Autophagy and Bacterial infections.

Autophagy is an evolutionarily conserved cellular process that is prominent during bacterial infections. In this review article, we discuss how direct pathogen clearance via xenophagy and regulation of inflammatory products represent dual functions of autophagy that coordinate an effective antimicrobial response. We detail the molecular mechanisms of xenophagy, including signals that indicate the presence of an intracellular pathogen and autophagy receptor-mediated cargo targeting, while highlighting pathogen counterstrategies, such as bacterial effector proteins that inhibit autophagy initiation or exploit autophagic membranes for replication.

MAIT cell enrichment in Lynch syndrome is associated with immune surveillance and colorectal cancer risk.

Tissue microenvironment characteristics associated with elevated risk of colorectal cancer (CRC) in Lynch syndrome (LS) are poorly characterized. We applied the multimodal single cell sequencing platform ExCITE-seq to define the colonic cellular composition and transcriptome of LS carriers with and without a history of CRC compared with general population controls. Our analysis revealed widespread remodeling in LS that included striking expansion of epithelial stem and progenitor cells, and loss of fibroblast populations.

MAIT cell enrichment in Lynch syndrome is associated with immune surveillance and colorectal cancer risk.

Tissue microenvironment characteristics associated with elevated risk of colorectal cancer (CRC) in Lynch syndrome (LS) are poorly characterized. We applied the multimodal single cell sequencing platform ExCITE-seq to define the colonic cellular composition and transcriptome of LS carriers with and without a history of CRC compared with general population controls. Our analysis revealed widespread remodeling in LS that included striking expansion of epithelial stem and progenitor cells, and loss of fibroblast populations.

Environmental stress drives clearance of a persistent enteric virus in mice.

Persistent viral infections are associated with long-term health issues and prolonged transmission. How external perturbations after initial exposure affect the duration of infection is unclear. Here we discovered that murine astrovirus, an enteric RNA virus, persists indefinitely when mice remain unperturbed but is cleared rapidly after cage change.

Gene-environment interactions shape the host-microbial interface in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a complex, multifactorial inflammatory disorder of the gut characterized by an imbalance in host-microbiota interactions. Here, we review how early events of IBD are shaped by gene-environment interactions, especially those involving microbial perturbations. Those perturbations eventually lead to chronic inflammation and tissue damage of the gastrointestinal tract.

Goblet Cell Loss Linked to NOD2 and Secondary Resection in Crohn's Disease is Induced by Dysbiosis and Epithelial MyD88.

Background & Aims: The role of goblet cells in small intestinal inflammation in Crohn's disease (CD) is unknown. Polymorphisms of NOD2 confer risk for CD and associate with small intestinal disease location. We previously showed in mice that Nod2 deficiency leads to overexpansion of Phocaeicola vulgatus in the gut and downstream goblet cell defects, which preceded small intestinal inflammation.

Heterozygosity for Crohn's disease risk allele of ATG16L1 promotes unique protein interactions and protects against bacterial infection.

The T300A substitution in ATG16L1 associated with Crohn's disease impairs autophagy, yet up to 50% of humans are heterozygous for this allele. Here, we demonstrate that heterozygosity for the analogous substitution in mice (Atg16L1), but not homozygosity, protects against lethal Salmonella enterica Typhimurium infection. One copy of Atg16L1 was sufficient to enhance cytokine production through inflammasome activation, which was necessary for protection.

Sex-dependent gastrointestinal colonization resistance to MRSA is microbiota and Th17 dependent.

Gastrointestinal (GI) colonization by methicillin-resistant (MRSA) is associated with a high risk of transmission and invasive disease in vulnerable populations. The immune and microbial factors that permit GI colonization remain unknown. Male sex is correlated with enhanced nasal carriage, skin and soft tissue infections, and bacterial sepsis.

Rewilding catalyzes maturation of the humoral immune system.

Inbred mice used for biomedical research display an underdeveloped immune system compared with adult humans, which is attributed in part to the artificial laboratory environment. Despite representing a central component of adaptive immunity, the impact of the laboratory environment on the B cell compartment has not been investigated in detail. Here, we performed an in-depth examination of B cells following rewilding, the controlled release of inbred laboratory mice into an outdoor enclosure.

Sex-dependent gastrointestinal colonization resistance to MRSA is microbiota and Th17 dependent.

Gastrointestinal (GI) colonization by methicillin-resistant (MRSA) is associated with a high risk of transmission and invasive disease in vulnerable populations. The immune and microbial factors that permit GI colonization remain unknown. Male sex is correlated with enhanced nasal carriage, skin and soft tissue infections, and bacterial sepsis.

Concomitant suppression of COX-1 and COX-2 is insufficient to induce enteropathy associated with chronic NSAID use.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used medications for the management of chronic pain; however, they are associated with numerous gastrointestinal (GI) adverse events. Although many mechanisms have been suggested, NSAID-induced enteropathy has been thought to be primarily due to inhibition of both cyclooxygenases (COX) -1 and -2, which results in suppression of prostaglandin synthesis. Yet surprisingly, we found that concomitant postnatal deletion of and over 10 months failed to cause intestinal injury in mice unless they were treated with naproxen or its structural analog, phenylpropionic acid, which is not a COX inhibitor.

Stress from environmental change drives clearance of a persistent enteric virus.

Persistent viral infections are associated with long-term health issues and prolonged transmission. How external perturbations after initial exposure affect the duration of infection is unclear. We discovered that murine astrovirus, an enteric RNA virus, persists indefinitely when mice remain unperturbed but is cleared rapidly after cage change.

Assessing immune phenotypes using simple proxy measures: promise and limitations.

The study of immune phenotypes in wild animals is beset by numerous methodological challenges, with assessment of detailed aspects of phenotype difficult to impossible. This constrains the ability of disease ecologists and ecoimmunologists to describe immune variation and evaluate hypotheses explaining said variation. The development of simple approaches that allow characterization of immune variation across many populations and species would be a significant advance.

Microbiota and metabolic adaptation shape virulence and antimicrobial resistance during intestinal colonization.

Depletion of microbiota increases susceptibility to gastrointestinal colonization and subsequent infection by opportunistic pathogens such as methicillin-resistant (MRSA). How the absence of gut microbiota impacts the evolution of MRSA is unknown. The present report used germ-free mice to investigate the evolutionary dynamics of MRSA in the absence of gut microbiota.

Functional characterization of helminth-associated Clostridiales reveals covariates of Treg differentiation.

Background: Parasitic helminths influence the composition of the gut microbiome. However, the microbiomes of individuals living in helminth-endemic regions are understudied. The Orang Asli, an indigenous population in Malaysia with high burdens of the helminth Trichuris trichiura, display microbiotas enriched in Clostridiales, an order of spore-forming obligate anaerobes with immunogenic properties.

Tofacitinib uptake by patient-derived intestinal organoids predicts individual clinical responsiveness.

Background & Aims: Despite increasing therapeutic options in the treatment of ulcerative colitis (UC), achieving disease remission remains a major clinical challenge. Nonresponse to therapy is common and clinicians have little guidance in selecting the optimal therapy for an individual patient. This study examined whether patient-derived materials could predict individual clinical responsiveness to the Janus kinase (JAK) inhibitor, tofacitinib, prior to treatment initiation.

The hyphal-specific toxin candidalysin promotes fungal gut commensalism.

The fungus Candida albicans frequently colonizes the human gastrointestinal tract, from which it can disseminate to cause systemic disease. This polymorphic species can transition between growing as single-celled yeast and as multicellular hyphae to adapt to its environment. The current dogma of C.

S1PR1 inhibition induces proapoptotic signaling in T cells and limits humoral responses within lymph nodes.

Effective immunity requires a large, diverse naive T cell repertoire circulating among lymphoid organs in search of antigen. Sphingosine 1-phosphate (S1P) and its receptor S1PR1 contribute by both directing T cell migration and supporting T cell survival. Here, we addressed how S1P enables T cell survival and the implications for patients treated with S1PR1 antagonists.

Cytokine signature in convalescent SARS-CoV-2 patients with inflammatory bowel disease receiving vedolizumab.

While differential antibody responses SARS-CoV-2 in patients with inflammatory bowel disease (IBD) receiving infliximab and vedolizumab are well-characterized, the immune pathways underlying these differences remain unknown. Prior to COVID-19 vaccine development, we screened 235 patients with IBD receiving biological therapy for antibodies to SARS-CoV-2 and measured serum cytokines. In seropositive patients, we prospectively collected clinical data.

Spatiotemporal-social association predicts immunological similarity in rewilded mice.

Environmental influences on immune phenotypes are well-documented, but our understanding of which elements of the environment affect immune systems, and how, remains vague. Behaviors, including socializing with others, are central to an individual's interaction with its environment. We therefore tracked behavior of rewilded laboratory mice of three inbred strains in outdoor enclosures and examined contributions of behavior, including associations measured from spatiotemporal co-occurrences, to immune phenotypes.

Temporal Tracking of Plasma Cells Using J-chain CreERT2 Reporter System.

Plasma cells (PCs) are essential for humoral immunity, as they are responsible for the production of antibodies and contribute to immunological memory. Despite their importance, differentiating between long-lived and short-lived PCs remains a challenge due to a lack of specific markers to distinguish these populations. Addressing this gap, our study introduces a novel J-chain CreERT2 GFP allele (IgJ) for precise genetic studies of PCs.

Beyond antiviral: Interferon induced by bacteria maintains tolerance in the gut.

Type I interferons are best known for their antiviral role. Here, Ayala et al. (https://doi.