Infection and Immunity最新文献

Campylobacter jejuni is a microaerophilic, gram-negative bacterium and one of the leading causes of bacterial gastroenteritis worldwide, most commonly transmitted through contaminated poultry products. The organism exhibits striking host-specific behavior, persisting as a harmless commensal in the chicken intestine while causing inflammatory disease and rapid proliferation in the human gut. Despite its clinical importance, the mechanisms underlying nutrient acquisition, metabolic adaptation, and fitness during infection remain incompletely understood. The ferret model of campylobacteriosis closely reproduces the colonic pathology observed in humans and has provided important insights into how C. jejuni modifies and exploits the intestinal environment during infection. Inflammation induced by infection alters gut physiology, increasing luminal oxygen availability and concentrations of metabolites such as L-lactate. Elevated L-lactate serves as a key nutrient source that enhances C. jejuni growth in vivo, illustrating the broader concept of host-pathogen metabolic crosstalk in which immune-mediated inflammation unintentionally creates nutrient-rich conditions favorable for pathogen expansion. Within the altered redox landscape of the inflamed intestine, redox-responsive signaling pathways may further regulate genes involved in lactate utilization and metabolic adaptation. Although many enteric pathogens produce virulence factors that manipulate host physiology to promote colonization, similar mechanisms in C. jejuni remain poorly defined. This review explores the potential contribution of the cytolethal distending toxin in reshaping the host environment to support bacterial growth and persistence. Understanding these metabolic and regulatory adaptations provides new insight into C. jejuni pathogenesis and highlights potential targets for therapeutic intervention.

Curli fibers produced by Escherichia coli are functional amyloids that activate Toll-like receptor 2 (TLR2), initiating innate immune responses at mucosal surfaces. While microbiome-derived curli contribute to host-microbe interactions, their intrinsic immunostimulatory activity limits their utility as programmable scaffolds for engineered probiotic systems, and dysregulated TLR2 activation has been associated with inflammatory bowel disease, systemic lupus erythematosus, neurodegeneration, and sepsis. Here, we engineered E. coli Nissle 1917 to produce modified curli fibers designed to reduce TLR2 signaling through two mechanistically distinct strategies: steric shielding via silk-elastin-like protein sequences and direct receptor antagonism via a known TLR2 antagonist, staphylococcal superantigen-like protein 3 (SSL3). Both engineered variants assembled into structurally intact amyloid fibers and exhibited significantly reduced intrinsic TLR2-dependent NF-κB activation in reporter cells. In competitive inhibition assays against structurally diverse TLR2 agonists, the SSL3 fusion achieved near-complete attenuation of TLR2-dependent signaling, maintained under rising agonist load, while steric shielding provided moderate, agonist class-dependent inhibition. In primary human monocyte-derived dendritic cells, the SSL3 fusion robustly attenuated IL-8 secretion and transcriptional induction of IL-8, IL-6, and IL-1β, whereas steric shielding produced only partial attenuation that did not translate to broad inflammatory suppression. These results establish engineered curli as a tunable platform for receptor-specific modulation of innate immune signaling and highlight the broader potential of modular microbial amyloids as programmable interfaces for engineering host-microbe interactions at mucosal surfaces.

Glycosaminoglycans (GAGs) are negatively charged polysaccharides composed of repeating disaccharide units and are essential components of the extracellular matrix throughout numerous tissues. The bladder urothelium has a protective GAG layer that primarily consists of chondroitin sulfate (CS), heparan sulfate (HS), and hyaluronic acid (HA), and urinary tract pathogens must either degrade or otherwise circumvent this layer to infect the urothelium. In this study, we investigated GAG degradation by Proteus mirabilis, a common and persistent colonizer of the catheterized urinary tract. Almost all P. mirabilis urinary tract isolates harbor a putative chondroitin endolyase (PMI2127), exolyase (PMI2128), and sulfatase (PMI2124). By generating mutant and complemented strains of these genes, we determined that P. mirabilis strain HI4320 degrades multiple forms of CS under numerous culture conditions, including during growth in human urine, and can use CS degradation products as a carbon source. Sulfatase and endolyase activities were required for efficient degradation of all CS types, while the exolyase only contributed to using CS-B or CS-C as a carbon source. Interestingly, only endolyase activity contributed to colonization in a murine model of catheter-associated urinary tract infection (CAUTI), although the colonization defect was even more pronounced when both the endolyase and exolyase were disrupted. The colonization defect was specific to the CAUTI model, likely due to the impact of catheterization on the GAG landscape of the bladder. Limiting CS degradation by P. mirabilis may therefore reduce the risk of ascending infection in catheterized patients.

Successful gastrointestinal (GI) colonization by bacterial pathogens requires adaptation to nutrient competition and host-derived stresses in the gut, with adaptation via the bacterial stringent stress response playing a critical role. Epidemiological data suggest that the GI tract serves as a reservoir from which K. pneumoniae can spread and cause invasive disease or transmit to another host. DksA is a conserved stringent response transcriptional regulator that was identified in an in vivo transposon mutagenesis screen as an important K. pneumoniae gut determinant. However, its role in K. pneumoniae pathogenesis and gut colonization remain uncharacterized. Here, we demonstrate that DksA is required for survival against membrane-targeting antibiotics, consistent with a role in cell envelope stress tolerance. In addition, DksA positively influences capsule biosynthesis gene expression and hypermucoviscosity, and is essential for robust biofilm formation. Using a murine model, we establish that DksA functions as a determinant of GI colonization, despite disruption of the resident gut microbiota. Furthermore, we demonstrate that DksA is important for environmental survival and transmission by regulating RpoS, thereby providing a mechanistic link between the stringent stress response, environmental survival, and subsequent transmission. Together, these findings establish DksA as a central integrator of the stringent response, coordinating membrane stress resistance, virulence traits, and gastrointestinal colonization in K. pneumoniae.

Coxiella burnetii is an obligate intracellular bacterial pathogen that causes the zoonotic disease Q fever. Coxiella extensively subverts host vesicle traffic and replicates within lysosome-derived, spacious vacuoles by secreting a suite of effectors through the type IVB secretion system (T4BSS). This study investigates the regulation and role of a fundamental lysosomal process, exocytosis, in the prolonged maintenance of Coxiella vacuolar niche. Biochemical, microscopic, and proteomic approaches indicate that infection promotes release of extracellular vesicles (EVs). Increase in extracellular levels of endolysosomal proteins and surface localization of LAMP1 were identified in both phagocytic and non-phagocytic cells, during later stages of infection. Interestingly, infection-induced exocytosis was dependent on the activity of the bacterial T4BSS. On one hand, knockdown of the lysosomal master transcriptional regulator TFEB significantly reduces basal exocytosis and enhances intracellular Coxiella replication, while deficiency of the exocytosis-associated SNARE, Syntaxin 11, does not reduce basal exocytosis and yet, increases Coxiella replication, suggesting that host exocytosis is not the sole or a dominant determinant of the infection process. On the other hand, modulating the activity of a key host exocytosis regulator- the calcium channel TRPML1, decreases intracellular Coxiella replication suggesting a tightly regulated role of TRPML1. Infection was also associated with the extracellular detection of LAMP1-associated Coxiella, suggesting an encased egress mechanism. Together, this study demonstrates that Coxiella infection activates exocytosis in a temporal, host-, and bacterial factor-dependent manner.

Enteric viruses are major causes of gastrointestinal disease worldwide and are primarily transmitted through the fecal-oral route. Upon entering the gastrointestinal tract, these viruses encounter the dense and diverse population of intestinal microbiota, leading to frequent interactions with commensal bacteria. Over the past decade, numerous studies have demonstrated that bacteria can enhance enteric viral replication, stability, and overall pathogenesis. Although direct binding interactions between enteric viruses and bacteria have been observed, the molecular determinants governing these interactions remain poorly understood. Defining the viral and bacterial factors that mediate binding is, therefore, critical for understanding how bacteria can influence viral infection, transmission, and disease. Here, in this minireview, we summarize the current findings on enteric viral-bacterial interactions, with a focus on the mechanisms of viral binding to bacteria and the implications of these interactions on enteric virus pathogenesis and transmission.

Iron and oxygen availability fluctuate spatially across mammalian tissues as well as temporally during bacterial infection. The [2Fe-2S] cluster-coordinating transcription factor IscR senses changes in iron and oxygen levels and plays a pivotal role in how Yersinia, Salmonella, and Vibrio regulate critical virulence genes, like the type III secretion system (T3SS). We previously showed that clusterless apo-IscR promotes expression of the Yersinia pseudotuberculosis T3SS master regulator LcrF by binding a type 2 IscR-binding motif in the lcrF promoter, thereby facilitating T3SS expression and disseminated infection. Here, we sought to address how IscR ligation of its [2Fe-2S] cluster impacts LcrF expression and bacterial virulence. We engineered a Y. pseudotuberculosis mutant strain with its native type 2 IscR-binding motif swapped with a type 1 motif that binds [2Fe-2S]-IscR but not apo-IscR. This lcrF^pType1 mutant hyperexpressed LcrF and T3SS-associated proteins in iron-replete anaerobic conditions that favor [2Fe-2S]-IscR. To understand the consequence of this dysregulated expression, we used barcoded Y. pseudotuberculosis libraries to probe infection dynamics of the WT and lcrF ^pType1 mutant strains following oral infection of mice. The lcrF^pType1 mutant experienced altered colonization bottleneck and dissemination patterns compared to WT Yersinia, suggesting that expressing LcrF and T3SS genes in response to [2Fe-2S]-IscR rather than apo-IscR may alter infection dynamics.

For all pathogenic microbes, metabolic processes are essential for growth, development, and survival during infection. However, host niches are dynamic environments where nutrient availability can vary, and host defense mechanisms often restrict access to host-derived nutrients. Therefore, microbes must adapt to these microenvironments by regulating nutrient acquisition and metabolism, and by employing mechanisms such as virulence factors that release host-derived nutrients. This metabolic plasticity is a key feature that enables certain microbes to thrive during host-microbe interactions. Hence, metabolism is essential for fungal virulence; however, the mechanisms by which carbon and nitrogen sources directly modulate virulence remain underexplored. Moreover, much remains to be learned about fungal species and host species specificity. In this review, we discuss the links between carbon and nitrogen metabolism and fungal virulence in human-pathogenic fungi, highlighting the roles of different nutrient types within the host and their influence on fungal virulence. Understanding fungal physiology could help to develop new strategies to control fungal disease.

It is well established that within a bacterial species, genotypic and phenotypic variation leads to differences in virulence, antibiotic susceptibility, and metabolism. However, there is also increasing evidence that often multiple variants of the same species co-inhabit the same site in the human body, both during health and disease. This within-host microdiversity can develop over time for pathogens in chronic infections and has been observed for many members of the microbiota, for instance in the gut and on the skin. Research is just beginning to uncover how this within-host intra-species diversity develops and why it matters. Intra-species diversity is largely stable over time, with occasional selective sweeps of new genotypes, and the overall level of diversity is modulated by both microbe-microbe and microbe-host interactions. Furthermore, data indicate that within-host microdiversity can impact the stability of bacterial communities, their antimicrobial resistance, and the efficacy of probiotics and microbiota transplants. Here, we describe the evolutionary and ecological processes that promote high or low within-host microdiversity and the extent of this diversity in the human microbiota and in infections. In addition, we consider how microdiversity within individuals shapes the functional role of the human microbiota and the progression of disease. Together, within-host microdiversity is a newly developing way to think about the diversity of human-associated microbes, with implications in how we treat chronic infections and manipulate our microbiota to promote health.

Urinary tract infections (UTIs) are a significant public health burden that impact millions of people every year and are highly prevalent among hospital-acquired infections. Klebsiella pneumoniae is globally the second most common cause of UTIs after uropathogenic Escherichia coli (UPEC). Thus far, the molecular mechanisms underlying pathogenesis are better understood in UPEC than in K. pneumoniae. UPEC is known to have virulence phenotypes such as fimbrial adhesion and evasion of complement-mediated killing. In other infection types, K. pneumoniae fitness has been associated with mucoidy and diverse capsular serotypes. To establish K. pneumoniae virulence phenotypes contributing to UTI, we examined how environmental cues regulate urovirulence-associated phenotypes in clinical K. pneumoniae UTI strains. These phenotypes included capsular polysaccharide properties, hemagglutination, serum resistance, adherence to bladder epithelial cells, and in vivo fitness. We found that clinical K. pneumoniae UTI isolates' phenotypes are highly heterogeneous and can change in response to human urine. Despite K. pneumoniae clinical isolates presenting heterogeneous fitness properties, all similarly colonize the urinary tract. These results suggest that additional fitness factors contribute to K. pneumoniae uropathogenesis. Identifying these shared fitness factors will provide mechanistic insights into Klebsiella uropathogenesis and reveal candidate therapeutic targets.