Cell host & microbe最新文献

Mucosal immunity deploys diverse defenses against fungal pathogens, yet the evolution of fungal resistance demands new antifungal strategies. Here, we uncover that intestinal epithelial cells secrete the host histidine methyltransferase METTL9 as a cross-kingdom, catalytic antifungal effector. Proteomic profiling revealed that exposure to Candida albicans induces robust METTL9 secretion into the intestinal lumen. Extracellular METTL9 directly binds the fungal zinc-scavenging protein PRA1, catalyzing histidine methylation of this zincophore to disrupt zinc acquisition-an essential micronutrient for fungal growth and virulence. This methylation-driven "nutritional sabotage" restricts C. albicans colonization and dissemination in vivo and also targets multidrug-resistant Candida auris, which retains PRA1. Clinically, reduced METTL9 levels in colonic mucosa from patients with inflammatory bowel disease correlate with increased C. albicans abundance, linking METTL9 to human antifungal mucosal homeostasis. Our findings reveal a host-derived, catalytic antifungal mechanism that bypasses conventional resistance pathways, establishing secreted methyltransferases as an arm of innate mucosal immunity.

Trained immunity confers innate immune memory via metabolic and epigenetic reprogramming, yet the intercellular mediators regulating this process in host defense remain largely elusive. Here, through plasma exosomal profiling of tuberculosis (TB)-resistant individuals, we identify a trained immunity-inducing long non-coding RNA (lncRNA), termed tuberculosisresister-derived CLOCK regulator 1 (TRCR1). Mechanistically, exosome-derived TRCR1 collaborates with the RNA-binding protein FXR2 to stabilize CLOCK mRNA by forming lncRNA-protein-mRNA complexes in monocytes, thus enhancing circadian regulator CLOCK expression and promoting CLOCK-mediated histone H3 acetylation (K9/K14) at immune gene promoters, ultimately establishing epigenetic memory-mediated antimicrobial activity. We further reveal that Mycobacterium tuberculosis (Mtb)-secreted protein MPT53 induces lung epithelial cells to release TRCR1-enriched exosomes. In mice, TRCR1 training strengthens host anti-Mtb immunity and improves Bacille Calmette-Guérin (BCG) vaccine efficacy. Collectively, our findings unveil an intercellular TRCR1-FXR2-CLOCK axis driving trained immunity at the lung-systemic immune interface, providing a strategy for refining BCG vaccination and preventing infectious diseases.

In this issue of Cell Host & Microbe, Qiao et al. show that Bacteroides asparaginase reshapes anti-tumor immunity. When bacteria deplete asparagine, CD8⁺ T cells lose stemness and effector capacity, promoting tumor progression and weakening anti-PD-1 therapy. Deleting asparaginase restores asparagine to the tumor, enhancing anti-tumor immunity and immunotherapy.

Early-life gut microbiome development is shaped by complex maternal and nutritional influences, yet the temporal and directional structure of these interactions remains unclear. In a longitudinal study of 152 mother-infant dyads in rural Burkina Faso, we examine how maternal gut and milk microbiomes, alongside milk components, influence infant gut microbiome development during the first 6 months. At 1-2 months, the infant gut microbiome clusters into three types: Escherichia-dominated, Bifidobacterium-dominated, and a diverse, pathogen-prevalent profile, which become less distinct by 5-6 months. Early infant gut microbiomes associate with maternal prenatal gut microbiota and early milk microbiome and oligosaccharides, while later variation links to other milk nutrients. Furthermore, early infant gut profiles predict subsequent milk composition, suggesting potential bidirectional communication between infant needs and maternal lactational physiology. These findings offer insights into early-life microbial development and inform future mechanistic studies and microbiome-targeted interventions, particularly in low-resource settings.

The gut mucosal immune system orchestrates diverse defense mechanisms against fungal pathogens. In this issue of Cell Host & Microbe, Bao and Yang et al.¹ demonstrate that intestinal epithelial cells secrete an anti-zincophore protein, METTL9, that limits fungal access to the essential micronutrient zinc, thereby diminishing colonization and growth.

Apoptosis is a defense response involving key players, including BH3-only proteins that engage BCL-2 family proteins BAX and BAK, initiating mitochondrial outer membrane permeabilization and caspase activation. However, Shigella flexneri subverts these death pathways to promote infection. Here, we identify the Shigella type III secretion system effector OspB as an enzyme that suppresses apoptosis by targeting BAX and BAK. OspB recognizes BAX/BAK in complex with BH3-only activators, notably tBID, and catalyzes a peptide-bond recombination between their BH3 domains. This reaction generates chimeric proteins comprising the N-terminal BH3-only segment fused to the C-terminal region of BAX or BAK, irreversibly inhibiting protein function and thus mitochondrial outer membrane permeabilization and apoptosis. OspB-mediated apoptosis inhibition enhances S. flexneri virulence in vivo. Homologous effectors with similar catalytic activity are conserved across various bacterial species. These findings reveal a bacterial strategy for apoptosis inhibition via remodeling of BCL-2 family proteins, offering avenues for therapeutic intervention.

Steroid hormone metabolism by the gut microbiome affects host physiology, however, the underlying microbial pathways remain incompletely understood. Here, we isolate a gut bacterial species, which we designate Clostridium steroidoreducens, that reduces cortisol and related steroid hormones to 3β,5β-tetrahydrosteroid products. Through transcriptomics and enzymatic discovery, we establish the C. steroidoreducens OsrABC steroid hormone pathway. OsrA is a 3-oxo-Δ¹-steroid hormone reductase that targets synthetic glucocorticoids, including prednisolone-a frontline Crohn's disease therapy. OsrB is a 3-oxo-Δ⁴-steroid reductase that converts steroid hormones to 5β-dihydrosteroid intermediates, which OsrC subsequently reduces to 3β,5β-tetrahydro products. Homologs of osrA and osrB predict steroid-reducing activity across gut bacteria and are enriched in metagenomes of Crohn's disease patients. Consistent with a role in modulating drug efficacy, C. steroidoreducens colonization decreases prednisolone bioavailability in gnotobiotic mice. These findings thus define a previously unrecognized pathway for microbial steroid hormone inactivation and establish a mechanistic basis for bacterial interference with anti-inflammatory therapies.

Plants utilize nucleotide-binding leucine-rich repeat (NLR) receptors to detect pathogen effectors and initiate a potent immune response called effector-triggered immunity (ETI). However, this defense relies on the presence of recognizable effectors in pathogens, which is often unpredictable during natural infections. To address this, we engineer plant endophytes, termed Sentinels, to heterologously express effectors that are recognized by the host's corresponding NLR. Using an OxyR regulatory circuit, effector expression is activated by reactive oxygen species-a common signal during pathogen infection. This circuit enables ETI activation against pathogens without recognizable effectors. Colonization by the sentinel bacterium slightly alters microbial abundance but maintains overall microbiota diversity and normal plant growth. We demonstrate the strategy's versatility by testing distinct effector-NLR recognition pairs in various plants against a range of pathogens. This strategy exploits the microbiota-host-pathogen interaction network to rapidly engineer a spectrum-expanded ETI, complementing synthetic microbial consortia for plant defense.

Exercise is beneficial to physical health, and it also helps to promote efficacy following immunotherapy. In a recent paper published in Cell, Phelps et al. identified that the gut microbiota plays a critical role in how exercise improves checkpoint inhibitor efficacy in melanoma.

Animals harbor divergent microbiota, including various Bifidobacterium species, yet their evolutionary relationships and functional adaptations remain understudied. Using samples from insects, reptiles, birds, and mammals, we integrated taxonomic, genomic, and predicted functional annotations to uncover how Bifidobacterium adapts to host-specific environments. Host phylogeny is a major determinant of gut microbial composition. Distinct microbiota in mammalian and avian hosts reflect evolutionary adaptations to dietary niches, such as carnivory, and ecological pressures. At a strain-resolved level, Bifidobacterium and their hosts exhibit strong co-phylogenetic associations, driven by vertical transmission and dietary selection. Functional analyses highlight striking host-specific adaptations in Bifidobacterium, particularly in carbohydrate metabolism and oxidative stress responses. In mammals, Bifidobacterium strains are enriched in glycoside hydrolases tailored to complex carbohydrate-rich diets, including multi-domain GH13_28 α-amylases associated with degradation of resistant starch. Together, these findings deepen our understanding of host-microbe co-evolution and the critical role of microbiota in shaping animal health and adaptation.