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Loss of antimicrobial proteins such as REG3 family members compromises the integrity of the intestinal barrier. Here, we demonstrate that overproduction of REG3 proteins can also be detrimental by reducing a protective species in the microbiota. Patients with inflammatory bowel disease (IBD) experiencing flares displayed heightened levels of secreted REG3 proteins that mediated depletion of Enterococcus faecium (Efm) from the gut microbiota. Efm inoculation of mice ameliorated intestinal inflammation through activation of the innate immune receptor NOD2, which was associated with the bacterial DL-endopeptidase SagA that generates NOD2-stimulating muropeptides. NOD2 activation in myeloid cells induced interleukin-1β (IL-1β) secretion to increase the proportion of IL-22-producing CD4+ T helper cells and innate lymphoid cells that promote tissue repair. Finally, Efm was unable to protect mice carrying a NOD2 gene variant commonly found in IBD patients. Our findings demonstrate that inflammation self-perpetuates by causing aberrant antimicrobial activity that disrupts symbiotic relationships with gut microbes. [Display omitted] • REG3 proteins deplete Enterococcus faecium in gut microbiota of IBD patients • E. faecium SagA inhibits intestinal inflammation in a NOD2-dependent manner • NOD2-activated myeloid cells produce IL-1β to induce IL-22 from lymphoid cells • The NOD2 R702W variant impairs E. faecium -mediated protection in mice Jang et al. demonstrate that antimicrobial REG3 proteins overproduced during inflammatory bowel disease perpetuate inflammation by depleting Enterococcus faecium from the microbiota. DL-endopeptidase SagA secreted by Enterococcus faecium activates myeloid NOD2 signaling to produce IL-1β, which induces the protective cytokine IL-22 from lymphoid cells. [ABSTRACT FROM AUTHOR]

The epidemic community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) USA300 lineage has recently become a leading cause of hospital-associated bloodstream infections (BSIs). Here, we leveraged this recent introduction into hospitals and the limited genetic variation across USA300 isolates to identify mutations that contribute to its success in a new environment. We found that USA300 BSI isolates exhibit altered virulence regulation. Using comparative genomics to delineate the genes involved in this phenotype, we discovered repeated and independent mutations in the transcriptional regulator sarZ. Mutations in sarZ resulted in increased virulence of USA300 BSI isolates in a murine model of BSI. The sarZ mutations derepressed the expression and production of the surface protein ClfB, which was critical for the pathogenesis of USA300 BSI isolates. Altogether, these findings highlight ongoing evolution of a major MRSA lineage and suggest USA300 strains can optimize their fitness through altered regulation of virulence. [Display omitted] • Bloodstream infection USA300 isolates have evolved altered virulence regulation • Altered virulence is associated with mutations in the transcription factor SarZ • Mutating sarZ leads to hypervirulence in a murine bloodstream infection model • ClfB contributes to the hypervirulence of sarZ mutant USA300 isolates Staphylococcus aureus is a versatile pathogen. Dyzenhaus et al. show that USA300 clinical isolates from the bloodstream naturally acquire mutations in the transcription factor SarZ that increase their virulence in a murine model of bloodstream infection. This study highlights the power of genomics to discover new biology in infectious disease. [ABSTRACT FROM AUTHOR]

The recent spread of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) has brought increasing concerns of heightened disease severity and persistence following invasive disease. In line with the need for new treatment paradigms, two recent reports have shown that antibody-based therapies can restrict acute S. aureus infection and persistence and improve pathological symptoms. [ABSTRACT FROM AUTHOR]

Free-living mammals, such as humans and wild mice, display heightened immune activation compared with artificially maintained laboratory mice. These differences are partially attributed to microbial exposure as laboratory mice infected with pathogens exhibit immune profiles more closely resembling that of free-living animals. Here, we examine how colonization by microorganisms within the natural environment contributes to immune system maturation by releasing inbred laboratory mice into an outdoor enclosure. In addition to enhancing differentiation of T cell populations previously associated with pathogen exposure, outdoor release increased circulating granulocytes. However, these "rewilded" mice were not infected by pathogens previously implicated in immune activation. Rather, immune system changes were associated with altered microbiota composition with notable increases in intestinal fungi. Fungi isolated from rewilded mice were sufficient in increasing circulating granulocytes. These findings establish a model to investigate how the natural environment impacts immune development and show that sustained fungal exposure impacts granulocyte numbers. • Controlled release of lab mice into the wild alters the state of the immune system • Rewilded mice harbor an altered microbiota including increases in intestinal fungi • Fungi from rewilded mice induce granulocyte expansion in laboratory mice Laboratory mice are maintained in artificial conditions that potentially impact immunity. In this issue of Cell Host & Microbe , Yeung et al. (2020) demonstrate that mice released into a wild enclosure display increases in circulating granulocytes that are associated with an altered microbiota, notably expansion of fungi. [ABSTRACT FROM AUTHOR]

Innate immune recognition of bacterial pathogens is a key determinant of the ensuing systemic response, and host or pathogen heterogeneity in this early interaction can impact the course of infection. To gain insight into host response heterogeneity, we investigate macrophage inflammatory dynamics using primary human macrophages infected with Group B Streptococcus. Transcriptomic analysis reveals discrete cellular states within responding macrophages, one of which consists of four sub-states, reflecting inflammatory activation. Infection with six additional bacterial species-Staphylococcus aureus, Listeria monocytogenes, Enterococcus faecalis, Yersinia pseudotuberculosis, Shigella flexneri, and Salmonella enterica-recapitulates these states, though at different frequencies. We show that modulating the duration of infection and the presence of a toxin impacts inflammatory trajectory dynamics. We provide evidence for this trajectory in infected macrophages in an in vivo model of Staphylococcus aureus infection. Our cell-state analysis defines a framework for understanding inflammatory activation dynamics in response to bacterial infection., Competing Interests: Declaration of interests V.J.T. has consulted for Janssen Research & Development, LLC and has received honoraria from Genentech and Medimmune. V.J.T. is also an inventor on patents and patent applications filed by New York University, which are currently under commercial license to Janssen Biotech Inc. Janssen Biotech Inc. provides research funding and other payments associated with a licensing agreement., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The pathogenesis of Staphylococcus aureus is thought to depend on the production of pore-forming leukocidins that kill leukocytes and lyse erythrocytes. Two leukocidins, Leukocidin ED (LukED) and γ-Hemolysin AB (HlgAB), are necessary and sufficient to kill mice upon infection and toxin challenge. We demonstrate that LukED and HlgAB cause vascular congestion and derangements in vascular fluid distribution that rapidly cause death in mice. The Duffy antigen receptor for chemokines (DARC) on endothelial cells, rather than leukocytes or erythrocytes, is the critical target for lethality. Consistent with this, LukED and HlgAB injure primary human endothelial cells in a DARC-dependent manner, and mice with DARC-deficient endothelial cells are resistant to toxin-mediated lethality. During bloodstream infection in mice, DARC targeting by S. aureus causes increased tissue damage, organ dysfunction, and host death. The potential for S. aureus leukocidins to manipulate vascular integrity highlights the importance of these virulence factors., (Copyright © 2019 Elsevier Inc. All rights reserved.)