Tissue kallikrein regulates alveolar macrophage apoptosis early in influenza virus infection

• Published in: American journal of physiology. Lung cellular and molecular physiology 2019-06, Vol.316 (6), p.L1127-L1140
• Main Authors: Magnen, Melia, Gueugnon, Fabien, Petit-Courty, Agnès, Baranek, Thomas, Sizaret, Damien, Brewah, Yambasu A, Humbles, Alison A, Si-Tahar, Mustapha, Courty, Yves
• Format: Article
• Language: English
• Subjects: A549 Cells; Acute Lung Injury - pathology; Acute Lung Injury - virology; Alveoli; Animals; Antiviral activity; Apoptosis; Apoptosis - physiology; Bronchus; CCL3 protein; Cell Line; Cellular Biology; Chemokine CCL2 - metabolism; Chemokine CCL3 - metabolism; Chemokine CCL5 - metabolism; Chemokine CXCL10 - metabolism; Chemokines; Chronic infection; Chronic obstructive pulmonary disease; Colony-stimulating factor; CXCL10 protein; Depletion; Dogs; Epithelial cells; Granulocyte-macrophage colony stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - analysis; Humans; Infections; Infectivity; Influenza; Influenza A Virus, H3N2 Subtype; Kallikrein; Killer Cells, Natural - immunology; KLK1 gene; Life Sciences; Lung diseases; Macrophages; Macrophages, Alveolar - pathology; Madin Darby Canine Kidney Cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiology and Parasitology; Monoclonal antibodies; Monocyte chemoattractant protein 1; mRNA; Natural killer cells; Obstructive lung disease; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - pathology; Pathogenesis; Pathogens; Phenotypes; Pulmonary Disease, Chronic Obstructive - pathology; Pulmonary Disease, Chronic Obstructive - virology; Respiratory Mucosa - metabolism; Rodents; Tissue Kallikreins - antagonists & inhibitors; Tissue Kallikreins - genetics; Tissue Kallikreins - metabolism; Tissues; Trypsin; Viral infections; Viruses
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00379.2018

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 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 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.