한빛사 논문
Chang Hyun Songa,1, Young Ho Kimb,1, Manisha Naskara, Byron W. Hayesc, Mathew A. Abrahamc, Joo Hwan Noha, Gyeongseo Suka, Min Jung Kima, Kyu Sang Choa, Minhye Shind, Eun-Jin Leea, Soman N. Abrahamc,e,f, and Hae Woong Choia,2
aDivision of Life Sciences, Korea University, Seoul, 02841, South Korea; bDepartment of Urology, Soonchunhyang University Bucheon Hospital, Bucheon-si, 14584, South Korea; cDepartment of Pathology, Duke University Medical Center, Durham, NC 27710; dDepartment of Microbiology, Inha University School of Medicine, Incheon, 22212, South Korea; eDepartment of Immunology, Duke University Medical Center, Durham, NC 27710; and fMolecular Genetics & Microbiology, Duke University Medical Center, Durham, NC 27710
1C.H.S. and Y.H.K. contributed equally to this work.
2To whom correspondence may be addressed.
Abstract
Many urinary tract infections (UTIs) are recurrent because uropathogens persist within the bladder epithelial cells (BECs) for extended periods between bouts of infection. Because persistent uropathogens are intracellular, they are often refractive to antibiotic treatment. The recent discovery of endogenous Lactobacillus spp. in the bladders of healthy humans raised the question of whether these endogenous bacteria directly or indirectly impact intracellular bacterial burden in the bladder. Here, we report that in contrast to healthy women, female patients experiencing recurrent UTIs have a bladder population of Lactobacilli that is markedly reduced. Exposing infected human BECs to L. crispatus in vitro markedly reduced the intracellular uropathogenic Escherichia coli (UPEC) load. The adherence of Lactobacilli to BECs was found to result in increased type I interferon (IFN) production, which in turn enhanced the expression of cathepsin D within lysosomes harboring UPECs. This lysosomal cathepsin D–mediated UPEC killing was diminished in germ-free mice and type I IFN receptor–deficient mice. Secreted metabolites of L. crispatus seemed to be responsible for the increased expression of type I IFN in human BECs. Intravesicular administration of Lactobacilli into UPEC-infected murine bladders markedly reduced their intracellular bacterial load suggesting that components of the endogenous microflora can have therapeutic effects against UTIs.
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