α-Hemolysin promotes uropathogenic E. coli persistence in bladder epithelial cells via abrogating bacteria-harboring lysosome acidification

Manisha Naskar, Viraj P. Parekh, Mathew A. Abraham, Zehra Alibasic, Min Jung Kim, Gyeongseo Suk, Joo Hwan Noh, Kwan Young Ko, Joonha Lee, Chungho Kim, Hana Yoon, Soman N. Abraham, Hae Woong Choi

Research output: Contribution to journalArticlepeer-review

Abstract

There is a growing consensus that a significant proportion of recurrent urinary tract infections are linked to the persistence of uropathogens within the urinary tract and their re-emergence upon the conclusion of antibiotic treatment. Studies in mice and human have revealed that uropathogenic Escherichia coli (UPEC) can persist in bladder epithelial cells (BECs) even after the apparent resolution of the infection. Here, we found that, following the entry of UPEC into RAB27b+ fusiform vesicles in BECs, some bacteria escaped into the cytoplasmic compartment via a mechanism involving hemolysin A (HlyA). However, these UPEC were immediately recaptured within LC3A/B+ autophagosomes that matured into LAMP1+ autolysosomes. Thereafter, HlyA+ UPEC-containing lysosomes failed to acidify, which is an essential step for bacterial elimination. This lack of acidification was related to the inability of bacteria-harboring compartments to recruit V-ATPase proton pumps, which was attributed to the defragmentation of cytosolic microtubules by HlyA. The persistence of UPEC within LAMP1+ compartments in BECs appears to be directly linked to HlyA. Thus, through intravesicular instillation of microtubule stabilizer, this host defense response can be co-opted to reduce intracellular bacterial burden following UTIs in the bladder potentially preventing recurrence.

Original languageEnglish
Article numbere1011388
JournalPLoS Pathogens
Volume19
Issue number5
DOIs
StatePublished - May 2023

Bibliographical note

Funding Information:
Funding:Thisworkwassupportedbythefollowing grants;theNationalResearchFoundationofKorea grant(NRF-2020R1C1C1003257)toHWC,theUS NationalInstitutesofHealthgrant(K12DK100024) toHWC,theinternalgrantofKoreaUniversityto HWC,andtheUSNationalInstitutesofHealth grants(R01DK121032andR01DK121969)to SNA.Thefundershadnoroleinstudydesign,data collectionandanalysis,decisiontopublish,or preparationofthemanuscript.

Funding Information:
This work was supported by the following grants; the National Research Foundation of Korea grant (NRF-2020R1C1C1003257) to HWC, the US National Institutes of Health grant (K12DK100024) to HWC, the internal grant of Korea University to HWC, and the US National Institutes of Health grants (R01DK121032 and R01DK121969) to SNA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
Copyright: © 2023 Naskar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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