Pichinde virus infection of outbred Hartley guinea pigs and mice as small animal models of human Lassa fever

Abstract

Arenaviruses are viruses that can cause severe and deadly hemorrhagic fever infections in Africa and South America, including Lassa virus that causes Lassa fever in several countries in west Africa. There are currently no vaccines and very limited therapeutics available for Lassa fever. There are also several under-addressed complications of Lassa fever such as high infant mortality during pregnancy infection and sensorineural hearing loss. An aspect of Lassa virus that makes it difficult to study is its designation as a highly pathogenic human virus that requires its handling in strict bio-containment laboratory (BSL4 level laboratory), which significantly limits the scope of studies to understand the host immune responses to this virus infection and disease pathology and pathogenesis. This thesis describes two studies that use two different small animal models of infection with the Pichinde virus as surrogate models of human Lassa fever that can be carried out in a conventional (BSL2 level) laboratory, as Pichinde virus is non-pathogenic in humans. The first study uses mice that are genetically engineered to be deficient in the viral RNA-sensing pathway, as the result of genetic ablation of the host proteins RIG-I and MDA5. This study was carried out to determine the importance of RIG-I and MDA5 in providing innate immune protection against Pichinde virus in mice, which may shed important light on virus-host interactions in the natural rodent reservoirs of Lassa virus and in human infection by this deadly virus. The second investigates whether outbred Hartley guinea pigs experienced hearing loss in addition to other disease signs that are similar in human Lassa fever. Taken together, these studies help establish Pichinde virus infection of small animals (mice and guinea pigs) as a useful and relevant model for human Lassa fever that can be used for future vaccine and/or therapeutic testing to benefit human patients.