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Tissue kallikrein regulates alveolar macrophage apoptosis early in influenza virus infection

Abstract : Host cell proteases are involved in influenza pathogenesis. We examined the role of tissue kallikrein 1 (KLK1) by comparing wild-type (WT) and KLK1-deficient mice infected with influenza H3N2 virus. The levels of KLK1 in lung tissue and in bronchoalveolar lavage (BAL) fluid increased substantially during infection. KLK1 did not promote virus infectivity despite its trypsin-like activity, but it did decrease the initial virus load. We examined two cell types involved in the early control of pathogen infections, alveolar macrophages (AMs) and natural killer (NK) cells to learn more about the antiviral action of KLK1. Inactivating the Klk1 gene or treating WT mice with an anti-KLK1 monoclonal antibody to remove KLK1 activity accelerated the initial virus-induced apoptotic depletion of AMs. Intranasal instillation of deficient mice with recombinant KLK1 (rKLK1) reversed the phenotype. The levels of granulocyte-macrophage colony-stimulating factor in infected BAL fluid were significantly lower in KLK1-deficient mice than in WT mice. Treating lung epithelial cells with rKLK1 increased secretion of this factor known to enhance AM resistance to pathogen-induced apoptosis. The recruitment of NK cells to the air spaces peaked 3 days after infection in WT mice but not in KLK1-deficient mice, as did increases in several NK-attracting chemokines (CCL2, CCL3, CCL5, and CXCL10) in BAL. Chronic obstructive pulmonary disease (COPD) patients are highly susceptible to viral infection, and we observed that the KLK1 mRNA levels decreased with increasing COPD severity. Our findings indicate that KLK1 intervenes early in the antiviral defense modulating the severity of influenza infection. Decreased KLK1 expression in COPD patients could contribute to the worsening of influenza.
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Submitted on : Wednesday, January 19, 2022 - 2:27:49 PM
Last modification on : Tuesday, May 17, 2022 - 10:58:35 AM

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Melia Magnen, Fabien Gueugnon, Agnès Petit-Courty, Thomas Baranek, Damien Sizaret, et al.. Tissue kallikrein regulates alveolar macrophage apoptosis early in influenza virus infection. American Journal of Physiology - Lung Cellular and Molecular Physiology, American Physiological Society, 2019, 316 (6), pp.L1127-L1140. ⟨10.1152/ajplung.00379.2018⟩. ⟨hal-03534467⟩

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