic-public-
private partnership is important to support future studies.
In this review, the epidemiology, diagnostics, and control strategies
are addressed, with the objective of facilitating awareness of toxoplas­
mosis and promoting trans disciplinary collaborations, an opportunity
for new partnerships focused on solutions to the complex problems.
According to the topics covered in this review, future research will
likely focus in aspects emphasizing studies from the perspective of
toxoplasmosis associated with the one health concept. The knowledge of
T. gondii interaction with its hosts is critical for the development of
vaccines, drugs and other approaches. In addition the presence of
T. gondii oocysts in environment is a continue challenge to the efficient
control of toxoplasmosis. For these reasons, clinical and basic research
about this infection and environment contamination should be main­
tained and stimulated, particularly in low-and middle-income countries,
where the epidemic causes its major social and economic cost. In addi­
tion, these studies could contribute to improvement in the clinical care
of patients to get better health and that will require a closer collabora­
tion between physicians and scientists.
Finally, the collaboration between professionals from different fields,
as well as, organizations and institutions from various countries would
aid the understanding of the ecological interactions cooperating for a
clearer understanding the impacts of this zoonotic disease on animal and
human health, as well as, in environment actions.
Author contribution statement
RAMB; ACT, VLP-C and BF conceived and designed the review
manuscript. RAMB, ACT, MAMM, MLM, VLP-C and BF wrote, contrib­
uted, and revised the manuscript. All authors approved the final version
submitted and published.
Disclosures
The authors have no other relevant affiliations or financial involve­
ment with any organization or entire with a financial interest in or
financial conflict with the subject matter or materials discussed in the
Fig. 2. EVs release from T. gondii and interac­
tion with host cells. Image captured by scan­
ning electron microscopy showing a tachyzoite
(magnification: 130,000x), and a schematic
figure releasing extracellular vesicles (EVs).
These nanomolecules carry virulent factors,
high concentration of parasite proteins used for
invasion and posterior replication within host
cells (A). Host cells releasing EVs after parasite
stimulus. The EVs-release cause an intense im­
mune response, with production of cytokines,
antibodies and miRNAs (B).
R.A.M. de Barros et al.
manuscript apart from those disclosed. No writing assistance was uti­
lized in the production of this manuscript or financial relationships that
could be construed as a potential conflict of interest.
Support
This review article was supported by grants from FAPESP (Fundação
de Amparo à Pesquisa do Estado de Sao Paulo, Brazil) 2018/04708-8,
2019/15909-0, 2020/07870-4; CNPq (Conselho Nacional de Desenvol­
vimento Científico e Tecnológico) 302327/2018-5. RAMB was sup­
ported by scholarship from FAPES (Fundação de Amparo à Pesquisa e
Inovação do Espírito Santo) 13/2019 and PROCAP 2020; VLP-C and
ACT, from CNPq, 302327/2018-5 and 302104/2019-4, respectively.
Declaration of Competing Interest
The authors have no other affiliations or financial involvement with
any organization or entire with a financial interest in or financial con­
flict with the subject matter or materials discussed in the manuscript
apart from those disclosed. No writing assistance was utilized in the
production of this manuscript or financial relationships that could be
construed as a potential conflict of interest.
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