Salmonella Typhimurium Diarrhea Reveals Basic Principles of Enteropathogen Infection and Disease-Promoted DNA Exchange  Sandra Y. Wotzka, Bidong D. Nguyen, Wolf-Dietrich Hardt  Cell Host & Microbe  Volume 21, Issue 4, Pages 443-454 (April 2017) DOI: 10.1016/j.chom.2017.03.009 Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 1 Three Mechanisms Contributing to CR (A) The microbiota produces inhibitory metabolites (e.g., short-chain fatty acids) and toxins like bacteriocins that inhibit enteropathogen colonization. (B) The efficient utilization of nutrients by the resident microbiota depletes the available metabolic niches for pathogens. In addition, the microbiota competes for potential binding sites on the mucus or the epithelium. (C) The stimulation of the host’s immune system can indirectly inhibit pathogen growth. The host’s epithelial cells (and/or the underlying sentinel cells of the mucosal immune system) sense microbial molecules (LPS, peptidoglycan, etc.) released by the microbiota. This boosts the secretion of mucus by goblet cells and the release of antimicrobial peptides by paneth cells, and promotes the production of secretory IgA (sIgA). These host responses may interfere with pathogen colonization. Cell Host & Microbe 2017 21, 443-454DOI: (10.1016/j.chom.2017.03.009) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 2 Stages of Gut Infection by S. Typhimurium (A) In a normal gut, CR usually prevents S. Typhimurium colonization. (B) However, in some hosts, S. Typhimurium can grow by consuming microbiota-derived molecular hydrogen (H2). (C) After reaching a critical density, S. Typhimurium invasion of the gut tissue triggers inflammation. This hinges on particular virulence factors, specifically flagella and the SPI-1- and SPI-2-encoded type III secretion systems (T3SS-1/T3SS-2), and the elicitation of an innate immune response program. (D) At later stages of infection, tissue defense is augmented by innate immune cells such as macrophages and neutrophils. The inflamed mucosa releases numerous nutrients and antimicrobial effectors, such as antimicrobial peptides (AMPs), lipocalin-2, reactive oxygen species (ROS), and reactive nitrogen species (RNS), into the gut lumen, thus fueling pathogen blooms. (E) By day 2 post-infection, pronounced inflammation can also kill off much of the gut luminal S. Typhimurium population. The underlying mechanisms are not yet fully understood. (F) Later, the remaining S. Typhimurium cells start to bloom again. Ten to fourteen days after infection, pathogen-specific secretory IgA (sIgA) is released in sufficient amounts to block further tissue invasion. (G) During remission, CR is restored and S. Typhimurium is outcompeted by the re-growing microbiota. Vaccination experiments suggest that IgA may promote pathogen elimination from the gut lumen by enforcing enchained growth. Cell Host & Microbe 2017 21, 443-454DOI: (10.1016/j.chom.2017.03.009) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 3 Additional Processes Affecting the Gut Luminal Pathogen Population (A) S. Typhimurium can successfully establish and maintain its niche in the gut for prolonged periods of time by using the type VI secretion system (T6SS) to kill commensal bacteria. (B) The administration of defined competing bacterial strains could be a promising therapeutic option to prevent intestinal colonization by S. Typhimurium. (C) Protozoans can hinder S. Typhimurium growth either by consuming the pathogen or indirectly by inhibiting the colonization through induction of IL-18. Cell Host & Microbe 2017 21, 443-454DOI: (10.1016/j.chom.2017.03.009) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 4 Gut Inflammation Boosts Horizontal Gene Transfer Horizontal gene transfer (HGT) is strongly favored in the inflamed gut. (A) In the case of plasmids, the enhanced HGT is attributable to blooms of the donor and the recipient. This allows the close physical contact required for efficient conjugation. (B) The inflammatory milieu also accelerates phage transfer. Both increased donor and recipient densities, as well as antimicrobial stimuli present in the inflamed gut, contribute to phage transfer. Inflammatory stimuli induce phage release and thereby promote lysogenic conversion. Cell Host & Microbe 2017 21, 443-454DOI: (10.1016/j.chom.2017.03.009) Copyright © 2017 Elsevier Inc. Terms and Conditions