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Summary Genome degradation correlates with host adaptation and systemic disease in Salmonella . Most lineages of the S. enterica subspecies Typhimurium cause gastroenteritis in humans; however, the recently emerged ST313 lineage II pathovar commonly causes systemic bacteremia in sub-Saharan Africa. ST313 lineage II displays genome degradation compared to gastroenteritis-associated lineages; yet, the mechanisms and causal genetic differences mediating these infection phenotypes are largely unknown. We find that the ST313 isolate D23580 hyperdisseminates from the gut to systemic sites, such as the mesenteric lymph nodes (MLNs), via CD11b + migratory dendritic cells (DCs). This hyperdissemination was facilitated by the loss of sseI , which encodes an effector that inhibits DC migration in gastroenteritis-associated isolates. Expressing functional SseI in D23580 reduced the number of infected migratory DCs and bacteria in the MLN. Our study reveals a mechanism linking pseudogenization of effectors with the evolution of niche adaptation in a bacterial pathogen. [ABSTRACT FROM AUTHOR]

Neuroepithelial crosstalk is critical for gut physiology. However, the mechanisms by which sensory neurons communicate with epithelial cells to mediate gut barrier protection at homeostasis and during inflammation are not well understood. Here, we find that Nav1.8+CGRP+ nociceptor neurons are juxtaposed with and signal to intestinal goblet cells to drive mucus secretion and gut protection. Nociceptor ablation led to decreased mucus thickness and dysbiosis, while chemogenetic nociceptor activation or capsaicin treatment induced mucus growth. Mouse and human goblet cells expressed Ramp1, receptor for the neuropeptide CGRP. Nociceptors signal via the CGRP-Ramp1 pathway to induce rapid goblet cell emptying and mucus secretion. Notably, commensal microbes activated nociceptors to control homeostatic CGRP release. In the absence of nociceptors or epithelial Ramp1, mice showed increased epithelial stress and susceptibility to colitis. Conversely, CGRP administration protected nociceptor-ablated mice against colitis. Our findings demonstrate a neuron-goblet cell axis that orchestrates gut mucosal barrier protection. [Display omitted] • Nav1.8+CGRP+ nociceptors neighbor goblet cells and induce rapid mucus secretion • Commensals trigger CGRP release, which signals to Ramp1 expressed by goblet cells • Nociceptor or Ramp1 ablation leads to decreased mucus levels and microbial dysbiosis • Neuron-goblet cell signaling via a CGRP-Ramp1 axis protects against colitis Pain sensory neurons induce mucus release from nearby intestinal goblet cells via a CGRP-Ramp1 axis in response to commensal and dietary cues to orchestrate gut mucosal protection. [ABSTRACT FROM AUTHOR]

Summary: Host-adapted Salmonella strains are responsible for a number of disease manifestations in mammals, including an asymptomatic chronic infection in which bacteria survive within macrophages located in systemic sites. However, the host cell physiology and metabolic requirements supporting bacterial persistence are poorly understood. In a mouse model of long-term infection, we found that S. typhimurium preferentially associates with anti-inflammatory/M2 macrophages at later stages of infection. Further, PPARδ, a eukaryotic transcription factor involved in sustaining fatty acid metabolism, is upregulated in Salmonella-infected macrophages. PPARδ deficiency dramatically inhibits Salmonella replication, which is linked to the metabolic state of macrophages and the level of intracellular glucose available to bacteria. Pharmacological activation of PPARδ increases glucose availability and enhances bacterial replication in macrophages and mice, while Salmonella fail to persist in Pparδ null mice. These data suggest that M2 macrophages represent a unique niche for long-term intracellular bacterial survival and link the PPARδ-regulated metabolic state of the host cell to persistent bacterial infection. [Copyright &y& Elsevier]

Many intracellular bacteria can establish chronic infection and persist in tissues within granulomas composed of macrophages. Granuloma macrophages exhibit heterogeneous polarization states, or phenotypes, that may be functionally distinct. Here, we elucidate a host-pathogen interaction that controls granuloma macrophage polarization and long-term pathogen persistence during Salmonella Typhimurium (S Tm) infection. We show that S Tm persists within splenic granulomas that are densely populated by CD11b+CD11c+Ly6C+ macrophages. S Tm preferentially persists in granuloma macrophages reprogrammed to an M2 state, in part through the activity of the effector SteE, which contributes to the establishment of persistent infection. We demonstrate that tumor necrosis factor (TNF) signaling limits M2 granuloma macrophage polarization, thereby restricting S Tm persistence. TNF neutralization shifts granuloma macrophages toward an M2 state and increases bacterial persistence, and these effects are partially dependent on SteE activity. Thus, manipulating granuloma macrophage polarization represents a strategy for intracellular bacteria to overcome host restriction during persistent infection. • M2-like granuloma macrophages are more permissive for Salmonella persistence • TNF signaling limits M2-like granuloma macrophages, thereby restricting Salmonella • Salmonella effector SteE promotes an M2 phenotype to overcome TNF-mediated restriction Pham et al. show that granulomas in Salmonella -infected tissues are composed of macrophages that exhibit heterogenous polarization states, or phenotypes, and are functionally distinct. They elucidate a pathogen-driven virulence mechanism that controls granuloma macrophage polarization and long-term pathogen persistence during Salmonella infection. [ABSTRACT FROM AUTHOR]

Summary The intestinal microbiota provides colonization resistance against pathogens, limiting pathogen expansion and transmission. These microbiota-mediated mechanisms were previously identified by observing loss of colonization resistance after antibiotic treatment or dietary changes, which severely disrupt microbiota communities. We identify a microbiota-mediated mechanism of colonization resistance against Salmonella enterica serovar Typhimurium ( S . Typhimurium) by comparing high-complexity commensal communities with different levels of colonization resistance. Using inbred mouse strains with different infection dynamics and S. Typhimurium intestinal burdens, we demonstrate that Bacteroides species mediate colonization resistance against S . Typhimurium by producing the short-chain fatty acid propionate. Propionate directly inhibits pathogen growth in vitro by disrupting intracellular pH homeostasis, and chemically increasing intestinal propionate levels protects mice from S. Typhimurium. In addition, administering susceptible mice Bacteroides , but not a propionate-production mutant, confers resistance to S . Typhimurium. This work provides mechanistic understanding into the role of individualized microbial communities in host-to-host variability of pathogen transmission. [ABSTRACT FROM AUTHOR]

Gut-innervating nociceptor sensory neurons respond to noxious stimuli by initiating protective responses including pain and inflammation; however, their role in enteric infections is unclear. Here, we find that nociceptor neurons critically mediate host defense against the bacterial pathogen Salmonella enterica serovar Typhimurium (STm). Dorsal root ganglia nociceptors protect against STm colonization, invasion, and dissemination from the gut. Nociceptors regulate the density of microfold (M) cells in ileum Peyer's patch (PP) follicle-associated epithelia (FAE) to limit entry points for STm invasion. Downstream of M cells, nociceptors maintain levels of segmentous filamentous bacteria (SFB), a gut microbe residing on ileum villi and PP FAE that mediates resistance to STm infection. TRPV1+ nociceptors directly respond to STm by releasing calcitonin gene-related peptide (CGRP), a neuropeptide that modulates M cells and SFB levels to protect against Salmonella infection. These findings reveal a major role for nociceptor neurons in sensing and defending against enteric pathogens. • Nociceptors mediate enteric defense against Salmonella colonization and PP invasion • Nociceptors shape the gut microbiota and SFB levels to resist Salmonella infection • Nociceptors suppress M cell density to regulate SFB and limit bacterial invasion • Nociceptors directly sense Salmonella to release CGRP to promote host defense Extrinsic nociceptor neurons mediate protection from Salmonella infection by direct sensing and release of CGRP, which leads to suppression of M cell density and maintenance of SFB colonization of the ileum. [ABSTRACT FROM AUTHOR]