Biological Sex and Pregnancy Affect Influenza Pathogenesis and Vaccination

Creisher, Patrick S.; Seddu, Kumba; Mueller, Alice L.; Klein, Sabra L.

doi:10.1007/978-3-031-35139-6_5

Cited by 1 publication

(1 citation statement)

References 151 publications

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“…The critical importance of this pathway in constraining viral replication and transmission is evidenced by almost universal antagonism of type I IFN signaling or effector function by successful viral pathogens (17). Notably, while the intended outcome of type I IFN induction is viral clearance, strong and sustained IFN responses are implicated in inflammatory disease, cancers, and significant tissue damage following viral infection (18)(19)(20)(21)(22). Tight regulation of these pathways by the host allows for efficient antiviral response with limited tissue damage.…”

Section: Introductionmentioning

confidence: 99%

Seoul orthohantavirus evades innate immune activation by reservoir endothelial cells

Klimaj,

LaPointe,

Martinez

et al. 2024

Preprint

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Pathogenic hantaviruses are maintained world-wide within wild, asymptomatic rodent reservoir hosts, with increasingly frequent human spillover infections resulting in severe hemorrhagic fever disease. With no approved therapeutics or vaccines, research has, until recently, focused on understanding the drivers of immune-mediated pathogenesis. An emerging body of work is now investigating the mechanisms that allow for asymptomatic, persistent infections of mammalian reservoir hosts with highly pathogenic RNA viruses. Despite limited experimental data, several hypotheses have arisen to explain limited or absent disease pathology in reservoir hosts. In this study, we directly tested two leading hypotheses: 1) that reservoir host cells induce a generally muted response to viral insults, and 2) that these viruses employ host-specific mechanisms of innate antiviral antagonism to limit immune activation in reservoir cells. We demonstrate that, in contrast to human endothelial cells which mount a robust antiviral and inflammatory response to pathogenic hantaviruses, primary Norway rat endothelial cells do not induce antiviral gene expression in response to infection with their endemic hantavirus, Seoul orthohantavirus (SEOV). Reservoir rat cells do, however, induce strong innate immune responses to exogenous stimulatory RNAs, type I interferon, and infection with Hantaan virus, a closely related hantavirus for which the rat is not a natural reservoir. We also find that SEOV-infected rat endothelial cells remain competent for immune activation induced by exogenous stimuli or subsequent viral infection. Importantly, these findings support an alternative model for asymptomatic persistence within hantavirus reservoir hosts: that efficient viral replication within reservoir host cells prevents the exposure of critical motifs for cellular antiviral recognition and thus limits immune activation that would otherwise result in viral clearance and/or immune-mediated disease. Defining the mechanisms that allow for infection tolerance and persistence within reservoir hosts will reveal novel strategies for viral countermeasures and inform rational surveillance programs.Author SummaryDespite the significant, and continual, threat to human health, limited experimental evidence explains the mechanisms that underly asymptomatic zoonotic RNA virus persistence within natural, mammalian reservoir hosts. Here, we investigated whether reservoir host target cells for hantavirus infection are competent for antiviral activation and tested the hypothesis that, through long-term co-evolution, Seoul orthohantavirus actively antagonizes innate antiviral signaling pathways to limit immune induction and prevent viral clearance in primary reservoir cells. While we find no evidence to support these hypotheses, our findings do support an alternative hypothesis that viral replication within the natural reservoir cells may not result in the production of immune-stimulating by-products. The factors that determine viral persistence within the reservoirs may include efficient use of host co-factors for efficient genome replication and/or packaging and warrant further investigation.

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