Abstract
Swine influenza is an acute respiratory disease in pigs caused by swine influenza virus (SIV). Highly virulent SIV strains cause mortality of up to 10%. Importantly, pigs have long been considered “mixing vessels” that generate novel influenza viruses with pandemic potential, a constant threat to public health. Since its emergence in 2009 and subsequent pandemic spread, the pandemic (H1N1) 2009 (H1N1pdm) has been detected in pig farms, creating the risk of generating new reassortants and their possible infection of humans. Pathogenesis in SIV or H1N1pdm-infected pigs remains poorly characterized. Proinflammatory and antiviral cytokine responses are considered correlated with the intensity of clinical signs, and swine macrophages are found to be indispensible in effective clearance of SIV from pig lungs. In this study, we report a unique pattern of cytokine responses in swine macrophages infected with H1N1pdm. The roles of mitogen-activated protein (MAP) kinases in the regulation of the host responses were examined. We found that proinflammatory cytokines IL-6, IL-8, IL-10, and TNF-α were significantly induced and their induction was ERK1/2-dependent. IFN-β and IFN-inducible antiviral Mx and 2′5′-OAS were sharply induced, but the inductions were effectively abolished when ERK1/2 was inhibited. Induction of CCL5 (RANTES) was completely inhibited by inhibitors of ERK1/2 and JNK1/2, which appeared also to regulate FasL and TNF-α, critical for apoptosis in pig macrophages. We found that NFκB was activated in H1N1pdm-infected cells, but the activation was suppressed when ERK1/2 was inhibited, indicating there is cross-talk between MAP kinase and NFκB responses in pig macrophages. Our data suggest that MAP kinase may activate NFκB through the induction of RIG-1, which leads to the induction of IFN-β in swine macrophages. Understanding host responses and their underlying mechanisms may help identify venues for effective control of SIV and assist in prevention of future influenza pandemics.
Highlights
Swine influenza is an acute respiratory disease caused by swine influenza viruses (SIV)
To examine the susceptibility of pig macrophages to H1N1pdm originating from a human host, we infected 3D/4 cells with the A/ Nanjing/108/2009 (H1N1)
Typical cytopathic effect (CPE) appeared 16 hrs post infection and the cell monolayer was destroyed 32 hrs post infection (Fig. 1A). This result demonstrated that H1N1pdm retains the ability to infect and replicate in swine macrophages, and can reach 1.86104 PFU/ml as shown in a replicative curve (Fig. 1B)
Summary
Swine influenza is an acute respiratory disease caused by swine influenza viruses (SIV). Pigs have long been considered to be the intermediate host of various subtype viruses and ‘‘mixing vessels’’ for the evolution and genesis of influenza viruses with pandemic potential because of their susceptibility to swine, avian, and human influenza viruses [4,5,6]. This broad susceptibility is due to the presence of both sialic acid (SA) Gal- and SA2,6-Gal receptors present in the respiratory epithelium. Effective control of circulating influenza viruses in swine populations is key to reducing consequent genesis of novel pandemic strains that threaten the health of both humans and animals
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