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. 2013 Oct;140(2):168-78.
doi: 10.1111/imm.12116.

The adaptive immune response does not influence hantavirus disease or persistence in the Syrian hamster

Joseph Prescott  1 , David Safronetz, Elaine Haddock, Shelly Robertson, Dana Scott, Heinz Feldmann
Affiliations

The adaptive immune response does not influence hantavirus disease or persistence in the Syrian hamster

Joseph Prescott et al. Immunology. 2013 Oct.

Abstract

Pathogenic New World hantaviruses cause severe disease in humans characterized by a vascular leak syndrome, leading to pulmonary oedema and respiratory distress with case fatality rates approaching 40%. Hantaviruses infect microvascular endothelial cells without conspicuous cytopathic effects, indicating that destruction of the endothelium is not a mechanism of disease. In humans, high levels of inflammatory cytokines are present in the lungs of patients that succumb to infection. This, along with other observations, suggests that disease has an immunopathogenic component. Currently the only animal model available to study hantavirus disease is the Syrian hamster, where infection with Andes virus (ANDV), the primary agent of disease in South America, results in disease that closely mimics that seen in humans. Conversely, inoculation of hamsters with a passaged Sin Nombre virus (SNV), the virus responsible for most cases of disease in North America, results in persistent infection with high levels of viral replication. We found that ANDV elicited a stronger innate immune response, whereas SNV elicited a more robust adaptive response in the lung. Additionally, ANDV infection resulted in significant changes in the blood lymphocyte populations. To determine whether the adaptive immune response influences infection outcome, we depleted hamsters of CD4(+) and CD8(+) T cells before infection with hantaviruses. Depletion resulted in inhibition of virus-specific antibody responses, although the pathogenesis and replication of these viruses were unaltered. These data show that neither hantavirus replication, nor pathogenesis caused by these viruses, is influenced by the adaptive immune response in the Syrian hamster.

Keywords: T cells; hantavirus; hantavirus cardiopulmonary syndrome; infectious disease; zoonosis.

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Figures

Figure 1
Figure 1
Andes virus (ANDV) is pathogenic, whereas Sin Nombre virus (SNV) causes an apathogenic infection in hamsters. (a) Groups of five hamsters were inoculated intranasally with ANDV or SNV and monitored for signs of disease and survival. (b, c) Hamsters (groups of six) were inoculated with ANDV or SNV and necropsied at the indicated time-points. (b) Lungs of virus-inoculated hamsters were analysed for the presence of viral S-segment RNA using virus-specific quantitative reverse transcription-PCR and in vitro transcribed RNA as standards. Data are represented as the mean and standard deviation of six hamsters per group. (c) Lung tissue was examined histologically after haematoxylin & eosin staining. *Areas of perivascular oedema.
Figure 2
Figure 2
Andes virus (ANDV) and Sin Nombre virus (SNV) differently induce immune gene expression in hamster lungs. Groups of six hamsters were inoculated with SNV or ANDV, or Dulbecco's modified Eagle's medium (DMEM) as a control. Hamsters were killed at the indicated time-points and total RNA was extracted from the lung tissue for quantitative reverse transcription-PCR analysis of host genes. Cycle threshold values were normalized to an internal reference gene (RPL18) and fold changes were calculated relative to control hamsters inoculated with DMEM. Mean and SEM are shown. A one-way analysis of variance with a Dunnett post-test was used to compare the individual groups with control hamsters (*P < 0·05).
Figure 3
Figure 3
Hantavirus infection results in immune cell expansion. Hamsters inoculated with Sin Nombre virus (SNV) or Andes virus (ANDV), or Dulbecco's modified Eagle's medium (DMEM; control) were euthanized 11 days post-infection (dpi). (a) Whole blood was used to measure immune cell parameters by haematology (WBC, white blood cells; NE, neutrophils; LY, lymphocytes; MO, macrophages; EO, eosinophils; BA, basophils). (b) Single-cell suspensions were prepared from the spleens and cells were counted after red blood cell lysis. The cells were then stained for CD4, CD8 and MHC II expression using fluorescently conjugated antibodies, and absolute numbers of these cell types were measured using flow cytometry. Bars represent the mean and standard deviation of six hamsters per group.
Figure 4
Figure 4
T-cell depletion is efficacious and inhibits specific B-cell responses. Groups of six hamsters were given CD4-depleting and CD8-depleting antibodies, or isotype control antibodies 2 days before inoculation with Andes virus (ANDV) or Sin Nombre virus (SNV), or mock infection (Dulbecco's modified Eagle's medium; DMEM). (a, b) Single-cell suspensions were prepared from the spleens 11 days post-infection (dpi) and stained with fluorescently conjugated anti-CD4 and anti-CD8 antibodies and analysed by flow cytometry. (a) Representative panels showing CD4 and CD8 staining for isotype control and T-cell-depleted hamsters 11 dpi. (b) The depletion efficiency was determined by flow cytometry and expressed as the per cent of CD4 or CD8 cells in the spleens of animals 11 dpi (13 days post-depletion). (c) Hamsters were given either isotype control or anti-CD4 and anti-CD8 antibodies 2 days before inoculation with SNV. Hamsters were bled 28 dpi and the sera were tested for the presence of anti-SNV N-specific antibodies by ELISA. Sera from uninfected hamsters were used as controls.
Figure 5
Figure 5
T-cell depletion does not influence survival or virus replication. Groups of six hamsters were given CD4-depleting and CD8-depleting antibodies, or isotype control antibodies 2 days before inoculation with Andes virus (ANDV) or Sin Nombre virus (SNV). (a) Hamsters were monitored for signs of disease and survival following depletion and hantavirus infection. (b) Total RNA was extracted from lung tissue of hamsters 11 days post-infection (dpi) (ANDV and SNV) and 28 dpi (SNV only), and virus-specific RNA was quantified by quantitative reverse transcription-PCR. Data are represented as the mean and standard deviation of six animals per group.
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