Seoul virus enhances regulatory and reduces proinflammatory responses in male Norway rats

Abstract

Zoonotic pathogens, including hantaviruses, are maintained in the environment by causing persistent infection in the absence of disease in their reservoir hosts. Spillover of hantaviruses to humans can cause severe disease that is mediated by excessive proinflammatory responses. The mechanisms mediating hantaviral persistence in rodent reservoirs remain largely unknown. Male Norway rats were inoculated with their species-specific hantavirus, Seoul virus (SEOV), and viral RNA, cytokine, and chemokine responses were evaluated in spleen and lung tissue. More viral RNA was detectable in the lungs than spleen, with copies of SEOV peaking 15-30 days post-inoculation (p.i.) and persisting for 60 days p.i. In the lungs, the expression and production of proinflammatory mediators (i.e. IL-1β, IL-6, TNF-α, IFN-γ, CCL5, CCL2, CX3CL1, CXCL10, VCAM, VEGF, and NOS2) remained at or below baseline throughout SEOV infection; whereas, regulatory factors, including TGF-β and FoxP3 were elevated. Conversely, in the spleen, proinflammatory responses were induced while regulatory responses remained unchanged during infection. To determine whether reduced proinflammatory responses mediate hantavirus persistence in the lungs, male rats were administered rIL-1β or vehicle for 30 days during SEOV infection. SEOV persistence and shedding were not affected by IL-1β treatment. Proinflammatory responses were elevated in rIL-1β-treated rats, but remained within physiological levels, suggesting that supra-physiological concentrations may be necessary for viral clearance at the cost of causing disease. Elevated regulatory responses may suppress excessively high proinflammatory responses at a site of elevated SEOV replication to contribute to viral persistence and prevent proinflammatory-mediated disease in reservoir hosts.

Landscape features and helminth co-infection shape bank vole immunoheterogeneity, with consequences for Puumala virus epidemiology

“…We thus examined whether we could detect an effect of Tnf-a and Mx2 constitutive gene expression (these genes do not seem to be upregulated in rodent spleen following hantavirus infection; Easterbrook and Klein, 2008;Schountz et al, 2012;Spengler et al, 2013) on PUUV replication in wild bank voles. We considered the data set including infected bank voles only (N ¼ 33).…”

“…We chose to extract RNA from the spleen because this organ has important immune functions (it is a secondary lymphoid organ) and is the site of low levels of PUUV replication (Korva et al, 2009). Moreover, experimental studies that have followed the kinetics of immune gene expression in rodent hosts infected by hantaviruses all showed that the expression of Tnf-a gene remained unchanged in the spleen of infected rodents from the time of infection to 40 days post-infection or compared with uninfected ones (Easterbrook and Klein, 2008;Schountz et al, 2012;Spengler et al, 2013). Spleens therefore reflect the constitutive levels of Tnf-a and Mx2 expression, not influenced by PUUV infection but potentially modulated by other infections that should mainly be randomly distributed between PUUV-infected and PUUV-non-infected voles.…”

“…The expression of these genes was quantified in the spleen, a secondary lymphoid organ in which hantavirus replication rates are low (for example, Botten et al, 2000) and Tnf-a gene expression is not induced in response to hantavirus infection (Easterbrook and Klein, 2008;Guivier et al, 2010b;Schountz et al, 2012, Spengler et al, 2013. This probably reflects the presence of macrophages constitutively expressing the Tnfa gene (Hutchinson et al, 1998;Herbst et al, 2002).…”

“…Periodic episodes of viral recrudescence may occur during the lifetime of the vole, because of changes in the virus and/or host immune response (Hardestam et al, 2008). Besides, anti-hantavirus immunoglobulin G are usually detectable 2 weeks after infection and seems to remain detectable for the lifetime of the rodents (see references in Easterbrook and Klein, 2008).…”

Kinetics of Immune Responses in Deer Mice Experimentally Infected with Sin Nombre Virus

“…In addition, some chemokines are elevated in the spleens of infected rats, including Ccl2 and Ccl5, but less so in the lungs (9).…”