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Natural rodent model of viral transmission reveals biological features of virus population dynamics.

ABSTRACT: Emerging viruses threaten global health, but few experimental models can characterize the virus and host factors necessary for within- and cross-species transmission. Here, we leverage a model whereby pet store mice or rats-which harbor natural rodent pathogens-are cohoused with laboratory mice. This "dirty" mouse model offers a platform for studying acute transmission of viruses between and within hosts via natural mechanisms. We identified numerous viruses and other microbial species that transmit to cohoused mice, including prospective new members of the Coronaviridae, Astroviridae, Picornaviridae, and Narnaviridae families, and uncovered pathogen interactions that promote or prevent virus transmission. We also evaluated transmission dynamics of murine astroviruses during transmission and spread within a new host. Finally, by cohousing our laboratory mice with the bedding of pet store rats, we identified cross-species transmission of a rat astrovirus. Overall, this model system allows for the analysis of transmission of natural rodent viruses and is a platform to further characterize barriers to zoonosis.

SUBMITTER: Fay EJ

PROVIDER: S-EPMC8713297 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Natural rodent model of viral transmission reveals biological features of virus population dynamics.

Fay Elizabeth J EJ Balla Keir M KM Roach Shanley N SN Shepherd Frances K FK Putri Dira S DS Wiggen Talia D TD Goldstein Stephen A SA Pierson Mark J MJ Ferris Martin T MT Thefaine Claire E CE Tucker Andrew A Salnikov Mark M Cortez Valerie V Compton Susan R SR Kotenko Sergei V SV Hunter Ryan C RC Masopust David D Elde Nels C NC Langlois Ryan A RA

The Journal of experimental medicine 20211227 2

Emerging viruses threaten global health, but few experimental models can characterize the virus and host factors necessary for within- and cross-species transmission. Here, we leverage a model whereby pet store mice or rats-which harbor natural rodent pathogens-are cohoused with laboratory mice. This "dirty" mouse model offers a platform for studying acute transmission of viruses between and within hosts via natural mechanisms. We identified numerous viruses and other microbial species that tran ...[more]

PMID: 34958350

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Project description:UnlabelledWhile simian immunodeficiency viruses (SIVs) are generally nonpathogenic in their natural hosts, dramatic increases in pathogenicity may occur upon cross-species transmission to new hosts. Deciphering the drivers of these increases in virulence is of major interest for understanding the emergence of new human immunodeficiency viruses (HIVs). We transmitted SIVsab from the sabaeus species of African green monkeys (AGMs) to pigtailed macaques (PTMs). High acute viral replication occurred in all SIVsab-infected PTMs, yet the outcome of chronic infection was highly variable, ranging from rapid progression to controlled infection, which was independent of the dynamics of acute viral replication, CD4(+) T cell depletion, or preinfection levels of microbial translocation. Infection of seven PTMs with plasma collected at necropsy from a rapid-progressor PTM was consistently highly pathogenic, with high acute and chronic viral replication, massive depletion of memory CD4(+) T cells, and disease progression in all PTMs. The plasma inoculum used for the serial passage did not contain adventitious bacterial or viral contaminants. Single-genome amplification showed that this inoculum was significantly more homogenous than the inoculum directly derived from AGMs, pointing to a strain selection in PTMs. In spite of similar peak plasma viral loads between the monkeys in the two passages, immune activation/inflammation levels dramatically increased in PTMs infected with the passaged virus. These results suggest that strain selection and a massive cytokine storm are major factors behind increased pathogenicity of SIV upon serial passage and adaptation of SIVs to new hosts following cross-species transmission.ImportanceWe report here that upon cross-species transmission and serial passage of SIVsab from its natural host, the sabaeus African green monkey (AGM), to a new host, the pigtailed macaque (PTM), viral adaptation and increased pathogenicity involve strain selection and a massive cytokine storm. These results permit the design of strategies aimed at preventing cross-species transmission from natural hosts of SIVs to humans in areas of endemicity. Furthermore, our study describes a new animal model for SIV infection. As the outcomes of SIVsab infection in PTMs, African green monkeys, and rhesus macaques are different, the use of these systems enables comparative studies between pathogenic, nonpathogenic, and elite-controlled infections, to gain insight into the mechanisms of SIV immunodeficiency and comorbidities.

Project description:Routes of virus transmission between hosts are key to understanding viral epidemiology. Different routes have large effects on viral ecology, and likelihood and rate of transmission; for example, respiratory and vector-borne viruses together encompass the majority of rapid outbreaks and high-consequence animal and plant epidemics. However, determining the specific transmission route(s) can take months to years, delaying mitigation efforts. Here, we identify the viral features and evolutionary signatures which are predictive of viral transmission routes and use them to predict potential routes for fully-sequenced viruses in silico and rapidly, for both viruses with no observed routes, as well as viruses with missing routes. This was achieved by compiling a dataset of 24,953 virus-host associations with 81 defined transmission routes, constructing a hierarchy of virus transmission encompassing those routes and 42 higher-order modes, and engineering 446 predictive features from three complementary perspectives. We integrated those data and features to train 98 independent ensembles of LightGBM classifiers. We found that all features contributed to the prediction for at least one of the routes and/or modes of transmission, demonstrating the utility of our broad multi-perspective approach. Our framework achieved ROC-AUC = 0.991, and F1-score = 0.855 across all included transmission routes and modes, and was able to achieve high levels of predictive performance for high-consequence respiratory (ROC-AUC = 0.990, and F1-score = 0.864) and vector-borne transmission (ROC-AUC = 0.997, and F1-score = 0.921). Our framework ranks the viral features in order of their contribution to prediction, per transmission route, and hence identifies the genomic evolutionary signatures associated with each route. Together with the more matured field of viral host-range prediction, our predictive framework could: provide early insights into the potential for, and pattern of viral spread; facilitate rapid response with appropriate measures; and significantly triage the time-consuming investigations to confirm the likely routes of transmission.

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Natural rodent model of viral transmission reveals biological features of virus population dynamics.

Publications

Natural rodent model of viral transmission reveals biological features of virus population dynamics.

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