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Veterinary Pathology
2020, Vol. 57(5) 681-686
Histopathologic Patterns and Susceptibility ª The Author(s) 2020
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of Neotropical Primates Naturally Infected DOI: 10.1177/0300985820941271
journals.sagepub.com/home/vet
With Yellow Fever Virus
Abstract
Yellow fever is an important zoonotic viral disease that can be fatal for both human and nonhuman primates. We evaluated
histopathologic changes in free-ranging neotropical primates naturally infected with yellow fever virus (YFV) compared with
uninfected cohorts. The most frequent lesions in primates infected with YFV were hepatic changes characterized by midzonal
necrosis with lipidosis and mild inflammation including lymphocytes, macrophages, plasma cells, and infrequently neutrophils.
Importantly, severe necrotizing hepatic lesions were often observed in Alouatta sp. (howler monkeys), whereas Callithrix sp.
(common marmosets) had nearly no hepatic changes. Moderate to severe hepatic necrosis was present in 21/23 (91%) of the YFV-
positive Alouatta sp. compared with 10/29 (34%) of the YFV-positive Callithrix sp. (P < .0001; odds ratio ¼ 20). Similarly, hepatitis
was more intense in Alouatta sp. compared with Callithrix sp. Furthermore, the frequency of YFV infection was significantly higher
in Alouatta sp. compared with Callithrix sp. or Sapajus sp. (capuchin monkeys). Therefore, these data support the notion that
Alouatta sp. is highly susceptible to infection and YFV-induced lesions, whereas Callithrix sp. is susceptible to infection but has a
lower frequency of YFV-induced lesions.
Keywords
Alouatta, Callithrix, arbovirus, flavivirus, liver, nonhuman primates, vector-borne diseases, zoonotic diseases
Yellow fever is a mosquito-borne viral hemorrhagic disease of conservation of free-ranging populations.2,7,21 During the syl-
both human and nonhuman primates caused by a flavivirus.12 vatic cycle of the disease, death of these animals usually pre-
Yellow fever occurs within sylvatic and urban environments, cedes human cases.22 Therefore, monitoring the occurrence of
where it is transmitted to a susceptible host by Haemagogus sp. yellow fever in nonhuman primates serves as an early warning
and Sabethes sp., or Aedes aegypti, respectively.12 In Brazil, to viral circulation in a given area, which should lead to pre-
the Amazon region is considered endemically affected, but ventive vaccination of the potentially exposed human popula-
outbreaks often occur in nonendemic areas. The most recent tions, as vaccination is the main preventive measure.3,15
outbreak took place mainly in the southeastern region of Brazil In Brazil, yellow fever is monitored by the Epizootics Sur-
from 2016 to 2018, resulting in more than 1000 confirmed veillance Program of the Brazilian Ministry of Health. Each
human cases, with a case fatality rate of 35.1%.4,8
Neotropical primates are divided into 5 large families: Cal-
lithrichidae, Cebidae, Aotidae, Pithecidae, and Atelidae, total- 1
Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
2
ing 110 species and 205 subspecies. At least 36 of these species Instituto Municipal de Medicina Veterinária Jorge Vaistman, Rio de Janeiro,
are endemic in Brazil, and all of them are included in the Brazil
Convention on International Trade in Endangered Species of Supplemental material for this article is available online.
Wild Fauna and Flora (CITES), indicating some degree of
vulnerability.17 Corresponding Author:
Renato Lima Santos, Universidade de Minas Gerais, Escola de Veterinária,
Studies published decades ago demonstrated the susceptibil- Departamento de Clı́nica e Cirurgia Veterinárias, Av, Antônio Carlos, 6627,
ity of neotropical primates to yellow fever virus (YFV),5,6 and 31270-901 Belo Horizonte, MG, Brazil.
since then yellow fever became a significant concern for Email: rsantos@vet.ufmg.br
682 Veterinary Pathology 57(5)
Figures 2–5. Yellow fever virus (YFV) infection, liver. Figure 2. Alouatta sp. Severe multifocal coalescing necrosis of hepatocytes affects all
regions of the hepatic lobule. Hematoxylin and eosin (HE). Figure 3. Alouatta sp. There is extensive necrosis of hepatocytes, lipidosis of
nonnecrotic hepatocytes, and a mild lymphocytic and neutrophilic inflammatory infiltrate. HE. Figure 4. Callithrix sp. The portal space has a
moderate inflammatory infiltrate composed of lymphocytes, plasma cells, and macrophages with a few neutrophils, and there is extensive
necrosis of hepatocytes. HE. Figure 5. Callithrix sp. Hepatocytes have marked microvacuolar change due to accumulation of glycogen. HE.
differences in histopathologic scores between YFV-infected histiocytes, but there were also neutrophils in some cases
primates and controls (Supplemental Table S2). Importantly, (Fig. 4). Inflammatory infiltrates were most often in the portal
occasional lesions observed in other organs had scores that region, but were occasionally randomly distributed in other
were statistically similar between both groups. Therefore, regions of the hepatic lobule. Lipidosis was more frequent in
these lesions were not considered to be associated with YFV YFV-positive primates than in controls (36/56 [64%] vs 10/51
infection and therefore they were not included in this study. [19%], respectively; P < .0001; odds ratio ¼ 7.38; w2 test;
The data for each individual animal is available in Supple- Fig. 2). Glycogenosis was less frequent in YFV-positive pri-
mentary Table S3. mates than in controls (20/56 [35%] vs 34/51 [66%], respec-
Severe hepatic necrosis (Fig. 2) was the most common and tively; P ¼ .0014; odds ratio ¼ 0.28; w2 test; Fig. 5).
marked lesion associated with YFV natural infection, affecting Hemorrhage was found in 2 YFV-positive animals that had
40/56 (71%; P < .0001; odds ratio ¼ 61.25; w2 test) of infected multifocal to coalescent areas of moderate to severe hemor-
neotropical primates. This lesion often extended to all zones of rhage in the midzonal region of the hepatic lobule.
the hepatic lobule (Fig. 3). Hepatitis was observed in both In order to evaluate whether there were differences in lesion
YFV-positive and YFV-negative groups, but it was signifi- intensity among different primate species, scores were com-
cantly more intense in YFV-positive animals. The inflamma- pared between YFV-positive and negative Alouatta sp. and
tory cells were mostly lymphocytes, plasma cells, and Callithrix sp. (Table 1). Based on this analysis, Alouatta sp.
684 Veterinary Pathology 57(5)
Table 1. Histopathologic Scores in the Liver of YFV-Positive and YFV-Negative Alouatta sp. (n ¼ 40) and Callithrix sp. (n ¼ 61).
Hepatic Lesion Species YFa Median Score Upper Limit Lower Limit P Valueb
infect invertebrate hosts is unknown and warrant further study 5. Davis NC. The transmission of yellow fever: experiments with the “woolly
of their role in YFV transmission. monkey” (Lagothrix lago-tricha Humboldt), the “spider monkey” (Ateleus ater
F. Cuvier), and the “squirrel monkey” (Saimiri scireus Linnaeus). J Exp Med.
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Monath,14 who demonstrated that renal function is not altered successful recovery of endangered golden lion tamarins. Sci Rep. 2019;9(1):
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monkeys experimentally infected with YFV.11,20 liver transplantation: new insights from the autopsy room for an old but re-
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Declaration of Conflicting Interests II. Microscopic pathology. Am J Pathol. 1928;4(5):407–418.
The author(s) declared no potential conflict of interest with respect to 12. Litvoc MN, Novaes CTG, Lopes MIBF. Yellow fever. Rev Assoc Med Bras
the research, authorship, and/or publication of this article. (1992). 2018;64(2):106–113.
13. Mares-Guia MAMM, Horta MA, Romano A, et al. Yellow fever epizootics in
Funding non-human primates, southeast and northeast Brazil (2017 and 2018). Parasit
Vectors. 2020;13(1):90.
The author(s) disclosed receipt of the following financial support for
14. Monath TP. Yellow fever: an update. Lancet Infect Dis. 2001;1(1):11–20.
the research, authorship, and/or publication of this article: Work in
15. Monath TP, Vasconcelos PFC. Yellow fever. J Clin Virol. 2015;64:160–173.
RLS lab is supported by CNPq (Conselho Nacional de Desenvolvi- 16. Quaresma JAS, Pagliari C, Medeiros DBA, et al. Immunity and immune
mento Cientı́fico e Tecnológico, Brazil), FAPEMIG (Fundação de response, pathology and pathologic changes: progress and challenges in immu-
Amparo à Pesquisa do Estado de Minas Gerais, Brazil), and CAPES nopathology of yellow fever. Rev Med Virol. 2013;23(5):305–318.
(Coordenação de Aperfeiçoamento de Pessoal de Nı́vel Superior, 17. Ryland AB, Schneider H, Languth A, et al. An assessment of the diversity of
Brazil). TAP and RLS have fellowships from CNPq (Brazil). New World Primates. Neotrop Primates. 2000;8(2):61–93.
18. Silva NIO, Sacchetto L, de Rezende IM, et al. Recent sylvatic yellow fever
ORCID iD virus transmission in Brazil: the news from an old disease. Virol J. 2020;
Renato Lima Santos https://orcid.org/0000-0002-4830-0470 17(1):9.
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