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

Abstract

<jats:p>Deer mice are the principal reservoir hosts of Sin Nombre virus, the etiologic agent of most hantavirus cardiopulmonary syndrome cases in North America. Infection of deer mice results in persistence without conspicuous pathology, and most, if not all, infected mice remain infected for life, with periods of viral shedding. The kinetics of viral load, histopathology, virus distribution, and immune gene expression in deer mice were examined. Viral antigen was detected as early as 5 days postinfection and peaked on day 15 in the lungs, hearts, kidneys, and livers. Viral RNA levels varied substantially but peaked on day 15 in the lungs and heart, and antinucleocapsid IgG antibodies appeared in some animals on day 10, but a strong neutralizing antibody response failed to develop during the 20-day experiment. No clinical signs of disease were observed in any of the infected deer mice. Most genes were repressed on day 2, suggesting a typical early downregulation of gene expression often observed in viral infections. Several chemokine and cytokine genes were elevated, and markers of a T cell response occurred but then declined days later. Splenic transforming growth factor beta (TGF-β) expression was elevated early in infection, declined, and then was elevated again late in infection. Together, these data suggest that a subtle immune response that fails to clear the virus occurs in deer mice.</jats:p>

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).…”

“…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).…”

“…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.…”

Differential Lymphocyte and Antibody Responses in Deer Mice Infected with Sin Nombre Hantavirus or Andes Hantavirus

“…About 200,000 cases of hantaviral disease occur each year, with fatality rates ranging from about 1% to more than 40%, depending on the virus (8,9). Each pathogenic hantavirus is hosted by a single principal rodent reservoir, with occasional spillover to other rodent species (9)(10)(11)(12), and infection of reservoirs results in persistence without signs of disease (2,13). In contrast, human disease is characterized by a vascular leak syndrome and thrombocytopenia without signs of virus-induced damage to the endothelium (11,(14)(15)(16)(17)(18), the principal target of infection in both humans and rodents (2,18).…”

“…Experimental Seoul virus infection of its reservoir host, the Norway rat (Rattus norvegicus), also results in seroconversion, and signatures of regulatory T cell re-sponses, including transforming growth factor ␤ (TGF-␤) and Fox-p3, are prominent (30). Infection of deer mice (Peromyscus maniculatus), the principal reservoir host of Sin Nombre virus (SNV), results in virus in many organs, including the lungs, heart, spleen, and kidneys, without conspicuous effects to the endothelium (2,13). CD4 ϩ T cells from acutely infected deer mice express many Th1 and Th2 cytokines, but TGF-␤ and Fox-p3 are expressed prominently from persistently infected deer mice, suggesting transition to a regulatory T cell response (31).…”