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Virulence mismatches in index hosts shape the outcomes of cross-species transmission.

ABSTRACT: Whether a pathogen entering a new host species results in a single infection or in onward transmission, and potentially an outbreak, depends upon the progression of infection in the index case. Although index infections are rarely observable in nature, experimental inoculations of pathogens into novel host species provide a rich and largely unexploited data source for meta-analyses to identify the host and pathogen determinants of variability in infection outcomes. We analyzed the progressions of 514 experimental cross-species inoculations of rabies virus, a widespread zoonosis which in nature exhibits both dead-end infections and varying levels of sustained transmission in novel hosts. Inoculations originating from bats rather than carnivores, and from warmer- to cooler-bodied species caused infections with shorter incubation periods that were associated with diminished virus excretion. Inoculations between distantly related hosts tended to result in shorter clinical disease periods, which are also expected to impede onward transmission. All effects were modulated by infection dose. Taken together, these results suggest that as host species become more dissimilar, increased virulence might act as a limiting factor preventing onward transmission. These results can explain observed constraints on rabies virus host shifts, describe a previously unrecognized role of host body temperature, and provide a potential explanation for host shifts being less likely between genetically distant species. More generally, our study highlights meta-analyses of experimental infections as a tractable approach to quantify the complex interactions between virus, reservoir, and novel host that shape the outcome of cross-species transmission.

SUBMITTER: Mollentze N

PROVIDER: S-EPMC7682402 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Virulence mismatches in index hosts shape the outcomes of cross-species transmission.

Mollentze Nardus N Streicker Daniel G DG Murcia Pablo R PR Hampson Katie K Biek Roman R

Proceedings of the National Academy of Sciences of the United States of America 20201029 46

Whether a pathogen entering a new host species results in a single infection or in onward transmission, and potentially an outbreak, depends upon the progression of infection in the index case. Although index infections are rarely observable in nature, experimental inoculations of pathogens into novel host species provide a rich and largely unexploited data source for meta-analyses to identify the host and pathogen determinants of variability in infection outcomes. We analyzed the progressions o ...[more]

PMID: 33122433

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Project description:While 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.We 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.

Dataset Information

Virulence mismatches in index hosts shape the outcomes of cross-species transmission.

Publications

Virulence mismatches in index hosts shape the outcomes of cross-species transmission.

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