Pathogenesis of a Pichinde Virus Strain Adapted to Produce Lethal Infections in Guinea Pigs

Abstract

A model for studying the pathogenesis of virulent arenavirus infection was developed by adapting Pichinde virus to produce lethal infections of inbred guinea pigs. This adapted Pichinde virus retained low virulence for primates, thus potentially reducing the biohazard to investigators. Whereas all inbred (strain 13) guinea pigs were infected and killed by 3 plaque-forming units or more of adapted Pichinde virus injected subcutaneously, outbred (Hartley strain) guinea pigs were relatively resistant. All infected, inbred guinea pigs died at 13 to 19 days after inoculation, with viremias in excess of 5 log 10 plaque-forming units/ml, severe lymphopenia (<1,000/mm 3 ), and elevated serum glutamic oxaloacetic acid transaminase levels. Immunofluorescent antibody examination of tissues and infectivity titrations of tissue homogenates obtained at 3- to 4-day intervals demonstrated significant viral replication in all visceral tissues examined, but not in brain. Livers of all moribund guinea pigs contained moderate to severe hepatocellular necrosis and diffuse fatty change. Splenic red pulp and adrenal cortical tissues were engorged with blood and contained necrotic foci. Pancreatic acinar tissues were atrophied and vacuolated; lung sections typically contained areas of moderate to severe interstitial pneumonia. Inflammatory cells were conspicuously absent from all lesions. The virological and pathological features of adapted Pichinde infection in guinea pigs are remarkably similar to those described for Lassa virus infections in rhesus monkeys and humans, suggesting that this model might provide insight into the pathogenesis and treatment of Lassa fever in humans.

Molecular Determinants of Pichinde Virus Infection of Guinea Pigs—a Small Animal Model System for Arenaviral Hemorrhagic Fevers

“…Serial passages in inbred guinea pigs dramatically in-creases the pathogenicity of the virus. 10 Upon infection of the adapted viruses, guinea pigs developed severe disease characterized by fever, severe weight loss, terminal vascular collapse, and death. 10,30,31 The illness in PICV-infected guinea pigs mimics human Lassa fever infection in many aspects.…”

“…The current knowledge of Lassa fever is based on limited data available from human infections 6 and studies of animal models for VHFs. [7][8][9][10][11] A distinct feature of arenavirus VHF is that viremia level is closely associated with disease outcome and can accurately predict mortality. 12 Postmortem studies have found high titers of LASV in multiple organs in the body, such as liver, lung, spleen, kidney, heart, placenta, and the mammary gland.…”

Arenavirus entry occurs through a cholesterol-dependent, non-caveolar, clathrin-mediated endocytic mechanism

“…Guinea pig-passaged variants of PICV strain CoAn 4763 were developed by Peter Jahrling (Jahrling et al, 1981). The high-passage virulent PICV-P18 (Zhang et al, 1999) was utilized at an MOI of 1 for all infection experiments.…”

“…The goal of this study was to clarify the roles of cholesterol, and caveolar or clathrin-mediated endocytic pathways in cellular infection of representative Old World and New World arenaviruses or their pseudotyped surrogates. Two arenaviruses were studied: (1) the guinea pig-passaged Pichindé virus (PICV) variant P18, which causes hemorrhagic fever in guinea pigs (Jahrling et al, 1981;Zhang et al, 1999), and does not utilize alpha-dystroglycan as a receptor (Rojek et al, 2006), and (2) the Lassa-pseudotyped murine leukemia virus (LASV-MLV), which enters by an alpha-dystroglycan dependent mechanism. We show that cholesterol is required for cellular infection of PICV and the LASV-MLV pseudotype in several relevant cell types in a caveolin-1 independent mechanism and that the effect of cholesterol depletion on infection is at the level of entry.…”

Comparative Pathogenesis and Systems Biology for Biodefense Virus Vaccine Development

“…Studies using Pichindé virus, a guinea pig model for Lassa fever, have taken advantage of two passage variants of the virus which cause either a severe hemorrhagic fever or a mild, self-limiting infection from which animals recover [31,32]. Proteomic and kinomic level studies using this system have been analyzed using pathway analysis and have shown that infection with the attenuated virus induced significantly more cellular signaling events and immune response activation than infection with the virulent virus, which more closely resembles patterns of protein expression and kinase activity seen following mock infection [33][34][35].…”