Broad protective vaccination against systemic Escherichia coli with autotransporter antigens.

Autor: Xing, Yikun, Clark, Justin R., Chang, James D., Chirman, Dylan M., Green, Sabrina, Zulk, Jacob J., Jelinski, Joseph, Patras, Kathryn A., Maresso, Anthony W.
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Zdroj: PLoS Pathogens; 2/17/2023, Vol. 18 Issue 2, p1-31, 31p
Abstrakt: Extraintestinal pathogenic Escherichia coli (ExPEC) is the leading cause of adult life-threatening sepsis and urinary tract infections (UTI). The emergence and spread of multidrug-resistant (MDR) ExPEC strains result in a considerable amount of treatment failure and hospitalization costs, and contribute to the spread of drug resistance amongst the human microbiome. Thus, an effective vaccine against ExPEC would reduce morbidity and mortality and possibly decrease carriage in healthy or diseased populations. A comparative genomic analysis demonstrated a gene encoding an invasin-like protein, termed sinH, annotated as an autotransporter protein, shows high prevalence in various invasive ExPEC phylogroups, especially those associated with systemic bacteremia and UTI. Here, we evaluated the protective efficacy and immunogenicity of a recombinant SinH-based vaccine consisting of either domain-3 or domains-1,2, and 3 of the putative extracellular region of surface-localized SinH. Immunization of a murine host with SinH-based antigens elicited significant protection against various strains of the pandemic ExPEC sequence type 131 (ST131) as well as multiple sequence types in two distinct models of infection (colonization and bacteremia). SinH immunization also provided significant protection against ExPEC colonization in the bladder in an acute UTI model. Immunized cohorts produced significantly higher levels of vaccine-specific serum IgG and urinary IgG and IgA, findings consistent with mucosal protection. Collectively, these results demonstrate that autotransporter antigens such as SinH may constitute promising ExPEC phylogroup-specific and sequence-type effective vaccine targets that reduce E. coli colonization and virulence. Author summary: Extraintestinal pathogenic Escherichia coli is the leading cause of adult life-threatening sepsis and urinary tract infections. A vaccine against E. coli is essential to both prevent the spread to susceptible hosts and reduce death and disease. Using a comprehensive computational virulome and metagenomics approach, we identified a surface-exposed, pathogen-specific autotransporter protein, SinH, as a potential vaccine candidate for E. coli infection. The known virulence functions of autotransporters include adhesion, aggregation, and invasion, all critical functions for systemic dissemination, thus highlighting their potential as prophylactic vaccines. We found that vaccination with SinH-based recombinant antigens is sufficient to elicit a broad protective immunity against colonization, bacteremia, and acute urinary tract infection while also lowering the risk of translocation from the intestinal tract. Induction of both systemic and mucosal antibodies likely play a role in protection against infection. The targeting of autotransporters shows promise to combat the increasing global burden caused by multi-drug resistant pathogens, especially against highly pleiotropic bacteria such as Escherichia coli. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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