Involvement of Pro-Inflammatory Macrophages in Liver Pathology of Pirital Virus-Infected Syrian Hamsters

Abstract

New World arenaviruses cause fatal hemorrhagic disease in South America. Pirital virus (PIRV), a mammarenavirus hosted by Alston’s cotton rat (Sigmodon alstoni), causes a disease in Syrian golden hamsters (Mesocricetus auratus) (biosafety level-3, BSL-3) that has many pathologic similarities to the South American hemorrhagic fevers (BSL-4) and, thus, is considered among the best small-animal models for human arenavirus disease. Here, we extend in greater detail previously described clinical and pathological findings in Syrian hamsters and provide evidence for a pro-inflammatory macrophage response during PIRV infection. The liver was the principal target organ of the disease, and signs of Kupffer cell involvement were identified in mortally infected hamster histopathology data. Differential expression analysis of liver mRNA revealed signatures of the pro-inflammatory response, hematologic dysregulation, interferon pathway and other host response pathways, including 17 key transcripts that were also reported in two non-human primate (NHP) arenavirus liver-infection models, representing both Old and New World mammarenavirus infections. Although antigen presentation may differ among rodent and NHP species, key hemostatic and innate immune-response components showed expression parallels. Signatures of pro-inflammatory macrophage involvement in PIRV-infected livers included enrichment of Ifng, Nfkb2, Stat1, Irf1, Klf6, Il1b, Cxcl10, and Cxcl11 transcripts. Together, these data indicate that pro-inflammatory macrophage M1 responses likely contribute to the pathogenesis of acute PIRV infection.

Hemorrhagic Fever-Causing Arenaviruses: Lethal Pathogens and Potent Immune Suppressors

“…However, the fatality rate can be as high as 87% among infected women during the third trimester of pregnancy ( 181 ), and maternal-fetal transmission of arenaviruses has been demonstrated in rodent models ( 64 ) as well as in one recent reported case in humans ( 182 ). Many other complications arise from severe arenaviral infections including liver ( 183 – 186 ) and vascular ( 185 , 187 , 188 ) damage, both of which have been recapitulated in a guinea pig arenaviral animal model ( 189 – 191 ) as well as in immunocompromised mice ( 192 , 193 ) and a novel hamster NW arenavirus model ( 194 ). While liver damage tends to be highly prominent in infections by OW arenaviruses with platelet factors and heme breakdown products as significant biomarkers of LASV disease, hemorrhaging, and vascular damage occur more frequently in NW arenavirus infections ( 195 ) ( Figure 5 ).…”