Abstract
BackgroundCathelicidins are a class of antimicrobial peptide, and the murine cathelicidin-related antimicrobial peptide (mCRAMP) has been demonstrated in vitro to impair Salmonella enterica serovar Typhimurium proliferation. However, the impact of mCRAMP on host responses and the microbiota following S. Typhimurium infection has not been determined. In this study mCRAMP−/− and mCRAMP+/+ mice (± streptomycin) were orally inoculated with S. enterica serovar 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 of Enterobacteriaceae and Veillonellaceae observed in infected null mice. The microbiota of mice that were administered the antibiotic and infected with Salmonella was dominated by Proteobacteria.ConclusionThe study findings showed that the absence of mCRAMP modulated both host responses and the enteric microbiota enhancing local and systemic infection by Salmonella Typhimurium.
Highlights
Cathelicidins are a class of antimicrobial peptide, and the murine cathelicidin-related antimicrobial peptide has been demonstrated in vitro to impair Salmonella enterica serovar Typhimurium proliferation
The only cathelicidin that has been identified is the murine cathelicin-related antimicrobial peptide [10]. mCRAMP was first isolated from bone marrow and has been the focus of investigation due to the homology in gene sequence, structure, and protein processing that it shares with the human cathelicidin, LL-37/hCAP-18 [11]. mCRAMP is mainly expressed in neutrophils; its presence has been observed in the testis, lung, urinary tract, and gastrointestinal tract [10]. mCRAMP is an amphipathic α-helical structure that binds to negatively charged groups of the outer bacterial membrane, altering its structure and permeability with ensuing bactericidal activity [12]
Several studies using mCRAMP null mice have shown the role that this cathelicidin plays in the protection of skin [13], the urinary tract [14], and the gastrointestinal tract (GIT) [3]; the studies conducted in the GIT were mainly restricted to the colonic tissue, and targeted colitis incited by Candida albicans, Escherichia coli and Citrobacter rodentium [15, 16]
Summary
Cathelicidins are a class of antimicrobial peptide, and the murine cathelicidin-related antimicrobial peptide (mCRAMP) has been demonstrated in vitro to impair Salmonella enterica serovar Typhimurium proliferation. Bescucci et al Gut Pathog (2020) 12:53 characterized by an N-terminal signal peptide, a cathelin-like propeptide, and a variable C-terminal domain, which is cleaved to release the antimicrobial activity [3]. These antimicrobial peptides have been identified in mammalian species including rats [4], human beings [5], rabbits [6], monkeys [7], pigs [8], and cows [9], among others. Cathelicidins participate in modulation of immune responses, including chemoattraction of leukocytes by activation of formyl peptide receptors (FPR) [17], stimulation of degranulation [18], enhancement of phagocytosis [19], and stimulation of humoral adaptive immune responses [17]. mCRAMP has been shown to stimulate neovascularization of cutaneous wounds [20], and to play a pivotal role in maintaining homeostasis of the colonic microbiota [21]
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