Abstract
Avian influenza A/H7N9 virus infection causes pneumonia in humans with a high case fatality rate. However, virus-induced modulation of immune responses is being recognized increasingly as a factor in the pathogenesis of this disease. In this study, we compared the pathogenicity of A/H7N9 infection in BALB/c and C57BL/6 mouse models, and investigated the putative involvement of proinflammatory cytokines in lung injury and viral clearance. In both mouse strains, A/Anhui/1/2013(H7N9) infection with 106 TCID50 resulted in viral replication in lung, severe body weight loss and acute lung injury. During the early infection stage, infected C57BL/6 mice exhibited more severe lung injury, slower recovery from lung damage, less effective viral clearance, higher levels of interlukine (IL)-6, monocyte chemotactic protein (MCP)-1, and IL-1β, and lower levels of tumor necrosis factor (TNF)-α and interferon (IFN)-γ than infected BALB/c mice. These results suggest that TNF-α and IFN-γ may help suppress viral gene expression and increase viral clearance, and that IL-6 and MCP-1 may contribute to lung injury in A/H7N9-infected individuals. In addition, lung damage and the distribution of virus antigen in tissues were similar in young and middle-aged mice. These results suggest that the more serious lung injury in middle-aged or older H7N9 cases is not mainly caused by differences in viral replication in the lung but probably by a dysregulated immune response induced by underlying comorbidities. These results indicate that the extent of dysregulation of the host immune response after H7N9 virus infection most probably determines the outcome of H7N9 virus infection.
Highlights
During March 2013, a novel avian influenza A/H7N9 virus was identified in Shanghai and Anhui, China [1]
Zhou et al [7] found that the levels of inducible protein 10 (IP-10), monokine induced by c interferon (MIG), macrophage inflammatory protein 1 beta (MIP1b), monocyte chemotactic protein (MCP)-1, IL-6, IL-8 and IFN-a were significantly higher in patients with A/H7N9 than in healthy subject controls
Lung injury in A/H7N9-infected C57BL/6 and BALB/c mice To determine whether the pathogenicity H7N9 virus infection differed between mouse strains, healthy 6-week-old C57BL/6 and BALB/c mice were infected i.n. with 106 TCID50 of AH/1/H7N9 virus
Summary
During March 2013, a novel avian influenza A/H7N9 virus was identified in Shanghai and Anhui, China [1]. Chi et al [5] reported that the serum concentrations of IFNc-inducible protein 10 (IP-10), IL-6, IL-17, and IL-2 were significantly higher in A/H7N9-infected patients than in normal individuals and that those of IP-10 and IL-6 were much higher in severe A/H7N9 patients than in non-sever patients. Zhou et al [7] found that the levels of IP-10, monokine induced by c interferon (MIG), macrophage inflammatory protein 1 beta (MIP1b), MCP-1, IL-6, IL-8 and IFN-a were significantly higher in patients with A/H7N9 than in healthy subject controls. Mok et al [8] reported that A/H7N9-infected BALB/c mice exhibited mild, selflimited disease with higher lung titers of H7N9 virus and higher serum levels of several proinflammatory cytokines and chemokines during the early stage of viral infection. The cytokines potentially involved in lung injury and viral clearance are not known
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