Abstract
New influenza A viruses that emerge frequently elicit composite inflammatory responses to both infection and structural damage of alveolar-capillary barrier cells that hinders regeneration of respiratory function. The host factors that relinquish restoration of lung health to enduring lung injury are insufficiently understood. Here, we investigated the role of endophilin B2 (B2) in susceptibility to severe influenza infection. WT and B2-deficient mice were infected with H1N1 PR8 by intranasal administration and course of influenza pneumonia, inflammatory, and tissue responses were monitored over time. Disruption of B2 enhanced recovery from severe influenza infection as indicated by swift body weight recovery and significantly better survival of endophilin B2-deficient mice compared to WT mice. Compared to WT mice, the B2-deficient lungs exhibited induction of genes that express surfactant proteins, ABCA3, GM-CSF, podoplanin, and caveolin mRNA after 7 days, temporal induction of CCAAT/enhancer binding protein CEBPα, β, and δ mRNAs 3–14 days after infection, and differences in alveolar extracellular matrix integrity and respiratory mechanics. Flow cytometry and gene expression studies demonstrated robust recovery of alveolar macrophages and recruitment of CD4+ lymphocytes in B2-deficient lungs. Targeting of endophilin B2 alleviates adverse effects of IAV infection on respiratory and immune cells enabling restoration of alveolar homeostasis.
Highlights
Pathogenic influenza A virus (IAV) strains that arise frequently by mutation or re-assortment of the viral genome have persistently caused seasonal epidemics, regional zoonotic infections, and periodic global pandemics with high morbidity and mortality for centuries[1, 2]
To investigate the role of endophilin B2 in IAV infection, WT and B2-deficient mice (B2−/−) were infected with 1000 ffc of the influenza H1N1 PR8 strain and severity of influenza was assessed by comparing body weight, survival and viral burden over time (Fig. 1)
IAV is capable of infecting multiple resident and incoming inflammatory cells[3,4,5,6,7,8, 45, 46] that contribute to the complex pathogenesis of the infection
Summary
Pathogenic influenza A virus (IAV) strains that arise frequently by mutation or re-assortment of the viral genome have persistently caused seasonal epidemics, regional zoonotic infections, and periodic global pandemics with high morbidity and mortality for centuries[1, 2]. Pathogenic IAV strains disrupt endothelial and epithelial tight junctions[4], enhancing microvascular permeability and leakage of fluid into air sacs, and perturb surfactant lipid and protein metabolism[3] by alveolar type II epithelial cells increasing surface tension at the air-liquid interface. A better understanding of the host factors that contribute to IAV pathogenicity is crucial for the development of therapies that prevent pneumonia and intractable lung injury from IAV infection. B2 dimerizes with its better known paralog endophilin B1(B1), which promotes mitochondrial apoptosis[16, 17], autophagosome formation[18], endocytic degradation of growth factor receptors[19], and adipose tissue lipid metabolism and insulin resistance[20]. The results identify endophilin B2 as a novel host factor that promotes IAV pathogenicity in vivo
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