The absence of murine cathelicidin-related antimicrobial peptide impacts host responses enhancing Salmonella enterica serovar Typhimurium infection

Abstract

AbstractBackgroundCathelicidins are a class of antimicrobial peptide, and the murine cathelicidin-related antimicrobial peptide (mCRAMP) has been demonstrated in vitro to impairSalmonella entericaserovar Typhimurium proliferation. However, the impact of mCRAMP on host responses and the microbiota followingS.Typhimurium infection has not been determined. In this study mCRAMP−/−and mCRAMP+/+mice (± streptomycin) were orally inoculated withS. entericaserovar Typhimurium DT104 (SA +), and impacts on the host and enteric bacterial communities were temporally evaluated.ResultsHigher densities of the pathogen were observed in cecal digesta and associated with mucosa in SA+/mCRAMP−/−mice that were pretreated (ST+) and not pretreated (ST−) with streptomycin at 24 h post-inoculation (hpi). Both SA+/ST+/mCRAMP−/−and SA+/ST−/mCRAMP−/−mice were more susceptible to infection exhibiting greater histopathologic changes (e.g. epithelial injury, leukocyte infiltration, goblet cell loss) at 48 hpi. Correspondingly, immune responses in SA+/ST+/mCRAMP–/−and SA+/ST−/mCRAMP–/−mice were affected (e.g.Ifnγ, Kc, Inos, Il1β, RegIIIγ). Systemic dissemination of the pathogen was characterized by metabolomics, and the liver metabolome was affected to a greater degree in SA+/ST+/mCRAMP–/−and SA+/ST−/mCRAMP–/−mice (e.g. taurine, cadaverine). Treatment-specific changes to the structure of the enteric microbiota were associated with infection and mCRAMP deficiency, with a higher abundance ofEnterobacteriaceaeandVeillonellaceaeobserved in infected null mice. The microbiota of mice that were administered the antibiotic and infected withSalmonellawas dominated byProteobacteria.ConclusionThe study findings showed that the absence of mCRAMP modulated both host responses and the enteric microbiota enhancing local and systemic infection bySalmonellaTyphimurium.