Immunological Mechanisms Mediating Hantavirus Persistence in Rodent Reservoirs

Abstract

Hantaviruses, similar to several emerging zoonotic viruses, persistently infect their natural reservoir hosts, without causing overt signs of disease. Spillover to incidental human hosts results in morbidity and mortality mediated by excessive proinflammatory and cellular immune responses. The mechanisms mediating the persistence of hantaviruses and the absence of clinical symptoms in rodent reservoirs are only starting to be uncovered. Recent studies indicate that during hantavirus infection, proinflammatory and antiviral responses are reduced and regulatory responses are elevated at sites of increased virus replication in rodents. The recent discovery of structural and non-structural proteins that suppress type I interferon responses in humans suggests that immune responses in rodent hosts could be mediated directly by the virus. Alternatively, several host factors, including sex steroids, glucocorticoids, and genetic factors, are reported to alter host susceptibility and may contribute to persistence of hantaviruses in rodents. Humans and reservoir hosts differ in infection outcomes and in immune responses to hantavirus infection; thus, understanding the mechanisms mediating viral persistence and the absence of disease in rodents may provide insight into the prevention and treatment of disease in humans. Consideration of the coevolutionary mechanisms mediating hantaviral persistence and rodent host survival is providing insight into the mechanisms by which zoonotic viruses have remained in the environment for millions of years and continue to be transmitted to humans.

Serosurvey of hantavirus infection in humans in the border region between Brazil and Argentina

“…The practice of storing food in barns suggests that the infection occurs around the home, since the abundance of food would attract a large population of rodents to the peridomicile area 3 .…”

“…Human infection is acquired by inhalation of aerosols containing excreta of rodents infected with hantavirus; i.e., infected by a virus of the family Bunyaviridae 2 , which includes than 20 hantaviruses identified throughout the American continent 3 .…”

“…The contact with hantavirus in and of itself does not cause HPS, since infection is dependent on the quantity of viral particles, such that lower concentrations of particles could lead to subclinical infection. However, another possibility is infection by a nonpathogenic strain that induces immune response activation with antibody production 3,7 .…”

“…The pathogenesis of HPS in humans is hypothesized to be mediated by immune activation and excess inflammatory responses, especially macrophages and CD8 + T cells 3 . Excess cytokines IL-1-α, IL-1-β, IL-6 and TNF-α interferon-γ, IL-2, IL-4 and TNF-β produced by activated macrophages in hantaviruses, specific T cells in recognition antigen infected pulmonary endothelial cells, are thought to be critical due to the increased permeability in the pathogenesis of HPS 8 .…”

Hantaviruses Induce Antiviral and Pro-Inflammatory Innate Immune Responses in Astrocytic Cells and the Brain

“…HFRS-associated hantaviruses cause vascular leakage and renal dysfunction, whereas HCPS-associated hantaviruses cause acute pulmonary edema (15,47). The mechanisms of hantavirus-induced pathogenesis are not fully understood, but both HFRS and HCPS share several clinical and pathologic features, including high fever, thrombocytopenia, increased capillary permeability and upregulation of tumor necrosis factor-a (TNF-a).…”