Primate hemorrhagic fever-causing arteriviruses are poised for spillover to humans.
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ABSTRACT:
SUBMITTER: Warren CJ
PROVIDER: S-EPMC9588614 | biostudies-literature | 2022 Oct
REPOSITORIES: biostudies-literature
Publications
Primate hemorrhagic fever-causing arteriviruses are poised for spillover to humans.
Warren Cody J CJ Yu Shuiqing S Peters Douglas K DK Barbachano-Guerrero Arturo A Yang Qing Q Burris Bridget L BL Worwa Gabriella G Huang I-Chueh IC Wilkerson Gregory K GK Goldberg Tony L TL Kuhn Jens H JH Sawyer Sara L SL
Cell 20220930 21
Simian arteriviruses are endemic in some African primates and can cause fatal hemorrhagic fevers when they cross into primate hosts of new species. We find that CD163 acts as an intracellular receptor for simian hemorrhagic fever virus (SHFV; a simian arterivirus), a rare mode of virus entry that is shared with other hemorrhagic fever-causing viruses (e.g., Ebola and Lassa viruses). Further, SHFV enters and replicates in human monocytes, indicating full functionality of all of the human cellular ...[more]
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Project description:Lassa fever virus is a zoonotic pathogen that plagues the endemic areas of West Africa. Rhesus macaques infected with a related arenavirus, LCMV-WE, serve as a model for Lassa-infection of human beings. Using a dose similar to that expected from a needle-stick, monkeys experience an early pre-viremic phase (day 1-3), a viremic phase with febrile onset (day 4-7), and, like human beings who succumb, they die within two weeks. Our goal was to monitor changes in gene expression that parallel disease progression in an effort to 1) identify genes with altered expression after infection, 2) identify genes that could discriminate between a virulent and non-virulent infection, and 3) identify genes encoding products that could serve as treatment targets for FDA-approved pharmaceuticals. Genes related to all three of these categories have been identified and some have been given preliminary validation by quantitative PCR and proteomic studies. These genes will be valuable candidates for future validation as prognostic biomarkers We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated genes during this process. Keywords: time course
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Project description:UnlabelledSimian hemorrhagic fever (SHF) is a highly lethal disease in captive macaques. Three distinct arteriviruses are known etiological agents of past SHF epizootics, but only one, simian hemorrhagic fever virus (SHFV), has been isolated in cell culture. The natural reservoir(s) of the three viruses have yet to be identified, but African nonhuman primates are suspected. Eleven additional divergent simian arteriviruses have been detected recently in diverse and apparently healthy African cercopithecid monkeys. Here, we report the successful isolation in MARC-145 cell culture of one of these viruses, Kibale red colobus virus 1 (KRCV-1), from serum of a naturally infected red colobus (Procolobus [Piliocolobus] rufomitratus tephrosceles) sampled in Kibale National Park, Uganda. Intramuscular (i.m.) injection of KRCV-1 into four cynomolgus macaques (Macaca fascicularis) resulted in a self-limiting nonlethal disease characterized by depressive behavioral changes, disturbance in coagulation parameters, and liver enzyme elevations. In contrast, i.m. injection of SHFV resulted in typical lethal SHF characterized by mild fever, lethargy, lymphoid depletion, lymphoid and hepatocellular necrosis, low platelet counts, increased liver enzyme concentrations, coagulation abnormalities, and increasing viral loads. As hypothesized based on the genetic and presumed antigenic distance between KRCV-1 and SHFV, all four macaques that had survived KRCV-1 injection died of SHF after subsequent SHFV injection, indicating a lack of protective heterotypic immunity. Our data indicate that SHF is a disease of macaques that in all likelihood can be caused by a number of distinct simian arteriviruses, although with different severity depending on the specific arterivirus involved. Consequently, we recommend that current screening procedures for SHFV in primate-holding facilities be modified to detect all known simian arteriviruses.ImportanceOutbreaks of simian hemorrhagic fever (SHF) have devastated captive Asian macaque colonies in the past. SHF is caused by at least three viruses of the family Arteriviridae: simian hemorrhagic fever virus (SHFV), simian hemorrhagic encephalitis virus (SHEV), and Pebjah virus (PBJV). Nine additional distant relatives of these three viruses were recently discovered in apparently healthy African nonhuman primates. We hypothesized that all simian arteriviruses are potential causes of SHF. To test this hypothesis, we inoculated cynomolgus macaques with a highly divergent simian arterivirus (Kibale red colobus virus 1 [KRCV-1]) from a wild Ugandan red colobus. Despite being only distantly related to red colobuses, all of the macaques developed disease. In contrast to SHFV-infected animals, KRCV-1-infected animals survived after a mild disease presentation. Our study advances the understanding of an important primate disease. Furthermore, our data indicate a need to include the full diversity of simian arteriviruses in nonhuman primate SHF screening assays.
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Project description:Viral hemorrhagic fevers are diseases caused by viruses which belong to different families, many of them causing severe diseases. These viruses may produce different symptomatology together with a severe multisystem syndrome, and the final result might be the production of hemorrhages in several sites of the body. The majority of them have no other treatment than supportive therapy, although some antiviral drugs can be used in some circumstances. Transmission of VHF has been demonstrated through contact with animal vectors or person-to-person through the contact with body fluids. No risk of transmission has been found during the incubation period, but when the viral load is high the risk of transmission is greatest. Both health care and clinical laboratory workers must safely handle patients and specimens by taking all required precautions during their management.
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Project description:Simian hemorrhagic fever (SHF) is lethal for macaques. Based on clinical presentation and serological diagnosis, all reported SHF outbreaks were thought to be caused by different strains of the same virus, simian hemorrhagic fever virus (SHFV; Arteriviridae). Here we show that the SHF outbreaks in Sukhumi in 1964 and in Alamogordo in 1989 were caused not by SHFV but by two novel divergent arteriviruses. Our results indicate that multiple divergent simian arteriviruses can cause SHF.
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Project description:Lassa fever virus is a zoonotic pathogen that plagues the endemic areas of West Africa. Rhesus macaques infected with a related arenavirus, LCMV-WE, serve as a model for Lassa-infection of human beings. Using a dose similar to that expected from a needle-stick, monkeys experience an early pre-viremic phase (day 1-3), a viremic phase with febrile onset (day 4-7), and, like human beings who succumb, they die within two weeks. Our goal was to monitor changes in gene expression that parallel disease progression in an effort to 1) identify genes with altered expression after infection, 2) identify genes that could discriminate between a virulent and non-virulent infection, and 3) identify genes encoding products that could serve as treatment targets for FDA-approved pharmaceuticals. Genes related to all three of these categories have been identified and some have been given preliminary validation by quantitative PCR and proteomic studies. These genes will be valuable candidates for future validation as prognostic biomarkers; We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated genes during this process. Experiment Overall Design: Rhesus macaques inoculated with a lethal dose of LCMV-WE were used to model human infection with Lassa fever virus (Lukashevich et al 2002, 2003; Rodas et al 2004). To identify molecular events that occur during the first few days of virus exposure, we monitored gene expression in peripheral blood mononuclear cell (PBMC) samples by microarray analysis. Approximately 150 samples from 23 different rhesus macaques (Table 1) were hybridized to Affymetrix U133 chips. Experiment Overall Design: Affymetrix U133 arrays cover the entire human genome with approximately 54,000 gene fragments representing approximately 22,000 genes. The use of these human arrays for macaque transcriptome analysis has been validated by other laboratories (Ace et al, 2004 Wang et al, 2004), i.e. 99.8% of the array elements for which human DNA gave a signal >1.4-fold over background were also >1.4 over background for macaque DNA (Rubins et al, 2004). LCMV-infected blood samples were compared to uninfected controls and genes with over two-fold change in expression were designated âdifferentially expressedâ (Fig. 1). Thus, out of 54,000 elements, 8410 (16%) were differentially regulated with a >2-fold change in expression [supplementary Table 1 has these genes in order of the magnitude of their differential expression]. Experiment Overall Design: Virus was detectable in these monkeys at day 4 after infection by plaque assay and by RT-PCR of blood cDNA (Djavani et al 2005). Although virus is replicating in monocytes, endothelial cells, liver, spleen, and peripheral lymphoid organs soon after inoculation (Rai et al, 1997; Lukashevich et al, 2002), virus is not detectable in the circulation for the first three days. Thus we define the early, pre-viremic stage as days 1-3, and a later viremic stage as days 4-7. Although the LCMV-Armstrong strain replicated as well in cell culture as LCMV-WE, the LCMV-Arm-infected monkeys did not experience viremia, i.e. viral nucleic acid were detected in tissues but virus loads were not high enough to be detected in the circulation. The Arm-infected monkeys resisted a lethal challenge with LCMV-WE, further confirming that they had been productively infected (Rodas et al, 2004). An overview of gene expression in monkeys shows a trend to down-regulate genes at the onset of viremia followed by a sharp increase in up-regulated genes. Those monkeys that did not experience viremia (Armstrong-infected) showed no dramatic down-regulation trend (Fig. 1). Over the entire study period of 7 days, the number of down-regulated genes in the WE-infected macaques was significantly more than the number seen in the Arm-infected monkeys (p < 0.005).
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