title: Leukotriene C4 increases the susceptibility of adult mice to Shiga toxin-producing Escherichia coli infection.
abstract: Shiga toxin-producing Escherichia coli (STEC) is a food-borne pathogen that causes hemorrhagic colitis. Under some circumstances, Shiga toxin (Stx) produced within the intestinal tract enters the bloodstream, leading to systemic complications that may cause the potentially fatal hemolytic-uremic syndrome (HUS). Despite STEC human infection is characterized by acute inflammation of the colonic mucosa, little is known regarding the role of proinflammatory mediators like cysteine leukotrienes (cysLTs) in this pathology. Thus, the aim of this work was to analyze whether leukotriene C4 (LTC4) influences STEC pathogenesis in mice. We report that exogenous LTC4 pretreatment severely affected the outcome of STEC gastrointestinal infection. LTC4-pretreated (LTC4+) and STEC-infected (STEC+) mice showed an increased intestinal damage by histological studies, and a decreased survival compared to LTC4-non-pretreated (LTC4-) and STEC+ mice. LTC4+/STEC+ mice that died after the infection displayed neutrophilia and high urea levels, indicating that the cause of death was related to Stx2-toxicity. Despite the differences observed in the survival between LTC4+ and LTC4- mice after STEC infection, both groups showed the same survival after Stx2-intravenous inoculation. In addition, LTC4 pretreatment increased the permeability of mucosal intestinal barrier, as assessed by FITC-dextran absorption experiments. Altogether these results suggest that LTC4 detrimental effect on STEC infection is related to the increased passage of pathogenic factors to the bloodstream. Finally, we showed that STEC infection per se increases the endogenous LTC4 levels in the gut, suggesting that this inflammatory mediator plays a role in the pathogenicity of STEC infection in mice, mainly by disrupting the mucosal epithelial barrier.
authors.affiliation: Laboratorio de Patogénesis e Inmunología de Procesos Infecciosos, Instituto de Medicina Experimental (IMEX-CONICET), Academia Nacional de Medicina, Buenos Aires, Argentina. Electronic address: galt132000@gmail.com.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Cabrera
authors.affiliation: Laboratorio de Patogénesis e Inmunología de Procesos Infecciosos, Instituto de Medicina Experimental (IMEX-CONICET), Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: Romina J
authors.initials: RJ
authors.lastname: Fernández-Brando
authors.affiliation: Laboratorio de Patogénesis e Inmunología de Procesos Infecciosos, Instituto de Medicina Experimental (IMEX-CONICET), Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: María Pilar
authors.initials: MP
authors.lastname: Mejías
authors.affiliation: Laboratorio de Patogénesis e Inmunología de Procesos Infecciosos, Instituto de Medicina Experimental (IMEX-CONICET), Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: María Victoria
authors.initials: MV
authors.lastname: Ramos
authors.affiliation: Laboratorio de Patogénesis e Inmunología de Procesos Infecciosos, Instituto de Medicina Experimental (IMEX-CONICET), Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: María Jimena
authors.initials: MJ
authors.lastname: Abrey-Recalde
authors.affiliation: Departamento de Patología, Centro de Estudios Oncológicos, Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: Silvia
authors.initials: S
authors.lastname: Vanzulli
authors.affiliation: Laboratorio de Inmunología Oncológica, Instituto de Medicina Experimental (IMEX-CONICET), Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: Mónica
authors.initials: M
authors.lastname: Vermeulen
authors.affiliation: Laboratorio de Patogénesis e Inmunología de Procesos Infecciosos, Instituto de Medicina Experimental (IMEX-CONICET), Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: Marina S
authors.initials: MS
authors.lastname: Palermo
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004927:Escherichia coli Infections / Q000150:complications* / Q000276:immunology / Q000382:microbiology; D006463:Hemolytic-Uremic Syndrome / Q000382:microbiology* / Q000473:pathology*; D007422:Intestines / Q000473:pathology; D017997:Leukotriene C4 / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D054323:Shiga-Toxigenic Escherichia coli / Q000472:pathogenicity*; D016019:Survival Analysis
chemical_list: D017997:Leukotriene C4
keywords: Leukotriene C4; STEC; Shiga toxin; hemolytic uremic syndrome