Abstract
Avian influenza viruses (AIVs) cause major economic losses to the global poultry industry. Many host factors have been identified that act as regulators of the inflammatory response and virus replication in influenza A virus (IAV) infected cells including nucleotide-binding oligomerization domain (NOD) like receptor (NLR) family proteins. Evidence is emerging that NLRC5, the largest NLR member, is a regulator of host immune responses against invading pathogens including viruses; however, its role in the avian immune system and AIV pathogenesis has not been fully explored. In this study, we found that NLRC5 is activated by a range of low and highly pathogenic AIVs in primary chicken lung cells and a chicken macrophage cell line. Further, siRNA mediated NLRC5 knockdown in chicken macrophages resulted in a significant reduction in AIV replication which was associated with the upregulation of genes associated with activated NFκB signaling pathway. The knockdown of NLRC5 enhanced the expression of genes known to be associated with viral defense and decreased innate cytokine gene expression following AIV infection. Overall, our investigation strongly suggests that NLRC5 is a pro-viral factor during IAV infection in chicken and may contribute to pathogenesis through innate cytokine regulation. Further studies are warranted to investigate the IAV protein(s) that may regulate activation of NLRC5.
Highlights
Influenza A viruses (IAVs) continue to spread globally and have increased the potential to cause epidemics due to their wide host range and mutation frequency
To determine if members of this family are upregulated during IAV infection, microarray analysis was performed in primary chicken lung cells after infection with classical or Eurasian lineage H5N1 highly pathogenic avian influenza viruses (HPAIVs), H2N3 Low pathogenic avian influenza viruses (LPAIVs), or sterile phosphate buffered saline (PBS)
Excessive pro-inflammatory cytokine production is a major pathogenicity factor during HPAIV infection in chicken, and macrophages are the major contributors of cytokines during viral infection (Kuribayashi et al, 2013)
Summary
Influenza A viruses (IAVs) continue to spread globally and have increased the potential to cause epidemics due to their wide host range and mutation frequency. While ducks and waterfowl are considered natural reservoirs for IAVs and typically harbor asymptomatic infection, the disease in chickens can range from mild to severe or even fatal in the case of highly pathogenic avian influenza viruses (HPAIVs). In such cases, death typically occurs within 6 days, before an adaptive immune response, suggesting that innate immune mechanisms play a crucial role. While the underlying molecular mechanisms that lead to this disparate pathogenesis are not fully understood, it has been suggested that the elevation of cytokines during HPAIV infection contributes to the mortality (Karpala et al, 2011; Moulin et al, 2011) and that rapid cell death could have a protective role (Kuchipudi et al, 2012).
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