Emerging roles for ABC transporters as virulence factors in uropathogenic Escherichia coli .

Autor:	Shea AE; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109., Forsyth VS; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109., Stocki JA; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109., Mitchell TJ; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109., Frick-Cheng AE; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109., Smith SN; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109., Hardy SL; Department of Microbiology and Immunology, College of Medicine, University of South Alabama, Mobile, AL 36688., Mobley HLT; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Apr 16; Vol. 121 (16), pp. e2310693121. Date of Electronic Publication: 2024 Apr 12.
DOI:	10.1073/pnas.2310693121
Abstrakt:	Urinary tract infections (UTI) account for a substantial financial burden globally. Over 75% of UTIs are caused by uropathogenic Escherichia coli (UPEC), which have demonstrated an extraordinarily rapid growth rate in vivo. This rapid growth rate appears paradoxical given that urine and the human urinary tract are relatively nutrient-restricted. Thus, we lack a fundamental understanding of how uropathogens propel growth in the host to fuel pathogenesis. Here, we used large in silico, in vivo, and in vitro screens to better understand the role of UPEC transport mechanisms and their contributions to uropathogenesis. In silico analysis of annotated transport systems indicated that the ATP-binding cassette (ABC) family of transporters was most conserved among uropathogenic bacterial species, suggesting their importance. Consistent with in silico predictions, we determined that the ABC family contributed significantly to fitness and virulence in the urinary tract: these were overrepresented as fitness factors in vivo (37.2%), liquid media (52.3%), and organ agar (66.2%). We characterized 12 transport systems that were most frequently defective in screening experiments by generating in-frame deletions. These mutant constructs were tested in urovirulence phenotypic assays and produced differences in motility and growth rate. However, deletion of multiple transport systems was required to achieve substantial fitness defects in the cochallenge murine model. This is likely due to genetic compensation among transport systems, highlighting the centrality of ABC transporters in these organisms. Therefore, these nutrient uptake systems play a concerted, critical role in pathogenesis and are broadly applicable candidate targets for therapeutic intervention. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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