Infection and Immunity最新文献

{"title":"Cytolethal distending toxin enhances <i>Escherichia coli</i> urinary tract infection.","authors":"Santosh Paudel, Benjamin E Curtis, Siena Stefa, Harry L T Mobley, Melanie M Pearson, Mark T Anderson","doi":"10.1128/iai.00103-26","DOIUrl":"10.1128/iai.00103-26","url":null,"abstract":"<p><p>Cytolethal distending toxin (CDT) is a virulence factor produced by several gram-negative bacteria, including <i>Escherichia coli</i>, the most prevalent etiological agent of urinary tract infections (UTIs). CDT causes DNA damage to eukaryotic cells, leading to the impairment of host defenses by disrupting epithelial barriers, suppressing acquired immunity, and promoting pro-inflammatory responses. <i>E. coli</i> strains encoding CDT have been previously identified in samples from UTI patients; however, the specific function of CDT in the development of UTI remains undefined. In this study, we used a mouse model of ascending UTI to determine the role of CDT during infection. An <i>E. coli</i> mutant strain lacking the <i>cdtABC</i> locus was generated and combined with wild-type bacteria to co-infect mice via transurethral inoculation. At 1 day post-inoculation, competitive indices demonstrated a significant disadvantage for the <i>cdt</i> mutant in urine, bladder, and kidneys. Single-strain infections were also performed as a further assessment of CDT impact, demonstrating that the <i>cdt</i> mutant had reduced kidney colonization, indicative of CDT contributions to pyelonephritis. Histopathological analysis of the urinary bladder and kidney tissues from mice infected with CDT-encoding <i>E. coli</i> demonstrated higher levels of inflammation and tissue damage within the kidneys at both 1 and 7 days post-inoculation and in the bladder after 7 days when compared to mice infected with <i>cdt</i> mutant bacteria. Collectively, these findings identify a role for CDT in UTI pathogenesis.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0010326"},"PeriodicalIF":3.4,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148430227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide association studies of <i>C. trachomatis</i> identify novel tissue tropism-predicting loci and sequences that discriminate among major genome sequence clades.","authors":"Robert J Suchland, Stephen A Ramsey, Valerie Tran, Steven J Carrell, Xisheng Wang, Kevin Hybiske, Daniel D Rockey","doi":"10.1128/iai.00266-26","DOIUrl":"10.1128/iai.00266-26","url":null,"abstract":"<p><p><i>Chlamydia trachomatis</i> infections cause chronic and debilitating diseases of the eye and genital tract. Recent data suggest that infections are common at other tissue sites, including the lower intestinal tract of both men and women. Our previous work demonstrated tropism-predicting sequences in male rectal isolates, with modification in the PmpE sequence and predicted structure being highly correlated with male rectal infection. An expanded collection of strains from five different tissue sites was used to identify novel tropism-predicting markers for the different tissues. These data demonstrate that <i>C. trachomatis</i> strains colonizing the male rectum are unique with respect to all other tested sites. Additionally, ocular strains have a consistent set of genes that separate them from strains isolated from any other tissue. Novel polymorphisms predictive of ocular tropism include a single indel in <i>mrcA</i> and a region between <i>pmpH</i> and <i>pmpI</i>, including the hypothetical gene <i>ct873</i>. These analyses also identified a novel urogenital clade, termed the variable-OmpA clade, in which strains carry a variety of <i>ompA</i> sequences in an otherwise shared genomic background. This clade is defined primarily by single-nucleotide polymorphisms (SNPs) within and adjacent to the highly variable plasticity zone. Collectively, this work explores the continuing evolution of <i>C. trachomatis</i> strains and clades in a genomic background that only engages in intraspecies horizontal gene transfer.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0026626"},"PeriodicalIF":3.4,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148470347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The diabetic wound microenvironment drives emergence and maintenance of CovRS variants in group B <i>Streptococcus</i>.","authors":"Rebecca A Keogh, Alyx M Job, Luke R Joyce, Madeline S Akbari, Amber Nguyen, Jeffrey S Kavanaugh, Alexander R Horswill, Kelly S Doran","doi":"10.1128/iai.00099-26","DOIUrl":"10.1128/iai.00099-26","url":null,"abstract":"<p><p>Diabetic wounds are often infected with microbes, which perpetuate inflammation, and stall wound healing. The bacterium Group B <i>Streptococcus</i> (GBS) is frequently isolated from diabetic wounds; however, little is known about how GBS adapts to survive in this niche. Previously, we found that GBS acquires stable mutations in the major two-component system CovRS during murine diabetic wound infection that result in increased pigmentation. Here, we further characterize these pigmented variants and determine the consequences on GBS survival. Using a murine model of wound infection, we find that <i>covRS</i> mutants arise specifically in diabetic hosts and are selected for across multiple GBS backgrounds. Whole genome sequencing of pigmented isolates revealed mutations in both <i>covR</i> and <i>covS</i>, with most isolates having a single nucleotide insertion or deletion in the <i>covR</i> promoter region. Phenotypic analysis of murine-acquired mutants reveals enhanced traits associated with virulence, including increased hemolytic activity, host cell cytotoxicity, and elevated nuclease activity. While our previous and current study indicated that engineered <i>covR</i> deletion mutants do not exhibit increased survival in the diabetic wound, we observe that a pigmented isolate survived better than wild-type during co-infection with <i>Enterococcus faecalis</i>, another frequently isolated wound pathogen. Finally, we find that depletion of neutrophils reduces the frequency of <i>covRS</i> mutant variants that arise in the population. Our work highlights the emergence of <i>covRS</i> mutations in GBS, and the consequences of these variations are associated with enhanced virulence and competitive fitness, underscoring the importance of these regulatory changes in the context of diabetic wounds.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0009926"},"PeriodicalIF":3.4,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148251474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vaginal microbiome composition in pregnant and non-pregnant women: community structure, population variation, clinical impact, and metagenomics approaches.","authors":"Daiki Jonouchi, Srusti Shenoy, Renise Saintlouis, Amar Singh, Dharambir Kashyap, Chandana Bhargavi, Raymond Mansoor, Edmond Mansoor, Prasanna Honnavar","doi":"10.1128/iai.00542-25","DOIUrl":"10.1128/iai.00542-25","url":null,"abstract":"<p><p>The vaginal microbiome plays a critical role in reproductive health and undergoes characteristic remodeling during pregnancy that influences maternal and neonatal outcomes. Although the non-pregnant vaginal microbiome shows substantial inter-individual variability, pregnancy is associated with reduced microbial diversity and increased dominance by <i>Lactobacillus</i> species, creating a protective environment for fetal development. Disruption of this balance, termed vaginal dysbiosis, has been linked to adverse obstetric and neonatal outcomes. This narrative review synthesizes current evidence on pregnancy-associated vaginal microbiome dynamics, with emphasis on community state types (CSTs), gestational changes, population-specific variation, and clinical implications. We review studies that use 16S rRNA sequencing, next-generation sequencing, and shotgun metagenomics to characterize microbial composition across pregnancy and the postpartum period. <i>Lactobacillus</i>-dominated communities, particularly those dominated by <i>Lactobacillus crispatus</i>, are consistently associated with microbiome stability and favorable pregnancy outcomes, whereas high-diversity anaerobic communities (CST IV) are linked to bacterial vaginosis, preterm birth, miscarriage, gestational diabetes mellitus, and infection-related complications. The vaginal microbiome composition varies significantly across racial, ethnic, and geographic populations. African-descended populations more often show <i>L. iners</i>-dominant or diverse anaerobic profiles, whereas European populations more commonly show <i>L. crispatus</i> dominance. Future longitudinal and mechanistic studies across diverse populations are needed to establish causality and evaluate microbiome-based interventions to improve maternal and neonatal health.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0054225"},"PeriodicalIF":3.4,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148251428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of cytochrome oxidases in bacterial virulence.","authors":"Liliana S McKay, Andrew Camilli, Peggy A Cotter","doi":"10.1128/iai.00609-24","DOIUrl":"10.1128/iai.00609-24","url":null,"abstract":"<p><p>Bacterial physiology plays an important role in virulence. Being a pathogen is energetically expensive, requiring the production of specialized virulence factors and other proteins that enable survival within the host. The most efficient way for bacteria to generate the energy required for virulence is by electron-coupled oxidative phosphorylation, with oxygen as the terminal acceptor, also called aerobic respiration. Cytochrome oxidases are critical components of the electron transport chain used in aerobic respiration. Studies on the role of cytochrome oxidases during infection in clinically relevant bacteria have shown that they are often critical, even in low-oxygen environments, such as the gastrointestinal tract. Cytochrome oxidases-especially <i>bd</i>-type, the class most associated with virulence-are thus being explored as possible antimicrobial drug targets. However, the mechanisms underlying the role of cytochrome oxidases, especially non-<i>bd</i>-type cytochrome oxidases, during infection remain poorly understood in most organisms. In this review, we examine what is known about the role of cytochrome oxidases during infection, highlighting four pathogens: <i>Mycobacterium tuberculosis</i> and uropathogenic <i>Escherichia coli</i>, in which the role of <i>bd</i>-type cytochrome oxidases during infection has been investigated mechanistically, and <i>Vibrio cholerae</i> and <i>Bordetella bronchiseptica</i>, in which non-<i>bd</i>-type cytochrome oxidases contribute to infection. These examples indicate the need to assess what role cytochrome oxidases play in a wider array of bacterial pathogens.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0060924"},"PeriodicalIF":3.4,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148251452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HnRNPA2B1 tunes antimycobacterial immune responses in macrophages through alternative splicing of <i>Irgm1</i>.","authors":"M J Chapman, J B Huskey, K S Armijo, S Hahn, J Spellman-Reliford, A K Coleman, C J Mabry, S Carpenter, R O Watson, K L Patrick","doi":"10.1128/iai.00732-25","DOIUrl":"10.1128/iai.00732-25","url":null,"abstract":"<p><p>The onset and progression of active tuberculosis disease result from upsetting the delicate balance between Mtb virulence and host defenses. Because it dynamically tunes the functional output of protein expression in cells, alternative splicing (AS), a process by which different mRNAs can be generated from a single gene, is positioned to play a critical role in maintaining an equilibrated Mtb-macrophage host-pathogen interface. To gain insight into how alternative splicing shapes antimycobacterial immune responses, we used RNA sequencing and splicing-aware computational pipelines to quantify alternative splicing in Mtb-infected bone marrow-derived murine macrophages. We found that ~5% of expressed macrophage genes exhibit one or more splicing changes at 8 h post-Mtb infection, highlighting alternative splicing as a key regulatory node in the macrophage response to Mtb. We next sought to identify RNA-binding proteins that play an outsized role in shaping the macrophage transcriptome during Mtb infection. We discovered that the splicing factor heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) promotes the early induction of inflammatory genes while dampening several type I interferon-stimulated genes in response to Mtb. HnRNPA2B1 also controls alternative splicing of many genes during Mtb infection, including Irgm1, a critical immunity-related GTPase. The balance of Irgm1-long vs. -short is differentially regulated in response to diverse inflammatory cues, and macrophages overexpressing Irgm1-short are defective in autophagosomal targeting, lysosomal homeostasis, and restriction of Mtb replication. These data highlight a key role for AS in shaping the macrophage transcriptome and pinpoint hnRNPA2B1 as a novel restriction factor in the cell-intrinsic response to Mtb.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0073225"},"PeriodicalIF":3.4,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148271349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Staphylococcus aureus</i> inhibits the NLRP3 inflammasome in macrophages to varying degrees during early and late stages of infection.","authors":"Saumya Bhagat, Khushpreet Kaur, Jenna R Petronglo, Luke O'Connor, Chun Wang, Yongjia Li, Gaurav Swarnkar, Kunjan Khanna, James E Cassat, Deborah J Veis, Gabriel Mbalaviele","doi":"10.1128/iai.00200-26","DOIUrl":"10.1128/iai.00200-26","url":null,"abstract":"<p><p><i>Staphylococcus aureus</i> (<i>S. aureus</i>) is a highly virulent pathogen responsible for chronic infections such as osteomyelitis. Although its interaction with the host immune system has been widely studied, the specific role of inflammasomes in regulating the infection within macrophages remains unclear. We investigated this question using bone marrow-derived macrophages (BMDMs) infected with <i>S. aureus</i> for up to 96 hours (h). We observed a significant reduction in intracellular bacterial load beginning at 18 h post-infection (hpi), which continued through 96 hpi; this response was partially attenuated in BMDMs lacking NLRP3. Mechanistically, activation of the NLRP3 inflammasome, including ASC speck formation, IL-1β secretion, and pyroptosis, was modest and detectable only after 18 hpi. Consistent with these findings, infected BMDMs failed to respond robustly to NLRP3 inflammasome activators, lipopolysaccharide (LPS) and nigericin, up to 18 hpi, with only partial restoration of responsiveness at later time points. We also found that NLRP3 deficiency did not significantly affect bacterial burden control or bone homeostasis in experimental <i>S. aureus</i> osteomyelitis. Thus, <i>S. aureus</i> is inadequately controlled by the NLRP3 inflammasome in macrophages and within the bone microenvironment.IMPORTANCE<i>Staphylococcus aureus</i> causes difficult-to-treat, long-lasting infections such as osteomyelitis. While many aspects of how the immune system responds to this pathogen are known, it is still unclear how the inflammasomes contribute to controlling the infection inside macrophages. In this study, we found that macrophages gradually reduced the number of bacteria they contained over time, but this ability was only partly dependent on one major inflammasome component, NLRP3. Importantly, the inflammasome response to <i>S. aureus</i> was weak and delayed, becoming noticeable only well after infection had begun. Even when stimulated with agents that normally trigger a strong inflammasome response, infected macrophages responded poorly. Consistent with these findings, the absence of NLRP3 did not significantly worsen bacterial control or bone damage in a mouse model of osteomyelitis. Together, these results suggest that <i>S. aureus</i> largely evades inflammasome-based defenses, limiting their effectiveness in controlling infection in immune cells and bone.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0020026"},"PeriodicalIF":3.4,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367054/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148211118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential activation of NF-Κβ and HIF-1α between fetal liver-derived and myeloid-derived macrophages drives inflammatory differences following <i>Mycobacterium abscessus</i> infection.","authors":"Haleigh N Gilliland, Soledad Soverina, Kayla N Conner, Taryn E Vielma, Andrew J Olive","doi":"10.1128/iai.00136-26","DOIUrl":"10.1128/iai.00136-26","url":null,"abstract":"<p><p>Pulmonary infections caused by <i>Mycobacterium abscessus</i> (Mab)<i>,</i> a rapidly growing nontuberculous mycobacterium (NTM), are rising in patients with preexisting lung disease. Unfortunately, the natural recalcitrance of Mab to antibiotics drives high rates of treatment failures. Understanding the initial host-pathogen interactions that result in Mab control or disease is critical to identify new therapeutic targets. Lung macrophages are the first immune cells that Mab encounters, yet how distinct macrophage subsets, including resident fetal liver-derived alveolar macrophages (AMs) and recruited myeloid-derived macrophages, differentially respond to and control Mab remains unknown. Using primary AMs or fetal-liver derived alveolar macrophages (FLAMs) as a model of AMs and bone marrow macrophages (BMDMs) as a model of recruited myeloid macrophages, we found distinct macrophage subsets that similarly control intracellular Mab in resting and interferon-gamma (IFNγ)-activated cells with similar levels of cell death. However, divergent inflammatory responses were observed with resting BMDMs robustly activating NF-κB-dependent proinflammatory cytokines, while FLAMs only transiently induced this key inflammatory signature. We further found that Mab-infected IFNγ activated FLAMs and did not robustly induce HIF1α, resulting in reduced Nos2 expression. Thus, differences in the activation of transcription factors in fetal liver- and myeloid-derived macrophages drives distinct host responses against the same Mab pathogen. Our results provide a new understanding of early interactions with Mab in the lungs and suggest differences that distinct macrophage subsets may contribute to susceptibility to Mab pulmonary disease.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0013626"},"PeriodicalIF":3.4,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148251436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Salmonella</i> Typhi asparaginase-dependent activation of GCN2 promotes bacterial killing in murine macrophages.","authors":"Zachary M Powers, Michael J McFadden, Gi Young Lee, Tracey Schultz, Luiza A Castro Jorge, Daniel F Edwards, Simon Sanchez-Paiva, Jonathan Z Sexton, Katherine R Spindler, Jeongmin Song, Mary X O'Riordan","doi":"10.1128/iai.00178-26","DOIUrl":"10.1128/iai.00178-26","url":null,"abstract":"<p><p>Many intracellular pathogens stimulate host cell stress by directly or indirectly causing an imbalance in host nutrients. Depletion of amino acid pools, in particular, can act as a danger signal to infected cells. Using a restrictive host model of <i>Salmonella enterica</i> serovar Typhi (<i>S</i>. Typhi) infection, we identify early induction of the integrated stress response (ISR) by viable bacteria, but not by heat-killed bacteria. Genetic deletion of the amino acid-sensing ISR kinase GCN2 (also known as EIF2AK4) prevented early ISR activation during <i>S</i>. Typhi infection and murine macrophages lacking GCN2 show impaired bacterial clearance and decreased cytokine output. Supplementation of wild-type C57BL/6 murine macrophages with only the non-essential amino acid asparagine was sufficient to suppress <i>S</i>. Typhi-induced ISR activation, and deletion of <i>S</i>. Typhi <i>ansB</i>, encoding an asparaginase, prevented ISR activation during infection. Pharmacological inhibition of mammalian target of rapamycin (mTOR), the other major amino acid-sensing pathway in eukaryotic cells, prevented GCN2 activation and ISR induction in murine macrophages, indicating an upstream role for mTOR in signaling to GCN2. These findings suggest a role for the ISR in macrophage innate immune responses to <i>S</i>. Typhi infection and highlight a potential difference in nutrient-dependent signaling between the <i>S</i>. Typhi-susceptible human host and the restrictive murine host centered around asparagine, mTOR, and GCN2.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0017826"},"PeriodicalIF":3.4,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148251498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lithocholic acid induces T3SS-dependent formation of invasion-competent <i>Shigella flexneri</i> aggregates.","authors":"Jonah Lanier, Jaden J Skelly, Freddie Salsbury, Volkan K Köseoğlu","doi":"10.1128/iai.00665-25","DOIUrl":"10.1128/iai.00665-25","url":null,"abstract":"<p><p><i>Shigella flexneri</i> causes shigellosis, the second leading cause of diarrheal deaths worldwide. The pathogen invades colonic epithelial cells using a type III secretion system (T3SS) that delivers effector proteins to remodel the host actin cytoskeleton. Following invasion, <i>S. flexneri</i> acquires actin-based motility and spreads cell to cell, driving epithelial destruction and bloody diarrhea. These intracellular infection processes have been investigated primarily using exponentially growing planktonic bacteria. However, recent animal studies revealed that <i>S. flexneri</i> also forms multicellular aggregates in the colonic lumen, yet the function of this extracellular phase remains unclear. Here, we show that lithocholic acid (LCA), an abundant secondary bile acid in the colon, acts as a potent signal that induces <i>S. flexneri</i> aggregation at physiological concentrations (≥50 µM). LCA-induced aggregation depends on the T3SS and its tip protein IpaD, which is required to initiate aggregate formation. LCA-induced aggregates are capable of invasion by eliciting actin remodeling and elevated T3SS activation during early interactions with colonic epithelial HT-29 and Caco-2 cells. These findings identify LCA as a luminal cue that links extracellular aggregation to intracellular infection through a new aggregate-mediated mode of epithelial invasion.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0066525"},"PeriodicalIF":3.4,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148054341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}