Author:
Sato Ko,Matsumoto Ikumi,Suzuki Koya,Tamura Atsushi,Shiraishi Aki,Kiyonari Hiroshi,Kasamatsu Jun,Yamamoto Hideki,Miyasaka Tomomitsu,Tanno Daiki,Miyahara Anna,Zong Tong,Kagesawa Takafumi,Oniyama Akiho,Kawamura Kotone,Kitai Yuki,Umeki Aya,Kanno Emi,Tanno Hiromasa,Ishii Keiko,Tsukita Sachiko,Kawakami Kazuyoshi
Abstract
AbstractCryptococcus deneoformans is an opportunistic fungal pathogen that infects the lungs via airborne transmission and frequently causes fatal meningoencephalitis. Claudins (Cldns), a family of proteins with 27 members found in mammals, form the tight junctions within epithelial cell sheets. Cldn-4 and 18 are highly expressed in airway tissues, yet the roles of these claudins in respiratory infections have not been clarified. In the present study, we analyzed the roles of Cldn-4 and lung-specific Cldn-18 (luCldn-18) in host defense against C. deneoformans infection. luCldn-18-deficient mice exhibited increased susceptibility to pulmonary infection, while Cldn-4-deficient mice had normal fungal clearance. In luCldn-18-deficient mice, production of cytokines including IFN-γ was significantly decreased compared to wild-type mice, although infiltration of inflammatory cells including CD4+ T cells into the alveolar space was significantly increased. In addition, luCldn-18 deficiency led to high K+ ion concentrations in bronchoalveolar lavage fluids and also to alveolus acidification. The fungal replication was significantly enhanced both in acidic culture conditions and in the alveolar spaces of luCldn-18-deficient mice, compared with physiological pH conditions and those of wild-type mice, respectively. These results suggest that luCldn-18 may affect the clinical course of cryptococcal infection indirectly through dysregulation of the alveolar space microenvironment.
Funder
Ministry of Education, Culture, Sports, Science and Technology
MSD Life Science Foundation, Public Interest Incorporated Foundation
Japan Agency for Medical Research and Development
Strategic International Collaborative Research Program
Chiba University
Publisher
Springer Science and Business Media LLC
Cited by
8 articles.
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