title: Cathepsin L Helps to Defend Mice from Infection with Influenza A.
abstract: Host-derived proteases can augment or help to clear infections. This dichotomy is exemplified by cathepsin L (CTSL), which helps Hendra virus and SARS coronavirus to invade cells, but is essential for survival in mice with mycoplasma pneumonia. The present study tested the hypothesis that CTSL protects mice from serious consequences of infection by the orthomyxovirus influenza A, which is thought to be activated by host-supplied proteases other than CTSL. Ctsl-/- mice infected with influenza A/Puerto Rico/8/34(H1N1) had larger lung viral loads and higher mortality than infected Ctsl+/+ mice. Lung inflammation in surviving infected mice peaked 14 days after initial infection, accompanied marked focal distal airway bronchiolization and epithelial metaplasia followed by desquamation and fibrotic interstitial remodeling, and persisted for at least 6 weeks. Most deaths occurred during the second week of infection in both groups of mice. In contrast to mycoplasma pneumonia, infiltrating cells were predominantly mononuclear rather than polymorphonuclear. The histopathology of lung inflammation and remodeling in survivors was similar in Ctsl-/- and Ctsl+/+ mice, although Ctsl+/+ mice cleared immunoreactive virus sooner. Furthermore, Ctsl-/- mice had profound deficits in CD4+ lymphocytes before and after infection and weaker production of pathogen-specific IgG. Thus, CTSL appears to support innate as well as adaptive responses, which confer a survival advantage on mice infected with the orthomyxovirus influenza A.
authors.affiliation: Department of Medicine, University of California at San Francisco, San Francisco, California, United States of America.
authors.forename: Xiang
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Medicine, University of California at San Francisco, San Francisco, California, United States of America.|Veterans Affairs Medical Center, San Francisco, California, United States of America.
authors.forename: John R
authors.initials: JR
authors.lastname: Greenland
authors.affiliation: Department of Medicine, University of California at San Francisco, San Francisco, California, United States of America.|Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California, United States of America.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Gotts
authors.affiliation: Department of Medicine, University of California at San Francisco, San Francisco, California, United States of America.|Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
authors.affiliation: Department of Medicine, University of California at San Francisco, San Francisco, California, United States of America.|Veterans Affairs Medical Center, San Francisco, California, United States of America.|Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California, United States of America.
authors.forename: George H
authors.initials: GH
authors.lastname: Caughey
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D056668:Cathepsin L / Q000494:pharmacology*; D005260:Female; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects*; D008168:Lung / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000188:drug therapy*; D011014:Pneumonia / Q000188:drug therapy / Q000821:virology
chemical_list: D056668:Cathepsin L