Critical Reviews in Microbiology

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Rotavirus-related systemic diseases: clinical

manifestation, evidence and pathogenesis

Ziqin Dian, Yi Sun, Guiqian Zhang, Ya Xu, Xin Fan, Xuemei Yang, Qiuwei Pan,
Maikel Peppelenbosch & Zhijiang Miao

To cite this article: Ziqin Dian, Yi Sun, Guiqian Zhang, Ya Xu, Xin Fan, Xuemei Yang, Qiuwei Pan,
Maikel Peppelenbosch & Zhijiang Miao (2021) Rotavirus-related systemic diseases: clinical
manifestation, evidence and pathogenesis, Critical Reviews in Microbiology, 47:5, 580-595, DOI:
10.1080/1040841X.2021.1907738

To link to this article: https://doi.org/10.1080/1040841X.2021.1907738

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Published online: 06 Apr 2021.

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CRITICAL REVIEWS IN MICROBIOLOGY
2021, VOL. 47, NO. 5, 580–595
https://doi.org/10.1080/1040841X.2021.1907738

REVIEW ARTICLE

Rotavirus-related systemic diseases: clinical manifestation, evidence and

pathogenesis
Ziqin Diana, Yi Suna, Guiqian Zhanga, Ya Xua, Xin Fana, Xuemei Yangb, Qiuwei Panc,
Maikel Peppelenboschc and Zhijiang Miaoc
a
Department of Clinical laboratory, The First People’s Hospital of Yunnan province, Kunming, Yunnan, China; bDepartment of Clinical
laboratory, Kunming Children’s Hospital, Kunming, Yunnan, China; cDepartment of Gastroenterology and Hepatology, Erasmus MC-
University Medical Center, Rotterdam, The Netherlands

ABSTRACT ARTICLE HISTORY

Rotaviruses, double-stranded, non-enveloped RNA viruses, are a global health concern, associated Received 7 November 2020
with acute gastroenteritis and secretory-driven watery diarrhoea, especially in infants and young Revised 12 March 2021
children. Conventionally, rotavirus is primarily viewed as a pathogen for intestinal enterocytes. Accepted 16 March 2021
This notion is challenged, however, by data from patients and animal models documenting Published online 30 March
2021
extra-intestinal clinical manifestations and viral replication following rotavirus infection. In add-
ition to acute gastroenteritis, rotavirus infection has been linked to various neurological disor- KEYWORDS
ders, hepatitis and cholestasis, type 1 diabetes, respiratory illness, myocarditis, renal failure and Rotavirus; systemic disease;
thrombocytopenia. Concomitantly, molecular studies have provided insight into potential mecha- complication; clinical
nisms by which rotavirus can enter and replicate in non-enterocyte cell types and evade host manifestation; pathogenesis
immune responses. Nevertheless, it is fair to say that the extra-intestinal aspect of the rotavirus
infectious process is largely being overlooked by biomedical professionals, and there are gaps in
the understanding of mechanisms of pathogenesis. Thus with the aim of increasing public and
professional awareness we here provide a description of our current understanding of rotavirus-
related extra-intestinal clinical manifestations and associated molecular pathogenesis. Further
understanding of the processes involved should prove exceedingly useful for future diagnosis,
treatment and prevention of rotavirus-associated disease.

Introduction
Rotaviruses (RVs) are non-enveloped double-stranded
RNA (dsRNA) viruses that belong to the Reoviridae fam-
ily (Trask et al. 2012). Their genome comprises 11 seg-
ments of dsRNA encoding six viral structural proteins
(VP1 to VP4, VP6 and VP7) and six non-structural pro-
teins (NSP1 to NSP6) (Trask et al. 2012) (Figure 1). Up to
now, ten rotavirus species (A to J) have been identified.
Four of these (A, B, C, and H) cause human disease,
with the rotavirus A species [featuring strains Wa, DS-1
and AU-1 (Matthijnssens et al. 2008)] being the most
significant in this respect (Crawford et al. 2017). Human
rotaviruses are important enteric pathogen, infecting
the epithelial compartment of the small intestine, and
are a major cause of gastroenteritis in infants and
young children (Crawford et al. 2017; B
anyai et al.
2018). Although the introduction of anti-rotavirus vac-
cines (Rotateq and Rotarix, two live-attenuated oral
vaccines) has raised hopes that the virus can eventually
be constrained (Burnett et al., 2020; Simsek et al. 2021),
clinical management of rotavirus-associated disease is
complicated by the absence of specific antiviral therapy
(Crawford et al. 2017; B
anyai et al. 2018). The canonical
view is that rotavirus infection is restricted to the intes-
tine, but this notion has become challenged (Kraft

mez-Rial
1958; Blutt and Conner 2007; Ramig 2007; Go
et al. 2019). During the acute phase of rotavirus infec-
tion, both antigenemia and viremia are readily detected
in both experimental animals and children, demonstrat-
ing that the virus can reach a multitude of potential
host compartments (Blutt et al. 2003; 2007; Ramig 2007;
Go
mez-Rial et al. 2019). In apparent agreement, the
presence of either rotaviral RNA, protein or infectious
particles during human or animal infection, has been
documented in brain, liver, spleen, lung, heart, kidney,
pancreas, thymus, adrenal gland, bladder testis and
immune cells (Kraft 1958; Crawford et al. 2006; Blutt

CONTACT Zhijiang Miao miaozhijiang@yeah.net Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center,
Rotterdam, The Netherlands
ß 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
 CRITICAL REVIEWS IN MICROBIOLOGY 581

Figure 1. Rotavirus infection-induced acute gastroenteritis. The rotavirus particle contains 11 segments of dsRNA as its genome, and the
capsid consists of three layers. The intestinal epithelium is characterized by the villi and crypt. Mature enterocytes locate at the top and
middle of villi allow SGLT-1-mediated absorption of water and salt. The ECs locate at the middle of villi are highly specialized cells with
endocrine function. Stem cells and Paneth cells locate in the crypt are functionally responsible for differentiation and secretion, respect-
ively. Thus, under normal conditions, the intact intestinal membrane barrier can keep homeostasis (absorption and secretion). While rota-
virus infection in mature enterocytes causes absorptive enterocyte death and secretory Paneth cell replacement, leading to shortening
and blunting of villi, and increasing infiltration of inflammatory cells in the lamina propria. The NSP4 stimulates the epithelium and ECs
to increase intracellular calcium, which further induces the secretion of 5-HT from ECs through a calcium-dependent manner. The
secreted 5-HT activates EGCs to increase release of GDNF which induces the expression of tight junction-associated protein ZO-1 in
infected and bystander cells. Thus neurotrophic factors and 5-HT can protect the intestinal barrier function during rotavirus insult.
Moreover, the number of enterocytes remaining following infection is functionally sufficient to allow SGLT-1-mediated absorption of
water and salt. However, 5-HT can also activate the intrinsic primary afferent nerves of the myenteric plexus. Such activation activates
the nerves of the submucosal plexus and leads to increase of intestinal motility which can be attenuated by an opioid-receptor-antagon-
ist (Loperamide). The activation of submucosal nerves further induce VIP release from nerve endings adjacent to crypt cells. Then, VIP
induces crypt cells to secret NaCl and water into the intestinal lumen by increasing cellular cAMP levels, which ultimately leading to
secretory diarrhoea. During these processes, the stimulated afferent vagal signalling activates the nausea and vomiting centre of the
brain to generate efferent vagal signalling which then results in vomiting by stimulating a nerve-muscle vomiting reflex in the stomach.
This event can be attenuated by 5-HT receptor antagonists (Ondansetron). Finally, intestinal rotavirus infection results in secretory-driven
watery diarrhoea accompanying by vomiting. dsRNA: double-stranded RNA; VPs: rotavirus structural proteins (VP4 is cleaved into VP5

and VP8
); NSP4: rotavirus non-structural protein; ENS: enteric nervous system; NaCl: sodium chloride; Ca2þ: calcium ions; SGLT-1:
sodium/glucose cotransporter 1; 5-HT: 5-hydroxytryptamine (serotonin); VIP: vasoactive intestinal peptide; ECs: enterochromaffin cells;
EGCs: enteric glial cells; GDNF: glial cell-derived neurotrophic factor; ZO-1: zona occludens 1; cAMP: cyclic adenosine monophosphate.

and Conner 2007; Ramig 2007). Accordingly, extra-intes-
tinal complications during rotavirus therapy have been
widely reported (Mossel and Ramig 2003; Ramig 2007;
Go
mez-Rial et al. 2019). Nevertheless, it is fair to say
that the extra-intestinal aspect of rotavirus infection is
largely ignored by the biomedical community. This
prompted us to assess the evidence for non-intestinal
diseases associated with rotavirus infection, the pos-
sible size of the clinical problem associated with such
infection, and the pathological mechanisms driving
extra-intestinal rotavirus-associated disease.
Rotavirus-induced gastrointestinal disease
Acute gastroenteritis
Before considering potential extra-intestinal rotavirus
infection, it is important to review the conventional
582 Z. DIAN ET AL.

Figure 2. Rotavirus-related systemic diseases and proposed mechanisms. The primary infection of rotavirus in the intestine leads
to acute gastroenteritis. However, the tropism and pathogenetic role of rotavirus infection is not only limited to the gastrointes-
tinal tract. The extra-intestinal dissemination and infection of rotavirus in non-intestinal tissues such as the spleen, liver, heart,
lung, kidney, testis, bladder, adrenal gland, pancreas and brain have been confirmed, which may sometimes lead to additional
extra-intestinal complications. Here we present rotavirus-induced acute gastroenteritis and the frequently reported complications
related to rotavirus extra-intestinal spread and propose the potential mechanisms. RV: rotavirus; VP7: viral structural protein;
NSP4: non-structural protein; ENS: enteric nervous system; NO: nitric oxide; IFN-c: interferon gamma.

presentation of the disease, acute gastroenteritis
(Figures 1 and 2). About 258 million diarrhoea episodes
and 129 000–200 000 associated deaths per year are
attributed to rotavirus infection, making it the leading
cause of gastroenteritis in young children (Tate et al.
2016; Crawford et al. 2017; B
anyai et al. 2018; Hartman
et al. 2019). As the vast majority of cases occurs in
developing countries, rotavirus infection is seen as a
global health concern, but also in developing countries
rotavirus associated gastroenteritis remains a major
cause of hospitalization in children (Crawford et al.
2017). Following the introduction of anti-rotavirus vac-
cination, hospitalizations and mortality has shown a
25–55% decline (Crawford et al. 2017; Troeger et al.
2018; Aliabadi et al. 2019; Burke et al. 2019; Burnett
et al., 2020). Nonetheless, 8–10% of all children with
gastroenteritis and 35–40% of hospitalized children are
positive for rotavirus (B
anyai et al. 2018). Compounding
the clinical problem is that children often suffer from
multiple episodes of rotavirus infection as multiple
serotypes are present in the population and both vac-
cine and prior disease fail to provide full immunity
(36 G genotypes and 51 P genotypes have been classi-
fied in species A rotavirus binary serotype system based
on the two outer capsid proteins VP4 and VP7
(Crawford et al. 2017; Simsek et al. 2021), respectively),
even if subsequent infections are less severe than first
infections (Vel
azquez et al. 1996; Mormile 2016). By the
age of five, nearly every child in the world will have
been infected with rotavirus at least once (Tate
et al. 2012).
The primary outcome of rotavirus infection is acute
gastroenteritis. Its clinical features range from subclin-
ical infection and mild watery diarrhoea to severe diar-
rhoea with vomiting and fever that can result in
dehydration with shock, electrolyte imbalance, and
death (Hjelt et al. 1985; Haffejee and Moosa 1990;
Leung et al. 2005; Parashar et al. 2013; Esona and
Gautam 2015) (Table 1). The importance of antiviral
immunity in controlling disease is highlighted by the
observation that the symptomology is more severe in
children with more immature immune systems
(Crawford et al. 2017; B
anyai et al. 2018), with disease
being the worst in the youngest children, where as
Table 1. Clinical manifestation and evidence summary of rotavirus-related systemic diseases.
Evidence
Systemic disease Clinical manifestation Human
Acute gastroenteritis 1. major AG symptoms including watery diarrhoea, 1. RV infection is the leading cause of active
vomiting, low-grade fever, dehydration and electrolyte gastroenteritis among young children (Tate et al. 2016;
imbalance (Hjelt et al. 1985; Haffejee and Moosa 1990; Crawford et al. 2017; B
anyai et al. 2018; Troeger
Leung et al. 2005; Parashar et al. 2013; Esona and et al. 2018);
Gautam 2015); 2. RV induces more severe symptoms in the youngest
2. other associated symptoms including: low children (Leung et al. 2005; Parashar et al. 2013;
inflammation, shock, coma, abdominal cramps, nausea, Hartman et al. 2019);
malaise, lethargy, pharyngeal erythema, rhinitis and 3. RV hospitalizations and deaths decreased by 25–55%
palpable cervical lymph nodes (Hjelt et al. 1985; following vaccination (Crawford et al. 2017; Troeger
Haffejee and Moosa 1990; Leung et al. 2005; Parashar et al. 2018; Aliabadi et al. 2019; Burke et al. 2019;
et al. 2013; Esona and Gautam 2015) Burnett et al., 2020);
4. histological and pathological examinations indicate that
RV infection and replication in the intestinal epithelium
(mature enterocytes and ECs) leading to significant
structural and functional alterations (severe mucosal
damage including shortening and blunting of villi and
increased immune infiltration in the lamina propria)
(Hagbom et al. 2012; 2016; Crawford et al. 2017)
Neurological diseases 1. seizures (diarrhoea, vomiting, fever, febrile, convulsions, 1. more CNS diseases (2–8% incidence of seizures
generalized bleeding) (Lloyd et al. 2010; Yeom omara et al. 2002; Lloyd et al. 2010; Pardo-
(Iturriza-G

et al. 2019); Seco et al. 2015 )) are reported in RV-gastroenteritis
2. meningitis (diarrhoea, vomiting, irritable, afebrile, children (Wong et al. 1984; Ushijima et al. 1986;
convulsions) (Wong et al. 1984); Nishimura et al. 1993; Lynch et al. 2001; Fukuda et al.
3. encephalopathy (diarrhoea, fever, dehydration, lethargy, 2009; Takanashi et al. 2010; Karampatsas et al. 2015;
convulsions, coma) (Lynch et al. 2001; Wong 2001; Laizane et al. 2019); higher positivity of RV in children
Karampatsas et al. 2015); with seizures or convulsions (Herrmann et al. 1993;
4. encephalitis (diarrhoea, vomiting, fever, dehydration, Wong 2001; Yeom et al. 2019);
convulsions, afebrile) (Ushijima et al. 1986) 2. rotavirus vaccination has resulted in reduced incidence
of paediatric seizures in the USA and Spain (Payne
et al. 2014; Pardo-Seco et al. 2015; Burke et al. 2018);
3. RV particles, antigens, antibodies and RNA are found in
CSF (Wong et al. 1984; Keidan et al. 1992; Pager et al.
2000; Lynch et al. 2001; Iturriza-G
omara et al. 2002); RV
infection and replication (viral VP6, NSP1, NSP3, NSP4,
and RNA) in brain tissue (Nakano et al. 2011);
4. infection and replication (structural protein VP7 and
non-structural protein NSP4) of RRV in neurons in vitro
(Weclewicz et al. 1998)
Hepatobiliary diseases 1. AG symptoms (diarrhoea, vomiting, fever, dehydration) 1. abnormal liver function results from RV infection
(Gilger et al. 1992); (Kovacs et al. 1986; Teitelbaum and Daghistani 2007);
2. liver dysfunction (elevated serum sodium and liver 2. RV infection (viral antigen) and replication (viral VP6,
transaminases such as AST, ALT and GGT, hepatitis, NSP1, NSP3, NSP4, and RNA) in liver tissue (Gilger et al.
liver steatosis, cirrhosis) (Gilger et al. 1992; Teitelbaum 1992; Riepenhoff-Talty et al. 1996; Nakano et al. 2011);
and Daghistani 2007); 3. continuous RV infection (viral RNA, VP4, VP6, and
3. biliary symptoms (extrahepatic biliary atresia, infectious virus) in human liver organoids results in
choledochal cyst, cholestasis, fibrosis) (Gilger et al. direct cytopathogenesis (Chen et al. 2020)
1992; Riepenhoff-Talty et al. 1996; Bezerra et al. 2002)
Animal model
RV infection in animal models induces morphological,
anatomical and functional changes in the small intestine
(Hagbom et al. 2012; 2016; 2016; Crawford et al. 2017):
1. piglets (thinning of the intestinal wall, completely
eroded intestinal villi, conversion of columnar villus
epithelium to cuboidal) (Shepherd et al. 1979);
2. calves (blunting of villus, conversion of columnar villus
epithelium to cuboidal) (Reynolds et al. 1985);
3. lambs (less severe histopathological changes and mild
clinical disease) (Greenberg et al. 1994);
4. mice (remarkable swollen and vacuolated enterocytes
but limited villus blunting) (Dharakul et al. 1988;
Osborne et al. 1988; Ward et al. 1990; Lundgren and
Svensson 2001; Hagbom et al. 2016)
1. isolation of virus particles by cell culture from the brain
of porcine RV-inoculated neonatal pigs (Janke et al.
1988; Shaw et al. 1989);
2. infectious virus is detected in the brain of heterologous
RRV (MMU-18006) or homologous murine strain (EDIM-
5099) inoculated mice (Kraft 1958; Shaw et al. 1989;
Czech-Schmidt et al. 2001)
1. RV infection (viral structural protein VP7) and active
replication (viral RNA, NSP4 and virus particles) in
murine biliary tracts and livers (Uhnoo et al. 1990;
Riepenhoff-Talty et al. 1993; Shivakumar et al. 2004);
2. hepatobiliary-tropic RVs strain-specifically induce high
incidence of hepatitis, bile duct obstruction and
mortality, as well as human BA-like symptoms and
hispathological changes in murine models (Uhnoo et al.
CRITICAL REVIEWS IN MICROBIOLOGY
1990; Riepenhoff-Talty et al. 1993; Shivakumar
et al. 2004)
(continued)
583
Table 1. Continued.
Systemic disease Clinical manifestation
Type 1 diabetes 1. AG symptoms (diarrhoea, vomiting, fever, dehydration) 1.
(Parri et al. 2010; Basturk et al. 2017);
2. acute pancreatitis (abdominal pain, elevated serum
transaminases such as pancreatic amylase and lipase,
transient moderately enlarged oedematous pancreas) 2.
(Parri et al. 2010; Basturk et al. 2017)
3.
Respiratory illness 1. AG symptoms (diarrhoea, vomiting, fever, dehydration) 1.
(Santosham et al. 1983; Fragoso et al. 1986; Zheng
et al. 1991; Grech et al. 2001);
2. respiratory symptoms (cough, mild respiratory distress,
rhinitis, rhinorrhea, nasal discharge, congestion, 2.
pneumonia, otitis media (Goldwater et al. 1979; Zhaori
et al. 1991; Santosham et al. 1983; Gurwith et al. 1981)
3.
4.
Heart diseases 1. elevated level of CK-MB (Zheng et al. 2017); 1.
2. myocyte necrosis (Cioc and Nuovo 2002);
3. myocarditis (Grech et al. 2001; Cioc and Nuovo 2002);
4. hypertrophic cardiomyopathy with focal disorganized
myocardial architecture (Nakano et al. 2011);
Renal failure 1. AG symptoms (diarrhoea, vomiting, fever, dehydration) 1.
(Fujinaga et al. 2005; Ashida et al. 2012; Kira
et al. 2016);
2. renal and urogenital symptoms (acute obstructive 2.
uropathy-ureteral stones (Kira et al. 2016; Ashida et al.
2012; Fujinaga et al. 2005), oliguria (Fujinaga et al.
2005), hypovolemia (Fujinaga et al. 2005; Shirasu et al.
2015), aciduria (Tsukida et al. 2018), azotaemia
(Fujinaga et al. 2005), hyperuricaemia and
hyponatremia (Ashida et al. 2012; Tsukida et al. 2018))
AG: acute gastroenteritis; RV-A: species A rotavirus; RRV: rhesus rotavirus; HRV: human rotavirus; GARV: bovine rotavirus; ECs: enterochromaffin cells; NSP1/3/4: rotavirus non-structural proteins; VP6/7: rotavirus
structural viral proteins; ENS: enteric nervous system; CSF: cerebrospinal fluid; ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGT: gammaglutamyl transferase; BA: biliary atresia; T1D: type 1 dia-
betes; NOD: Non-Obese Diabetic; CK-MB: Creatine Kinase-MB, an indication for myocardial damage.
Evidence
Human
more acute pancreatitis cases with transient abnormal
size and function of pancreas are reported in RV-
gastroenteritis children (Nigro 1991; Parri et al. 2010;
Basturk et al. 2017);
the incidence of T1D decreased in RV-vaccinated
children younger 4 years in the USA and Australia
(Perrett et al. 2019; Rogers et al. 2019);
RV infection (viral antigen and RNA) in the pancreas
(Lynch et al. 2003; Ramig 2007)
respiratory illness is the major extra-intestinal symptom
that preceded or concurrently occurred with rotavirus-
induced gastroenteritis in children (Fragoso et al. 1986;
Sharma et al. 2002; Grimprel et al. 2008);
RV infection (viral antigen) in upper respiratory tract
(oropharyngeal aspirates (Zheng et al. 1991) and
nasopharyngeal secretions (Fragoso et al. 1986)) and
lower respiratory tract (tracheal aspirate (Zhaori
et al. 1991));
RV infection (viral RNA) in lung tissue (Lynch
et al. 2003);
RV as a part of virome frequently identified in
respiratory tract samples (Taboada et al. 2014; Madi
et al. 2018; Thi Kha Tu et al. 2020)
infection and replication (viral VP6, NSP1, NSP3, NSP4,
and RNA) in heart tissue possibly induce hypertrophic
cardiomyopathy and myocardial damage (Cioc and
Nuovo 2002; Lynch et al. 2003; Nakano et al. 2011;
Zheng et al. 2017)
diarrhoea-induced dehydration is associated with pre-
and post-renal failure (Ashida et al. 2012; Kira et al.
2016; Tsukida et al. 2018);
RV infection (viral antigen and RNA) and replication
(viral non-structural protein) in kidney tissue (Gilger
et al. 1992; Lynch et al. 2003)
584
Animal model
1. replication of human and monkey RV (infectious virus)
in monkey islet cells (Coulson et al. 2002);
2. monkey RRV infection increases insulitis development
and accelerates diabetes in NOD mouse (Graham
Z. DIAN ET AL.
et al. 2008);
3. RRV antigen and infectious virus are found in the
pancreas of NOD mice and rats (Crawford et al. 2006;
Graham et al. 2007);
4. RRV infection induces transient pancreatic involution
and hyperglycaemia in weanling mice (Honeyman
et al. 2014)
1. HRV (Wa) induces viremia, antigenemia and nasal virus
shedding in piglets (Azevedo et al. 2005);
2. respiratory infection (viral antigen in pnueumocytes
and lymphoid cells of lungs, viral RNA in nasal fluid
secretions and lungs) of GARV (KJ9-1) induces
pneumonia and increases infiltration-mediated
cellularity in calves (Kim et al. 2011);
3. RRV infection and replication (viral antigen, structural
and non-structural protein and infectious virus) in the
lower respiratory tract (macrophages and pneumocytes)
induce parenchymas inflammation and respiratory
secretion of virus in rats (Crawford et al. 2006);
4. homologous (murine rotavirus) and heterologous RRV
infection and replication (viral RNA, NSP4 and virus
particles) in the lung tissue of newborn mice (Fenaux
et al. 2006); intranasal but not oral inoculation of RRV
induces immune protection against challenge in mice
(Coffin and Clark 2001)
1. viral antigen is detected in the heart of RRV-infected
rats (Crawford et al. 2006)
1. infectious RV (EDIM) is found in the kidney of normal
mice (Kraft 1958);
2. RV-A induces cellular degeneration and immune
infiltration in the kidney of suckling mice (Kashyap
et al. 2018);
3. homologous (murine rotavirus) and/or heterologous
RRV infection and replication (viral antigen, NSP4, RNA
and virus particles) in the kidney of newborn mice and
rats (Crawford et al. 2006; Fenaux et al. 2006);
4. monkey kidney cells are highly susceptible for RV
infection in vitro (Ward et al. 1984)

severe dehydration, electrolyte disturbances and emesis
are not uncommon following rotavirus infection (Leung
et al. 2005; Parashar et al. 2013; Hartman et al. 2019). In
both humans and animal models (piglets, calves, lambs
and mice) rotavirus infection may provoke histological
and functional alterations changes in the small intes-
tine, which include intestinal wall hypotrophy, loss of
epithelial microvilli, villous atrophy and intraepithelial
lymphocytosis, and loss of disaccharidase activity
(Dharakul et al. 1988; Haffejee and Moosa 1990;
Crawford et al. 2017) (Figure 1). Examination of intes-
tinal biopsies from rotavirus-infected children, however,
show poor correlation between histological abnormal-
ities and diarrhoea (Ko €hler et al. 1990; Ramig 2004;
Hagbom et al. 2016). Interestingly, rotavirus-induced
anatomical changes were linked to the slightly
increased intussusception (a serious condition where an
intestinal segment folds into an adjacent part of the
intestine) observed primarily in application of the first-
generation vaccine, but more substantial evidence has
demonstrated that neither natural rotavirus infection
nor vaccination are significantly associated with intus-
susception (Robinson et al. 2004; Lu et al. 2019; Burnett
et al., 2020). In general, rotavirus-induced gastrointes-
tinal disease manifests as acute gastroenteritis is associ-
ated with watery diarrhoea, low-grade fever, vomiting,
low inflammation, and intestinal wall damage (Hagbom
et al. 2020).
The pathogenesis of rotavirus gastroenteritis is multi-
factorial (Figures 1 and 2). Conventionally, gastroenter-
itis is viewed as the consequence of rotavirus infecting
mature enterocyte and enterochromaffin cells (ECs, one
type of enteroendocrine cell) at the tip and the body of
intestinal villi, causing loss of enterocytes and second-
ary expansion of the Paneth cell compartment.
Consequently, secretion of digestive enzymes and dis-
accharidase is impaired, in turn increasing osmolarity of
the intestinal lumen and thus provoking diarrhoea and
malabsorption (Colbere-Garapin et al. 2007; Hagbom
et al. 2016). This concept has been challenged by obser-
vation in experimental rodents that show that the num-
ber of enterocytes remaining following infection is
functionally sufficient to allow sodium/glucose cotrans-
porter (SGLT-1)-mediated absorption of water and salt
(Hagbom et al. 2011; 2012; 2016). Thus it has been pro-
posed that the diarrhoea is an active defense mechan-
ism controlled by neurotrophic factors and the
serotonin 5-hydroxytryptamine (5-HT) (Istrate et al.
2014; Hagbom et al. 2020), in which the enteric nervous
system is activated as Loperamide (an opioid receptor
agonist) appears to attenuate rotavirus-induced diar-
rhoea (Li et al. 2007; Hagbom et al. 2012). The notion
CRITICAL REVIEWS IN MICROBIOLOGY 585
that diarrhoea is an active process and not the result
from loss of absorptive function is supported by the
success of rehydration in rotavirus-induced diarrhoea
(Rautanen et al. 1997; Hagbom et al. 2012) or the obser-
vation that zinc-mediated inhibition of cAMP-depend-
ent chloride secretion counteracts rotavirus-induced
diarrhoea (Baqui et al. 2002; Dalgic et al. 2011; Hagbom
et al. 2012). Altogether, these studies indicate that rota-
virus-induced watery diarrhoea is of a secretory nature.
At the molecular level, rotavirus replication in enter-
ocytes and ECs results in expression and release of the
rotaviral non-structural protein 4 (NSP4), which is a
major viral enterotoxin due to its virporin activity and
subsequently provoked increased levels of intracellular
Ca2þ (Van Den Brink et al. 1999; Hagbom et al. 2012;
Hyser et al. 2012). This provokes release of 5-HT by the
EC compartment, in turn activating the primary afferent
nerves of the myenteric plexus of the enteric nervous
system (ENS) (Hagbom et al. 2011; 2012; 2016; Crawford
et al. 2017). The resulting neurotransmission in turn is
responsible for increased intestinal motility as well as
the release of vasoactive intestinal peptide (VIP) from
synaptic terminals located adjacent to crypt cells
(Hagbom et al. 2012; 2016; Crawford et al. 2017). As a
hormone, VIP stimulates secretion of sodium, chloride,
potassium and indirectly of water into the small intes-
tine diarrhoea through increased cAMP production
(Hagbom et al. 2012; 2016; Crawford et al. 2017).
During this process the afferent component of the ner-
vus vagus becomes stimulated, and this provokes vom-
iting through a reflex relay to the stomach (Hagbom
et al. 2011; 2012; 2016; Crawford et al. 2017), again 5-
HT being a prominent neurotransmitter in thus process
as evident by the attenuation of emesis following the
use of receptor antagonist (Ondansetron) (Yamashiro
et al. 1989; Kordasti et al. 2004; Hagbom et al. 2012;
Crawford et al. 2017). Apart from provoking 5-HT
release, NSP4 also stimulates production of nitric oxide
(NO) release and this also modulates ENS signalling
(Hagbom et al. 2012). Thus the notion that rotavirus-
provoked diarrhoea is secretory in nature can be mech-
anistically substantiated.
Apart from diarrhoea, rotavirus infection provokes
systemic activation of immunity as for instance evident
from the fever that often accompanies disease
(Figure 2). Clinical studies show that rotavirus gastro-
enteritis is associated with increased levels of the pro-
inflammatory cytokines interleukin-1b (IL-1b), IL-6, IL-8
and interferon gamma (IFN-c) (Mormile 2016; Crawford
et al. 2017), which have been linked to fever and mal-
aise. Much of the tissue damage observed in rotavirus
gastroenteritis may be secondary to immune cell
586 Z. DIAN ET AL.
activation by such cytokines and not as much from dir-
ect viral cytopathic effects (Mormile 2016). Especially
serum IL-8 appears a distinctive biomarker for clinical
rotavirus-mediated disease (Chen et al. 2014; Mormile
2016). IFN-c production may well be instrumental in
inducing clearance of virus as it is a canonical mediator
of cell autonomous and T cell-mediated immune
responses (Mormile 2016). Indeed, adult life is charac-
terized by stronger IFN-c production and subsequent T
cells activation, as compared to infants, which fits well
with the decreased susceptibility of adults to rotavirus
infection as compared to children (Mormile 2016).
While we understand the interaction of rotavirus with
mucosal immunity fairly well, potential interactions out-
side the intestine are, however, less well understood.
Rotavirus-related extra-intestinal
complications
Central nervous system diseases
Extra-intestinal manifestations reported following
paediatric rotavirus infection in infants and children
most commonly involve the central nervous system
(CNS) (Ramig 2007; Go
mez-Rial et al. 2019). Following
early reports from East Asia, also Western countries
reported cases apparently rotavirus-related cases of
neurological disorders, such as seizures, meningitis,
encephalopathy, encephalitis, and cerebellitis (Wong
et al. 1984; Ushijima et al. 1986; Nishimura et al. 1993;
Lynch et al. 2001; Iturriza-Go
mara et al. 2002; Fukuda
et al. 2009; Takanashi et al. 2010; Karampatsas et al.
2015; Laizane et al. 2019). The severity of the disease
varies widely from well-tolerated seizures and mild
encephalitis/encephalopathy concomitant with cerebel-
litis to death, corresponding to neurological manifesta-
tions ranging from benign convulsions and reversible
white matter injury to fatal Reye’s syndrome (Lynch
et al. 2001; Karampatsas et al. 2015) (Table 1). Seizures
presenting as benign convulsions are the most com-
monly reported. Neurological manifestations of rota-
virus may be underestimated as rotavirus stool levels in
newborn infants presenting convulsion were consider-
ably higher than the healthy control group or rotavirus-
negative control groups, whereas co-presentation of
convulsion and acute gastroenteritis in children is
higher as expected when compared to other aetiologies
(Herrmann et al. 1993; Wong 2001; Yeom et al. 2019).
Rotavirus infection represents an independent risk fac-
tor for neonatal seizure increasing risk by four times
(Yeom et al. 2019). Strikingly, in paediatric rotavirus
gastroenteritis, the incidence of seizures ranges from 2
to 8% (Iturriza-Go
mara et al. 2002; Lloyd et al. 2010;
Pardo-Seco et al. 2015).
Supporting a neurological substrate for rotavirus rep-
lication is that rotavirus particles, antigens, antibodies
and RNA have been detected in cerebrospinal fluid
(CSF) (Wong et al. 1984; Keidan et al. 1992; Pager et al.
2000; Lynch et al. 2001; Iturriza-Go
mara et al. 2002).
Indeed, study showed that neurons can sustain infec-
tion with rhesus rotavirus (RRV), NSP4 protein being
detectable in dendritic processes (Weclewicz et al.
1998). In vivo data in animals are more ambiguous but
brain cell cultures from pigs and mice inoculated with
heterologous RRV (MMU-18006, species A, serotype G3)
or homologous murine strain (EDIM-5099) respectively,
showed productive infection (Kraft 1958; Janke et al.
1988; Czech-Schmidt et al. 2001). Accordingly, in the
USA and Spain, rotavirus vaccination has resulted in
reduced incidence of paediatric seizures (Payne et al.
2014; Pardo-Seco et al. 2015; Burke et al. 2018),
although later studies failed to detect such an effect
(Biggart et al. 2018; Orrico-S
anchez et al. 2018; Go

mez-
Rial et al. 2019). Hence, the overall contribution of rota-
virus neuronal infection as a trigger for seizures
remains unclear.
Four hypotheses have been brought forward for
explaining neurological manifestations of rotavirus
infection (Figure 2). The presence of rotavirus in the
CSF, which is mostly documented by reverse transcrip-
tion-polymerase chain reaction (RT-PCR) data (presence
of viral genome), and the infectious capacity of neurons
to sustain rotavirus infection points towards direct rota-
virus-mediated neuronal cytotoxicity (Kraft 1958; Wong
et al. 1984; Keidan et al. 1992; Czech-Schmidt et al.
2001; Lynch et al. 2001; Iturriza-Go
mara et al. 2002;
Ramig 2007; Nakano et al. 2011), but it also possible
that the rotavirus presence signals the presence of
other pathogens that mediate the actual neurotoxicity
(e.g. zika virus, influenza virus, or adenovirus)
(Karampatsas et al. 2015). A further alternative is that
the neuronal damage is the consequence of circulating
NSP4, possibly in conjunction with NO generation
(DiFazio et al. 2007). NSP4 can act as a virporin and
thus provoke Ca2þ-mediated excitotoxicity (Hagbom
et al. 2012; 2016; Crawford et al. 2017), whereas NO
production (which is a reactive free radical (Goldwater
et al. 2001)) may further provoke neuronal damage.
Interestingly, a significant elevation of NO was observed
in the spinal fluid of patients suffering from rotavirus-
induced seizures (DiFazio et al. 2007). Finally, rotavirus-
activated host immune responses may provoke
neurological damage as well. A pilot study showed that
the expression of monocyte chemoattractant protein-1

and macrophage inflammatory protein-1b was higher
in rotavirus-infected newborns with white matter injury
than in newborns without such damage or in healthy
controls (Yeom et al. 2019). Another small study
reported elevated levels of IL-6, IL-10 and IFN-c and
immune cells in the CSF of rotavirus-infected patients
with mild encephalopathy (Miyata et al. 2012;
Karampatsas et al. 2015). Thus the neurological mani-
festations of rotavirus infection may well relate to mul-
tiple aetiological mechanisms.
Hepatobiliary diseases
An increasing body of evidence relates rotavirus to
acute and chronic liver disease and to cholestatic dis-
ease (Ramig 2007). Rotavirus-induced acute and chronic
hepatitis usually results in liver dysfunction, and rota-
virus-induced cholestasis often leads to obstructive
jaundice. Biliary atresia (BA), characterized by perinatal
progressive obliteration of the extrahepatic bile duct, is
one of the most frequent causes of neonatal cholestasis
and will progress as biliary cirrhosis and end-stage liver
disease requiring liver transplantation (Shivakumar
et al. 2004; Allen et al. 2007). A diagnosis of acute hepa-
titis, prompted by elevated alanine aminotransferase
(ALT), aspartate aminotransferase (AST) and gammaglu-
tamyl transferase (GGT) levels, in children with rota-
virus-gastroenteritis has been reported (Table 1) and
associated with the presence of hepatic positivity for
rotaviral non-structural proteins in immunostaining
(Gilger et al. 1992; Teitelbaum and Daghistani 2007;
Nakano et al. 2011). Especially, in immunocompromised
or immunodeficient children with rotavirus infection,
liver involvement is often obvious (Gilger et al. 1992;
Ramig 2007). A significant association between rota-
virus and cholestatic disease was also reported, in
which species C rotavirus RNA was detected in liver
biopsy samples of extrahepatic BA (EHBA) infants
(Riepenhoff-Talty et al. 1996). Recently it was shown
that human liver organoids are highly susceptible to
simian rotavirus (SA11, species A, serotype G3) infection
and sustain the entire life cycle of the virus (Chen et al.
2020). In the liver of severe combined immunodefi-
ciency (SCID) mice and immunocompetent BALB/c
mice, the heterologous RRV (MMU-18006) provoked
hepatitis, the immunocompetent BALB/c mice more
resistant to this effect, in line with human data (Uhnoo
et al. 1990; Ramig 2007). Thus host immunity appears
to be a critical factor with respect to the development
of rotavirus-induced hepatobiliary diseases (Uhnoo
et al. 1990; Shivakumar et al. 2004; Mack et al. 2006)
(Figure 2). Importantly, high incidence of cholestasis
CRITICAL REVIEWS IN MICROBIOLOGY 587
(over 80%) and mortality (over 90%) due to obstruction
of extrahepatic bile ducts was observed in neonatal
mice following inoculation of the animals with RRV
(MMU-18006) and with an apparent tropism to the bile
duct (Shivakumar et al. 2004; Ramig 2007).
Furthermore, in neonatal BALB/c mice infected with
two hepatobiliary-tropic RV strains (HCR-3 and RRV, spe-
cies A), active virus replication was detected in the bil-
iary tract and liver as early as two days after inoculation
(Riepenhoff-Talty et al. 1993), and later jaundice, acholic
stool and other hallmarks of BA were present as well
(Riepenhoff-Talty et al. 1993; Petersen et al. 1997;
Ramig 2007). In apparent agreement, transcriptomic
analysis of BA infants finds evidence of ongoing inflam-
mation and activation of IFN-c-mediated antiviral
immunity (Bezerra et al. 2002), whereas in experimental
animals adoptive transfer of B cells into rotavirus-
infected B cell-deficient mice was essential for biliary
damage (Bednarek et al. 2018). Thus a role for rotavirus
infection in the development of BA either through dir-
ect cytopathy or indirect through immunological dam-
age have been proposed.
An underappreciated aspect with regard to the dis-
cussion on the role of rotavirus in BA development is
that biliary and hepatic manifestations of the infection
appear highly strain and context dependent. Whereas
inoculation of experimental rodents with the bovine
(WC3), human (Wa) strains or the murine strain EDIM-
5099 provoked no sign of hepatobiliary disease (Uhnoo
et al. 1990; Allen et al. 2007), in the same model the
simian rotavirus strain (SA11-SM) produces hepatocyte
infection but not cholangiocyte infection and the SA11-
FM strain (identical to SA11-SM except for the presence
of the bovine rotavirus VP4 protein gene) targets biliary
epithelial cells causing bile duct obstruction and high
mortality (Figure 2). Furthermore, disease outcome in
rotavirus-infected mouse models are highly age-
dependent: whereas rotaviral infection of neonatal mice
(<2 days of age) results in hepatobiliary inflammation
and obstruction, such infection in adult mice is asymp-
tomatic (Riepenhoff-Talty et al. 1993; Shivakumar et al.
2004; Mack et al. 2006; Hertel and Estes 2012).
Experiments in which effect of rotavirus infection in foe-
tal and adult liver organoids are contrasted may shed
light on to which extent the outcome of cholangiocyte
infection are host age mediated (Saxena et al. 2016;
Ramani et al. 2018). Notably, immunization against rota-
virus in female mice protects newborn mice from devel-
oping rotavirus-induced cholestasis and EHBA (Czech-
Schmidt et al. 2001). It is thus well possible that rota-
virus vaccination of pregnant women will substantially
reduce the incidence of neonatal BA.
588 Z. DIAN ET AL.
Type 1 diabetes
Type 1 diabetes (T1D) is an autoimmune disease char-
acterized by the destruction of insulin-producing pan-
creatic b cells, and is frequently and also increasingly
diagnosed in children in the USA (Rogers et al. 2017;
Burke et al. 2020). Although the aetiology of T1D is not
fully understood yet, links with different pathogens are
well-recognized (Filippi and von Herrath 2008; Rewers
and Ludvigsson 2016; Burke et al. 2020). Rotavirus has
been proposed as an etiologic trigger for T1D (Table 1),
but also for other autoimmune disease such as coeliac
disease (Smatti et al. 2019; Burke et al. 2020; Go
mez-
Rial et al. 2020). Support for rotavirus as a potential
causative agent in the development of T1D comes from
the observation that incidence of T1D decreased by
3–14% in rotavirus-vaccinated children aged 0–4 years
in the USA and Australia (Perrett et al. 2019; Burke et al.

mez-Rial et al. 2020). However, Finnish studies
2020; Go
in children up to 10 years and American studies in chil-
dren with follow-up of 5–12 years, failed to detect asso-
ciation between rotavirus vaccination and T1D
development (Vaarala et al. 2017; Hemming-Harlo et al.
2019; Burke et al. 2020; Glanz et al. 2020). Animal stud-
ies, however, largely support the idea that rotavirus
infection can be a trigger of T1D. Both in vitro as well in
neonates in vivo, infection by rotavirus of Non-Obese
Diabetic (NOD) mouse islet cells has been convincingly
demonstrated (Ramig 2007; Graham et al. 2008; Pane
and Coulson 2015) and results in transient (pre-)diabetic
symptoms like hyperglycaemia, pancreatic cell death
and reduced insulin production (Honeyman et al. 2014).
Mechanistically, this effect may linked to the spread of
rotavirus in infected NOD mice to the pancreatic lymph
nodes (PLN) and mesenteric lymph nodes (MLN)
(Webster et al. 2013) where the infection leads to the
activation of antigen presenting cells and accumulation
of autoreactive lymphocytes (Graham et al. 2008; Pane
et al. 2014; Pane and Coulson 2015), which may pro-
voke T1D development (Burke et al. 2020) (Figure 2).
The induction of anti-islet autoimmunity may be further
stimulated by similarity of the rotavirus VP7 protein to
two T1D-associated autoantigens, glutamic acid decarb-
oxylase (GAD65) and insulinoma antigen 2 (IA-2) pro-
tein. Support for this notion comes from the
observation that the presence of anti-GAD65 antibody
levels in children shows positive correlation with anti-
rotavirus IgG levels (Burke et al. 2020). With the more
widespread introduction of anti-virus vaccination
around the globe, the overall contribution of rotavirus
to the aetiology of T1D should become more evident.
Although a rare complication, various cases of acute
pancreatitis, accompanied by diarrhoea, abdominal
pain and elevated serum pancreatic enzymes, following
an earlier rotavirus gastroenteritis have been reported
in children (Nigro 1991; Parri et al. 2010; Basturk et al.
2017) (Table 1). The role for rotavirus in the pancreatitis
is supported by the presence of stool rotavirus particles
and the absence of other pathogens therein. Also, in
two cases of pancreatitis-associated paediatric fatalities,
rotavirus antigen and RNA was detected in the pan-
creas (Lynch et al. 2003; Ramig 2007). Hence, paediatri-
cians should be aware of the possibility that severe
rotavirus-mediated gastroenteritis can become compli-
cated by the development of acute pancreatitis.
Respiratory illness
Spreading of rotavirus infection is classically attributed
solely to fecal-oral transmission (Esona and Gautam
2015). Nevertheless, the possibility of a contribution of
respiratory rotavirus transmission cannot be discounted
(Goldwater et al. 1979). Indeed, occurrence of respira-
tory symptoms (rhinorrhea, nasal congestion, coughing,
vomiting or pneumonia; Table 1) shortly after or con-
comitant with rotavirus gastroenteritis appears com-
mon in infants and children (30–65%) (Goldwater et al.
1979; Gurwith et al. 1981; Santosham et al. 1983;
Fragoso et al. 1986; Zhaori et al. 1991; Brouard et al.
2000; Sharma et al. 2002; Grimprel et al. 2008; Yu et al.
2012). Furthermore, rotavirus antigen was found in oro-
pharyngeal, nasopharyngeal and tracheal aspirates
(Yolken and Murphy 1982; Fragoso et al. 1986; Zhaori
et al. 1991; Zheng et al. 1991), and RT-PCR detected
rotavirus RNA in the lungs from a patient with fatal
diarrhoea-associated disease (Lynch et al. 2003). Also,
with the advent of metagenomics, the rotavirus gen-
ome is frequently found in tracheal aspirates or throat
and nasal swabs from patients with respiratory tract
infections, concurrently with bona-fide respiratory
viruses (adenovirus, influenza A virus, respiratory syn-
cytial virus and rhinovirus) and bacteria (Taboada et al.
2014; Madi et al. 2018; Thi Kha Tu et al. 2020). In appar-
ent agreement, in Sus scrofa intranasal inoculation with
virulent human rotavirus (HRV, Wa) was not inferior to
oral or gavage inoculation with regard to provoking
diarrhoea, and viremia relative to oral or gavage-medi-
ated inoculation, and provoked nasal viral shedding
(Azevedo et al. 2005). In Bos bovis, colostrum-deprived
and thus infection-prone calves were orally inoculated
with the bovine rotaviruses (GARVs, KJ9-1, species A)
and developed transient interstitial pneumonia accom-
panied by the presence of GARV antigen and viral RNA
in the pneumocytes and lung lymphocytes (Kim et al.
2011). Analogously, in neonatal rats, replicating RRV

was detected in alveolar macrophages and pneumo-
cytes (Crawford et al. 2006). The latter study described
that rotavirus antigen levels in the lower respiratory
tract and stomach showed strong correlation and thus
proposed that rotavirus was released into respiratory
secretions and swallowed. Also in newborn mice, fol-
lowing murine rotavirus or heterologous RRV infection,
viral RNA, NSP4 protein and viral particles were found
in lung tissues (Fenaux et al. 2006), whereas it has also
been shown that intranasal immunization of mice with
inactivated RRV protects against subsequent rotavirus
challenge (Coffin and Clark 2001). Intriguingly, oral
immunization was not protective, possibly suggesting
alternative handling of the rotavirus vaccine by the
bronchial and intestinal mucosal immune system. In
toto, there seems to be a contribution of the respiratory
compartment in rotavirus-provoked pathogenesis, even
while it remains unclear whether respiratory illness pro-
vokes susceptibility to rotavirus infection or rotavirus
infection can provoke respiratory illness (Taboada et al.
2014; Madi et al. 2018; Thi Kha Tu et al. 2020) (Figure 2).
Other extra-intestinal complications
A number of case reports have described additional
extra-intestinal complications of rotavirus infection,
including myocarditis, renal failure and thrombocyto-
penia (Ramig 2007) (Table 1 and Figure 2). Indeed, both
autopsy examinations and animal studies have
described the presence of rotavirus RNA, antigens and
replication in heart and kidney (Cioc and Nuovo 2002;
Lynch et al. 2003; Crawford et al. 2006; Ramig 2007).
Post-mortem histopathological reports showed that car-
diac rotavirus infection could contribute to hyper-
trophic cardiomyopathy with focal disorganized
myocardial architecture, myocyte necrosis and myocar-
ditis (Grech et al. 2001; Cioc and Nuovo 2002; Nakano
et al. 2011). Prominent lymphocytic infiltration was
found in the myocardium in cases of rotavirus myocar-
ditis, suggesting that antiviral immunity may provoke
myocardial damage (Cioc and Nuovo 2002) and indeed
rotavirus infection has been associated to increased
Creatine Kinase-MB signalling damage to the heart dur-
ing infection (Zheng et al. 2017).
With respect to renal manifestations, interpretation
is complicated by that the rotavirus diarrhoea-induced
dehydration can lead to pre- and post-renal failure and
thus renal problems following infection may not reflect
direct infection of the kidneys (Fujinaga et al. 2005;
Ashida et al. 2012; Shirasu et al. 2015; Kira et al. 2016;
Tsukida et al. 2018). Nevertheless, although direct rota-
virus damage to renal epithelial cells has not been
CRITICAL REVIEWS IN MICROBIOLOGY 589
reported, kidney lesions due to cellular degeneration
and mild infiltration of mononuclear cells have been
identified in mice infected with rotavirus (Kashyap et al.
2018). The fact that monkey kidney cells (secondary
and permanent cell lines) are highly susceptible for RV
infection in vitro is compatible with the view that kid-
neys can be productively infected in vivo (Ward et al.
1984; Gilger et al. 1992; Lynch et al. 2003; Crawford
et al. 2006; Fenaux et al. 2006).
In addition to the kidneys and the heart, also the
bone marrow may be affected following rotavirus infec-
tion. Thrombocytopenia and significantly lower mean
platelet volume (MPV) are more common in children
with rotavirus gastroenteritis than in controls (Mete
et al. 2014; Tanju et al. 2014; Ai et al. 2016), but as there
is no significant association between MPV and gastro-
enteritis score (Mete et al. 2014; Tanju et al. 2014), the
relation may be indirect, for instance relating to dis-
turbed vitamin uptake.
Conclusions
As the leading cause of severe acute gastroenteritis,
rotavirus infection has a substantial effect on morbidity
and mortality in infants and young children. Rotavirus
primarily infects the intestinal enterocytes and induces
secretory-driven watery diarrhoea. In addition, both
human and animal experimentation demonstrates that
extra-intestinal tissue can be susceptible to rotavirus
infection in turn provoking further pathology, which
may be the consequence of virus-mediated destruction
of the cells involved, or indirect secondary to anti-viral
immune responses. Nevertheless, the involvement of
rotavirus in extra-intestinal tissue damage is much bet-
ter documented in animal models than in humans, and
there are gaps in the understanding of mechanisms of
pathogenesis. It is to be expected that together with
rotavirus-mediated gastroenteritis such extra-intestinal
manifestations will become less prevalent as conse-
quence from the introduction of anti-rotavirus vaccin-
ation. For now, however, clinicians, particularly
paediatricians caring for rotavirus-infected children
should be aware of the possible extra-intestinal compli-
cations of rotavirus infection.
Acknowledgments
The authors thank freepik and edraw for their assistance
with regard to graphic illustrations.
Disclosure statement
The authors declare that they have no conflict of interest.
590 Z. DIAN ET AL.
Funding
This work was supported by the following: the National
Natural Science Foundation of China [81960606 to Z.D.];
Yunnan Fundamental Research Projects [grant no.
2017FE468(-124) to Z.D.]; the China Scholarship Council for
funding PhD fellowships [201708530234 to Z.M.].
Author contributions
Q.P. and Z.M. designed and directed the project; Z.D. wrote
the manuscript with support from M.P., Y.S., G.Z. and Y.X.;
X.F. and X.Y. searched and reviewed the literatures, and they
aided in interpreting the results. Z.D., Y.S., X.F. and X.Y.
assessed the screened literatures; Z.M. designed the figures;
G.Z. and Y.X. drew the figures; Q.P. and M.P. directed the
revision of the manuscript; all authors provided critical feed-
back and contributed to the final version of the manuscript.
ORCID
Zhijiang Miao http://orcid.org/0000-0001-7778-2010
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