Viruses have evolved strategies to counter the host response to infection. One of these strategies is directed towards tumor necrosis factor (TNF) and TNF-mediated pathways. Poxviruses encode viral TNF receptor (vTNFR) homologs of the extracellular domain of mammalian TNFR thus allowing them to inhibit and/or interfere with the normal signalling pathway and evade host immune responses. Ectromelia virus (ECTV) is a poxvirus and a natural mouse pathogen; it causes a disease in mice that is similar to smallpox in humans. We previously showed that TNF is critical for recovery of the host from respiratory ECTV infection. Cytokine response modifier D (CrmD) is the vTNFR homolog encoded by ECTV. CrmD shares 21% and 26% amino acid sequence identity with murine TNFRI and TNFRII, respectively. It binds to TNF and neutralizes its activity in vitro.
To investigate the function of vTNFR during an infection, we compared wildtype ECTV (ECTVWT) with a deletion mutant virus lacking CrmD (ECTVΔCrmD). We found that C57BL/6 mice that are resistant to ECTVWT, succumbed to disease when infected with ECTVΔCrmD. Further, lungs from mice infected with ECTVΔCrmD showed significantly more pathology compared to lungs from mice infected with ECTVWT. Histologically, ECTVΔCrmD-induced pathology was associated with diffuse edema, necrosis of bronchial epithelium and loss of normal lung architecture. The increased susceptibility of mutant virus-infected mice was not related to increased viral load but due to dysregulation of inflammatory mediators. Our data highlights the vital role of CrmD in modulating the host response to ECTV infection and dampening immunopathology. This may function to allow the host to live long enough to permit transmission of virus from one host to the next.