mBio最新文献

Gammaherpesviruses are ubiquitous pathogens that establish lifelong infection and are associated with the development of cancer and multiple sclerosis. Unlike other viral families, gammaherpesviruses selectively target B cells to establish chronic infection. Specifically, gammaherpesvirus-driven differentiation of latently infected cells through the germinal center supports chronic infection and seeds viral lymphomagenesis. CD11c⁺ B cells are induced by most viral infections and are also observed in aged individuals and autoimmune diseases. Classically, CD11c⁺ B cells differentiate via an extrafollicular pathway that does not involve germinal center response, generating antibodies of beneficial (antiviral) or pathogenic (self-reactive) nature. While CD11c⁺ B cells are induced during B cell-tropic gammaherpesvirus infection, their role in chronic infection remains poorly defined. Here, we demonstrate that infection of the CD11c⁺ B cells, including those expressing germinal center markers, contributes to the overall latent gammaherpesvirus reservoir during natural infection. Both T-bet⁺ and T-bet^neg CD11c⁺ B cell subsets expanded and underwent germinal center differentiation during chronic gammaherpesvirus infection. Furthermore, B cell-intrinsic T-bet expression attenuated the long-term latent viral reservoir, gammaherpesvirus-driven germinal center responses, and differentiation of self-reactive B cells. In summary, our study for the first time defines CD11c⁺ splenic B cells as a reservoir of latent gammaherpesvirus during mucosal chronic infection and reveals an important role of T-bet⁺ B cells in controlling long-term infection and gammaherpesvirus-driven pathogenic host processes.IMPORTANCEGammaherpesviruses are ubiquitous pathogens that are associated with cancer and multiple sclerosis. These viruses selectively infect B cells and drive their differentiation through the germinal center response to establish chronic infection. Here, we demonstrate that gammaherpesvirus infection drives expansion and germinal center-based differentiation of CD11c⁺ B cells that host the latent viral reservoir. We also show that B-cell-intrinsic T-bet expression is important for control of long-term gammaherpesvirus infection and pathogenesis.

Excessive binding of antibodies to the bacterial cell surface can paradoxically increase resistance of some Gram-negative pathogens to complement-mediated killing (CMK). We examined the CMK of 336 Neisseria gonorrhoeae isolates from 283 participants recruited to a clinical trial. Serum bactericidal assays revealed 3% (9/283) of the autologous participant sera blocked CMK. Gonococci isolated from these participants were resistant to the autologous host serum, but sensitive to pooled healthy control sera (HCS) and protected by autologous host serum in a 1:1 mixture with HCS. Analysis of clinical metadata showed that there was a significantly higher proportion of blocking sera found in participants with urethral infection and from men within the transmission network of men who have sex with women, when compared to the whole cohort. Following antibody purification from participants with blocking sera (5/9), total IgG protected autologous isolates from HCS-mediated killing. A closer examination of IgG subclasses using whole gonococcal cell ELISAs revealed a significant correlation between increased IgG2 binding and decreased IgG3 binding to the cell surface of isolates that were resistant to CMK. This indicates that IgG2 prevents bactericidal IgG3 from initiating CMK, with an increased IgG2:IgG3 ratio blocking CMK of gonococci. We therefore reveal a previously unrecognized mechanism by which blocking antibodies prevent CMK of N. gonorrhoeae.

Importance: The antigenic variation of Neisseria gonorrhoeae and a limited mechanistic understanding of immune responses to this bacterium have presented multiple challenges to generating a protective vaccine. Here, we use a collection of N. gonorrhoeae clinical isolates (n = 336) for a robust analysis of the host immune response to infection. We reveal a mechanism for serum resistance in which some isolates of N. gonorrhoeae drive the production of inhibitory IgG2 antibodies, which block the activity of IgG3 bactericidal antibodies. Importantly, an increased ratio of IgG2:IgG3 bound to the bacterium promotes serum resistance. Recently, there has been increased interest in developing a vaccine against N. gonorrhoeae given the observation that the licensed outer membrane vesicle-based vaccine against Neisseria meningitidis (MeNZB) generated some cross-protection against N. gonorrhoeae. Thus, the mechanism described here should guide the development of a vaccine that simultaneously prevents serum resistance and promotes serum killing of the gonococcus.

Degenerative genome evolution is widely found among obligatory bacterial mutualists, as observed in plant-sucking hemipteran insects whose symbiont genomes are highly reduced and specialized for provisioning of essential amino acids. Originally, such symbionts must have been derived from environmental free-living bacteria. It is elusive, however, what evolutionary changes are involved in the early stages of such elaborate mutualistic associations. Here, we addressed this evolutionary question using the experimental symbiotic system consisting of the stinkbug Plautia stali and the model bacterium Escherichia coli. In E. coli, metJ encodes a repressor of the methionine synthesis pathway, and its disruption upregulates production of the essential amino acid methionine. We found that, when metJ-disrupted E. coli was inoculated to P. stali, the insects exhibited significantly elevated hemolymphal methionine levels and improved adult emergence rates, demonstrating that the single-gene mutation makes E. coli mutualistic to P. stali. In comparison with mutualistic E. coli single-gene mutants that upregulate another essential amino acid tryptophan, the phenotypic effects on P. stali were somewhat different: the adult emergence rate was improved by both the methionine-overproducing and tryptophan-overproducing E. coli mutants, whereas the adult body color was improved by the tryptophan-overproducing E. coli mutant only. When we generated a double mutant E. coli ΔmetJΔtnaA and inoculated it to P. stali, the adult emergence rate was not improved but rather attenuated, uncovering non-additive fitness consequences of these single-gene mutations. These results provide insights into what genetic changes may have facilitated the early evolution of the insect-microbe mutualism.IMPORTANCEWhat is the evolutionary origin of elaborate bacterial mutualists entailing drastic genome reduction, specialized metabolism, and uncultivability? This question is important but challenging to address, because the evolution of such symbiotic associations occurred in the past and cannot be observed directly. However, the recent development of an experimental symbiotic system consisting of the stinkbug Plautia stali as host and the model bacterium Escherichia coli as symbiont has opened an avenue to empirically investigate the evolution of host-microbe mutualism. We demonstrated that, strikingly, single-gene mutations of E. coli that upregulate the production of methionine and tryptophan make the non-symbiotic bacterium mutualistic to P. stali, plausibly via provisioning of the essential amino acids that complement the nutritional requirements of the plant-sucking insect host. Our finding provides insight into what genetic changes of the symbiont side can be involved in the early evolution of the host-microbe mutualism.

Extracellular vesicles (EVs) play crucial roles in fungal communication and host immune modulation, representing potential therapeutic targets for fungal infections. This study investigated the role of fungal EVs in both intra- and interspecies communication, focusing on their effects on virulence and immune responses. Co-incubation experiments were performed using EVs derived from Candida albicans and Candidozyma auris to assess interactions with C. albicans planktonic cells and biofilms, as well as Cryptococcus neoformans and Cryptococcus gattii EVs interacting with C. neoformans cultures. EVs were observed associating with recipient cell surfaces, suggesting subsequent internalization. Functional assays revealed that EV exposure led to increased expression of CAP59, LAC1, URE1, and ERG11 genes, correlating with reduced antifungal susceptibility in both planktonic and biofilm forms. Additionally, EVs facilitated cross-species communication, enhancing biofilm adhesion and dispersion, which emphasizes their role in phenotypic modulation. Macrophages stimulated with fungal EVs exhibited receptor-specific gene expression changes (dependent on the EVs' origin, including variation among species of the same genus), along with a pro-inflammatory phenotype marked by increased iNOS expression, enhanced TBK1/STAT1 production, and elevated levels of IL-1β, IL-6, and IL-8. Collectively, these findings underscore a critical role for fungal EVs in interspecies communication, biofilm regulation, and immune modulation, offering valuable insights into fungal pathogenicity mechanisms.IMPORTANCECurrently, no vaccines exist to prevent fungal infections, underscoring the need for new therapies. As fungal diseases increase globally, understanding fungal biology is essential to identifying treatment targets. Fungi use extracellular vesicles (EVs) to communicate and evade immune responses. EVs mediate cell-cell communication, transporting proteins, polysaccharides, lipids, and nucleic acids, serving as "messages" exchanged within a fungal network. Understanding how these vesicles facilitate communication not only within a single species but also across different fungal species can shed light on their contribution to infection persistence and cross-species adaptability. Moreover, EVs may have a broader role in inter-kingdom signaling, influencing how fungi interact with host immune cells. The impact of fungal EVs on human innate immune responses remains a largely underexplored area, with significant gaps in our knowledge. This study aims to examine how fungal EVs affect immune responses and whether their signaling varies across species, potentially revealing new therapeutic targets.

Pseudomonas putida KT2440 has long served as a reference strain in environmental microbiology, biotechnology, and synthetic biology. Its recent taxonomic reclassification as P. alloputida, however, exemplifies the tensions generated by top-down renaming decisions that overlook long-standing community practice. Although phylogenetic analyses suggest that KT2440 differs from the type strain of P. putida, the new name disrupts decades of accumulated knowledge, continuity, and shared identity built around the original designation. We argue that ever-changing taxonomic orthodoxy should not override practical utility, historical coherence, and sense of community. Given the strain's global relevance and the insignificant acceptance of the proposed new name, we advocate for retaining the traditional species name or, if necessary, adopting an alternative solution developed through broad consultation. The case of strain KT2440 highlights the need for common sense and community involvement in microbial nomenclature, especially for iconic species and strains whose names have been part of scientific communication and practice.

Harmful algal blooms (HABs) pose public health and ecological risks in aquatic environments. HABs drive the bioaccumulation of a specific family of specialized metabolites known as "kainoids." Kainoid derivatives, such as kainic acid (KA) and domoic acid (DA), are among the most toxic marine-derived metabolites produced by a limited number of algal species. While recent studies have provided insights into the molecular basis of KA and DA production in red algae and diatoms, knowledge of the biosynthesis of kainoids remains insufficient. In a new report published in mBio, Wood-Rocca et al. decode the DA biosynthetic route in the widespread Western Pacific benthic diatom Nitzschia navis-varingica (S. M. Wood-Rocca, N. Allsing, Y. Ashida, M. Mochizuki, et al., mBio 16:e02079-25, 2025, https://doi.org/10.1128/mbio.02079-25). We discuss how evolutionary genomics studies bridge the gap between fundamental biology and applied environmental and biotechnological research, enhancing our ability to understand, predict, and harness marine natural products.

Coronaviruses (CoVs) hijack host RNA-binding proteins (RBPs) to facilitate their replication, but the viral proteins and host RBDs that participate in the synthesis of viral RNA and protein are unclear. In this study, we revealed that DEAD-box helicase (DDX5) and staphylococcal nuclease domain-containing protein (SND1) facilitate viral RNA synthesis and that RNA guanine-7 methyltransferase (RNMT) enhances viral protein translation to promote viral replication via coronaviral subgenomic RNA-protein interactomes. DDX5 and SND1 positively regulate PEDV replication by promoting viral RNA synthesis via the binding of DDX5 to positive-sense viral RNA, whereas SND1 specifically detects negative-sense viral RNA. The interaction of DDX5/SND1 and N/nsp9/nsp12 promotes the formation of replication-transcription complexes for viral RNA synthesis to facilitate viral replication. We found that RNMT captures the host protein translation system to cyclize viral mRNA to assist in viral protein translation to promote viral replication. We also found that DDX5 broadly interacts with the N protein of CoVs and promotes the RNA synthesis of bovine coronavirus and porcine delta-coronavirus to promote viral replication. These results indicate that CoVs use host proteins to assist in the synthesis of viral RNA and protein to facilitate viral replication.

Importance: The synthesis of viral RNA and proteins is a crucial process in the life cycle of CoVs. Our observations indicate that DDX5 and SND1 facilitate the assembly of viral replication-transcription complexes and enhance viral RNA synthesis, with DDX5 binding to positive-sense RNA and SND1 binding to negative-sense RNA. Meanwhile, RNMT promotes viral protein translation by hijacking the host translation machinery and mediating the circularization of viral mRNA. These findings offer new insights into the mechanisms through which coronaviruses exploit both viral and host proteins to synthesize viral RNA and proteins.

Down syndrome, or Trisomy 21, is associated with excessive interferon (IFN) signaling and concomitant susceptibility to both autoimmunity and immunodeficiency. One of the many clinical phenotypes observed in people with Down syndrome is increased risk for oral candidiasis. Because oral candidiasis can be caused by excessive IFN-γ signaling, we asked whether IFN-gammopathy could be playing a role in susceptibility to oral candidiasis in Down syndrome. We used the Dp16 mouse model of Down syndrome, which displays mild systemic interferonopathy, to model oral candidiasis. We found that the Dp16 model does not exhibit oral IFN-gammopathy and is not susceptible to oral candidiasis. We exposed the Dp16 mice to various inflammatory and infectious stimuli with the goal to induce enhanced local IFN-γ responses, but these did not induce oral IFN-gammopathy or promote susceptibility to oral candidiasis. We conclude that the Dp16 model is not well-suited to study oral IFN-gammopathy or oral candidiasis. Clinical studies of oral candidiasis in people with Down syndrome are warranted.IMPORTANCEDown syndrome, caused by three copies of chromosome 21, presents with different medical conditions in different people. One such condition for some people with Down syndrome is increased susceptibility to oral infection with the fungus Candida albicans. C. albicans is a normal member of the human oral microbiome, but it can also cause painful infections. Down syndrome causes an excess of inflammatory molecules called interferons (IFNs). Excessive inflammation due to one type of IFN, IFN-γ, can cause susceptibility to oral C. albicans infection in certain settings. Thus, we wanted to assess whether excessive IFNs may cause susceptibility to oral C. albicans infection in Down syndrome. We used the Dp16 mouse model of Down syndrome. We found, however, that Dp16 mice did not exhibit excessive IFN-γ oral mucosal responses and were not susceptible to oral C. albicans and thus are not a suitable model for studying this phenomenon.

Epigenetic mechanisms are increasingly recognized as critical regulators of host-microbiota interactions, yet their specific roles in gut homeostasis remain elusive. Here, we demonstrate that intestinal epithelial-specific deletion of the DNA demethylase Tet2 leads to structural abnormalities, impaired barrier function, and remarkable reprogramming of the gut microbiota. Mechanistically, Tet2 deficiency downregulated the apical sodium-dependent bile acid transporter ASBT/Slc10a2, resulting in altered bile acid homeostasis with luminal accumulation of hyocholic acid (HCA). This metabolic shift created a favorable niche for the selective expansion of bile salt hydrolase (BSH)-expressing Lactobacillus species. Furthermore, we identified an age-dependent regulatory role of HCA, which promoted Lactobacillus in young mice but enriched Akkermansia in aged animals. Our findings establish an epigenetic-metabolic-microbial axis centered on Tet2-mediated bile acid regulation, providing new insights into how host epigenetic factors shape the gut microbial ecosystem in an age-sensitive manner.IMPORTANCEWhile the gut microbiota is known to influence host physiology, the molecular mechanisms by which the host epigenetically regulates microbial composition remain largely unexplored. Our work reveals that the epigenetic enzyme Tet2 in intestinal epithelial cells acts as a master regulator of gut microbial ecology by modulating bile acid metabolism. The discovery that Tet2 deletion drives hyocholic acid (HCA) accumulation-which exerts age-dependent effects on Lactobacillus and Akkermansia-provides a novel principle for understanding host-microbe interactions across the lifespan. By linking epithelial DNA demethylation to bile acid transport and microbial phenotype, we establish a previously unrecognized Tet2-ASBT-HCA pathway that expands the conceptual framework for microbiota research. These insights open new avenues for therapeutic interventions aimed at reversing microbial dysbiosis through epigenetic or metabolic modulation.