Experimental Andes Virus Infection in Deer Mice: Characteristics of Infection and Clearance in a Heterologous Rodent Host

Elaine Haddock,Joseph Prescott,Gary P Kobinger,Heinz Feldmann,Brian Hjelle,Don Gardner,Jessica R Spengler

doi:10.1371/journal.pone.0055310

Abstract

New World hantaviruses can cause hantavirus cardiopulmonary syndrome with high mortality in humans. Distinct virus species are hosted by specific rodent reservoirs, which also serve as the vectors. Although regional spillover has been documented, it is unknown whether rodent reservoirs are competent for infection by hantaviruses that are geographically separated, and known to have related, but distinct rodent reservoir hosts. We show that Andes virus (ANDV) of South America, carried by the long tailed pygmy rice rat (Oligoryzomys longicaudatus), infects and replicates in vitro and in vivo in the deer mouse (Peromyscus maniculatus), the reservoir host of Sin Nombre virus (SNV), found in North America. In experimentally infected deer mice, viral RNA was detected in the blood, lung, heart and spleen, but virus was cleared by 56 days post inoculation (dpi). All of the inoculated deer mice mounted a humoral immune response by 14 dpi, and produced measurable amounts of neutralizing antibodies by 21 dpi. An up-regulation of Ccl3, Ccl4, Ccl5, and Tgfb, a strong CD4+ T-cell response, and down-regulation of Il17, Il21 and Il23 occurred during infection. Infection was transient with an absence of clinical signs or histopathological changes. This is the first evidence that ANDV asymptomatically infects, and is immunogenic in deer mice, a non-natural host species of ANDV. Comparing the immune response in this model to that of the immune response in the natural hosts upon infection with their co-adapted hantaviruses may help clarify the mechanisms governing persistent infection in the natural hosts of hantaviruses.

Highlights

Pathogenic New World hantaviruses (Family: Bunyaviridae) are rodent-borne negative-sense RNA viruses that were first described in 1993 in the Four Corners region of the United States following an outbreak of an acute respiratory distress syndrome associated with high human mortality [1]
TCR-b expression was elevated on 7, 14, and 21 dpi, respectively. It is was previously unknown whether hantaviruses, which are associated with specific rodent or insectivore host species, could infect, or cause persistent infection in closely-related animal species that are hosts to a related hantavirus
We demonstrate that Andes virus (ANDV) infects and replicates in deer mouse embryonic fibroblasts in vitro, as well as in deer mice in vivo, though it does not cause persistent infection

Summary

Introduction

Pathogenic New World hantaviruses (Family: Bunyaviridae) are rodent-borne negative-sense RNA viruses that were first described in 1993 in the Four Corners region of the United States following an outbreak of an acute respiratory distress syndrome associated with high human mortality [1]. Hantaviruses cause two distinct diseases; hemorrhagic fever with renal syndrome and hantavirus cardiopulmonary syndrome (HCPS, or HPS), caused by Old World and New World viruses, respectively. Several hantavirus species are highly pathogenic and infection results in high case fatality rates in humans [2]. There are no approved vaccines for New World hantaviruses [3,4], and treatment is largely supportive. Since their discovery in North America, pathogenic hantaviruses have been identified as causing HCPS in Central and South America, where infection can result in high mortality [5]. Sin Nombre virus (SNV) and Andes virus (ANDV) are the principal etiologic agents of HCPS in North America and South America, respectively

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