Comparison of transcriptional responses between pathogenic and nonpathogenic hantavirus infections in Syrian hamsters using NanoString

Background Syrian hamsters infected with Andes virus (ANDV) develop a disease that recapitulates many of the salient features of human hantavirus pulmonary syndrome (HPS), including lethality. Infection of hamsters with Hantaan virus (HTNV) results in an asymptomatic, disseminated infection. In order to explore this dichotomy, we examined the transcriptome of ANDV- and HTNV-infected hamsters. Results Using NanoString technology, we examined kinetic transcriptional responses in whole blood collected from ANDV- and HTNV-infected hamsters. Of the 770 genes analyzed, key differences were noted in the kinetics of type I interferon sensing and signaling responses, complement activation, and apoptosis pathways between ANDV- and HTNV-infected hamsters. Conclusions Delayed activation of type I interferon responses in ANDV-infected hamsters represents a potential mechanism that ANDV uses to subvert host immune responses and enhance disease. This is the first genome-wide analysis of hantavirus-infected hamsters and provides insight into potential avenues for therapeutics to hantavirus disease. Author summary Hantaviruses co-evolved in specific animal hosts (e.g. rodents) where they persistently infect endothelial cells without causing disease. When these zoonotic viruses cross into humans, usually by inhalation, ingestion, or bite, the endothelium becomes infected, and this infection leads to severe and often lethal disease. Attempts to develop animal models for hantavirus disease have only met with partial success. Syrian hamsters infected with Andes virus (ANDV), a New World hantavirus, develop a disease that closely mimics hantavirus pulmonary syndrome (HPS) in humans. Old World hantaviruses, such as Hantaan virus (HTNV), readily infect Syrian hamsters but do not cause disease. We were interested in understanding why both ANDV and HTNV can readily infect hamsters, but only ANDV causes disease. To investigate this, Syrian hamsters were infected with ANDV or HTNV and a transcriptomics (i.e., NanoString) approach was used to evaluate the animals' responses to exposure. We identified key differences in gene activity. For example, HTNV exposure triggered early activity in the interferon pathway, whereas the interferon response was delayed following ANDV exposure. This difference in host response will be the focus of future studies aimed at understanding hantavirus pathogenesis and developing HFRS animal models. This Syrian hamster NanoString codset can be used for studying pathogenesis in other disease models, such as SARS-CoV-2.