Deficiency of lung-specific claudin-18 leads to aggravated infection with Cryptococcus deneoformans through dysregulation of the microenvironment in lungs

Ko Sato, Ikumi Matsumoto, Koya Suzuki, Atsushi Tamura, Aki Shiraishi, Hiroshi Kiyonari, Jun Kasamatsu, Hideki Yamamoto, Tomomitsu Miyasaka, Daiki Tanno, Anna Miyahara, Tong Zong, Takafumi Kagesawa, Akiho Oniyama, Kotone Kawamura, Yuki Kitai, Aya Umeki, Emi Kanno, Hiromasa Tanno, Keiko IshiiSachiko Tsukita, Kazuyoshi Kawakami

Research output: Contribution to journalArticlepeer-review

Abstract

Cryptococcus 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.

Original languageEnglish
Article number21110
JournalScientific reports
Volume11
Issue number1
DOIs
Publication statusPublished - 2021 Dec

ASJC Scopus subject areas

  • General

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