Biology subjects

Cohen, S.

Publications and source records attributed to Cohen, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Genomic classification and immune profiling define mucosal melanoma

Mucosal melanoma is a rare, lethal melanoma subtype with distinct genetics and limited benefit from immunotherapy. To define features associated with mucosal melanoma clinical outcomes, we assembled a large, multimodally profiled cohort spanning primary and metastatic disease. Compared with cutaneous melanoma, primary mucosal melanoma showed greater genomic heterogeneity, ploidy and aneuploidy, and a more dedifferentiated, proliferative transcriptional state. Analysis of genomic sequencing of 339 patients with mucosal melanoma identified four mutually exclusive genomic subtypes: CDK4/MDM2/CCND1, SF3B1-mutated, TP53/ATRX, and mucosal melanoma Triple WT, associated with distinct anatomic sites but similar outcomes. In the tumor microenvironment, we observed reduced T cell infiltration and increased CD163+ tumor-associated macrophages in mucosal melanoma relative to cutaneous melanoma. In matched longitudinal samples, CD163+ tumor-associated macrophages increased with disease progression and immunotherapy resistance. CD163+ tumor-associated macrophages engaged non-regulatory T cells through GAL9-TIM-3 interactions, nominating TIM-3 blockade as a therapeutic strategy for mucosal melanoma. These findings define the distinct aggressive biology of mucosal melanoma and highlight potential therapeutic targets and mechanisms of immune resistance.

cancer biology↗

bioRxiv2026

Evolutionary adaptation of helminth immunomodulators to their hosts

Background: Parasitic nematodes have evolved secreted effector proteins which interact with host molecules to modulate the host immune response. These interactions can be highly specific and are under strong selective pressure. Here, we investigate the host-pathogen interaction between Heligmosomoides bakeri and its natural host Mus musculus, and between H. polygyrus and its natural host Apodemus sylvaticus. We focus on the Alarmin Release Inhibitor family (previously called HpARI) produced by heligmosomid parasites, which interact with IL-33 and heparan sulphate. Results: Using comparative genomics, we identified duplications and diversifications of the ARI family including multiple copies of ARI1 and conserved ARI3 homologues in both H. bakeri and H. polygyrus. We identify a new family member, HpolARI4, encoded by H. polygyrus, as well as a more distant homologue, HmixARI, encoded by Heligmosomum mixtum, a parasite of the bank vole (Myodes glareolus). Our functional assays identify that HpolARI4 preferentially blocks A. sylvaticus IL-33 but has little activity against M. musculus IL-33, whereas HbakARI2 is highly specific for M. musculus IL-33. We furthermore show differential interaction with host heparan sulphate, with HbakARI2 and HpolARI4 showing high affinity binding, whereas HbakARI3 shows no binding. We further test this family against non-host human IL-33 and show that functional suppression can be achieved by HbakARI3 in vitro and in vivo. Conclusion: By integrating genomic data, structural insights, and functional assays, we reveal how the expansion and diversification of the ARI family drive host-specific IL-33 modulation, providing a molecular model for nematode-host co-evolution.

immunology↗

bioRxiv2026

Subunit vaccination enhances protection conferred by prior Mycobacterium tuberculosis exposure

Mycobacterium tuberculosis (Mtb) remains the leading cause of death from a single infectious agent. Although BCG protects against disseminated tuberculosis in infants, it has failed to curb transmission among adults. Animal models are used to prioritize vaccines entering clinical trials, but current models use Mtb-naive mice, limiting their relevance to humans in endemic settings, the primary targets of vaccine trials. Here we used a mouse model of Mtb exposure, CoMtb, where a cervical lymph node Mtb infection protects against aerosol challenge, consistent with historical observations in humans that prior Mtb exposure reduces disease risk. When we compared the impact of CoMtb on vaccine efficacy, BCG failed to provide added protection over CoMtb, while protein subunit vaccination further reduced lung burdens. This protection was associated with decreased KLRG1+ vascular CD4+ T cells and enhanced polyfunctional lung CD4+ T cells before and after aerosol challenge. Our findings were corroborated in an analysis of vaccinated humans stratified by QuantiFERON-TB status, which revealed a similar enrichment of polyfunctional CD4+ T cells in Mtb-exposed individuals. These data support the use of CoMtb to test vaccine efficacy in Mtb-exposed individuals and highlight the potential of subunit vaccines in endemic regions.

immunology↗

bioRxiv2026

Artificial endoplasmic reticulum-lipid droplet tethers facilitate lipid incorporation into lipid droplets

Lipid droplets (LDs) are ubiquitous organelles that store neutral lipids to meet cellular energetic and signaling needs. As a unique monolayer structure, LDs arise from the endoplasmic reticulum (ER) and acquire proteins and lipids through their membrane contact sites (MCSs) with the ER. In this study, we exogenously induce ER-LD MCSs using a dimerization-dependent fluorescent protein (ddFP) system. Strikingly, inducing these MCSs increases LD size without influencing LD total amount per cell, in a manner that is distinct from LD biogenesis induced by the dietary fatty acid oleic acid. By examining the trafficking of the triacylglycerol synthesis enzyme DGAT2 under ddFP induction, we found that artificial tethering recruits LD proteins to the ER-LD interface but not to the LD surface, unlike oleic acid supplementation. However, by supplementing ddFP-transfected cells with fluorescent fatty acids, we found that ddFP-positive LDs preferentially incorporate exogenous lipid, suggesting that inducing MCSs can facilitate ER-to-LD lipid transfer. These results demonstrate ddFPs as a tool for manipulating LD MCSs and elucidate the role of ER-LD MCSs following LD biogenesis to continue to promote LD growth.

Cell Biology↗

bioRxiv2026

APOE interacts with COX-2 on lipid droplets to modulate inflammatory lipid signaling

Alzheimers Disease (AD) is the leading cause of dementia worldwide. Expression of the E4 variant of apolipoprotein E (APOE) greatly increases individuals risk of developing AD. In response to lipogenesis in astrocytes, APOE can escape secretion and traffic to the cytoplasmic surface of lipid droplets (LDs), but protein interactors of APOE at the LD were unknown. Here we find that LD-localized APOE physically interacts with the inflammatory lipid signaling enzyme cyclooxygenase-2 (COX-2). Like APOE, COX-2 can avoid the secretory pathway and traffic to LDs in response to lipogenesis. APOE3, but not APOE4, increases COX-2 localization to LDs. Computational modeling, microscopy-based assays, and targeted lipidomics reveal that APOE3 promotes while APOE4 suppresses COX-2 enzymatic activity at LDs and intracellular prostaglandin production. This work identifies a novel and targetable protein-protein interaction of APOE and provides a mechanistic link between APOE4 and dysregulated inflammatory lipid signaling.

cell biology↗

bioRxiv2026

Cholesterol links blood feeding to mosquito development and reproduction

Mosquitoes undergo major metabolic remodeling as they transition from aquatic larvae to terrestrial, blood-feeding adults, yet the biochemical principles supporting these life cycle transitions remain poorly understood1. Early metabolic studies established that mosquitoes are sterol auxotrophs2,3; however, the extent to which this auxotrophy influences developmental progression and stage transitions remains unknown. Here, using sterol-defined culture systems, we uncover a central and stage-specific role for sterol metabolism in mosquitoes. We show that eggs of multiple mosquito species, from Anopheles gambiae (Giles 1902; hereafter A. gambiae) to Aedes species in both wild and laboratory settings, are enriched in cholesterol consistent with maternal provisioning. In the Asian tiger mosquito Aedes albopictus (Skuse, 1894; hereafter Ae. albopictus), egg cholesterol supports early larval development, after which larvae depend on the acquisition of dietary sterols to complete development. Like cholesterol, dietary plant- and fungal-derived sterols support late larval development; however, their utilization is associated with the accumulation of the intermediate sterol desmosterol. Using biochemical assays, we showed that desmosterol is converted to cholesterol through the activity of the Ae. albopictus DHCR-24 enzyme. This metabolic axis of desmosterol-to-cholesterol conversion supports late larval development when mosquitoes rely on plant- and fungal-derived sterols for development. dhcr-24 expression is upregulated during the developmental window of dietary sterol acquisition and is selectively induced by its substrate desmosterol, revealing a diet-encoded regulatory mechanism that coordinates metabolic conversion capacity. Extending the analysis to adulthood, we developed a sterol-defined artificial blood-feeding system that enables precise manipulation of dietary sterols in reproductive females and show that cholesterol availability in the diet of females is an essential metabolic driver of egg laying. These findings reveal a developmentally coordinated sterol-use strategy in the life cycle of Aedes mosquitoes, identifying sterol utilization as a central physiological axis linking development, blood feeding, and reproduction, and revealing a sterol-dependent metabolic vulnerability in mosquitoes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/725405v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@13c7843org.highwire.dtl.DTLVardef@fb9203org.highwire.dtl.DTLVardef@2f0db8org.highwire.dtl.DTLVardef@12db355_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

Tubulin polyglutamylation modulates Golgi morphodynamics and neurite branching during neuronal morphogenesis

Neurons establish functional networks through morphological remodeling during neuronal differentiation. Microtubule polyglutamylation is a key microtubule post-translational modification that is highly enriched during this process and plays an important role in differentiation. However, how remodeling of organelle features such as morphology, distribution and interactions depend on tubulin polyglutamylation during neuronal differentiation remain unclear. Here, we employed multispectral imaging combined with quantitative 3D organelle analysis to comprehensively profile eight organelles simultaneously in human induced pluripotent stem cell-derived neurons. We discovered that depletion of tubulin polyglutamylation induces pronounced alterations in somatic Golgi morphology and associated organelle interactions. In addition, Golgi-derived compartments in proximal neurites exhibited altered morphology and dynamics, namely decreased retrograde directionality. These changes were accompanied by increased neurite branching and tortuosity. Together, our findings reveal a previously unrecognized role for tubulin polyglutamylation in coordinating organelle organization with neurite architecture, providing a mechanistic link between tubulin post-translational modification, Golgi morphology, dynamics, and neuronal morphogenesis.

cell biology↗

bioRxiv2026

Attomolar fecal cytokine profiling reveals gut immune dynamics and disease states

The gut modulates systemic health, influencing immune, neurological, and cardiovascular processes. While fecal sequencing of microbial nucleic acids provides a non-invasive view of microbial composition, sensitive measurement of host-derived signals in stool remains limited. Here we introduce DIGEST (Digital Immunoassay for Gut-Environment Single-molecule Targets), an ultrasensitive digital immunoassay that quantifies proteins in fecal extracts to attomolar levels. In mice, longitudinal profiling during a high-fat diet perturbation revealed coordinated host cytokine responses that occurred within 24 hours, with sustained elevation after diet withdrawal, enabling non-invasive tracking of within-subject immune dynamics. Application of DIGEST to quantify a panel of host inflammatory cytokines in patients with inflammatory bowel disease distinguished active ulcerative colitis from quiescent disease and non-IBD controls (AUC=0.98). In advanced melanoma patients receiving PD-1 blockade, pretreatment fecal IL-23 concentrations discriminated responders from non-responders with an AUC of 0.87. Together, these results establish DIGEST as a generalizable platform for sensitive, non-invasive quantification of host protein activity at the gut interface, with broad applications in basic science discovery, disease surveillance, and therapy response prediction.

systems biology↗

bioRxiv2026

Context-dependent determinants of CRISPR-Cas9 editing efficiency revealed through cross-species endogenous editing analysis

Accurate prediction of CRISPR-Cas9 guide RNA (gRNA) editing efficiency remains limited, particularly outside human systems, where models trained on exogenous human datasets show poor generalization. We analyzed Cas9 efficiency and repair outcomes using novel endogenous editing data from four human cell types, two tomato cell types, and cells from giant river prawn and black soldier fly. While integrating publicly available predictors via ensemble frameworks improved performance, our analysis revealed hundreds of novel features affecting activity. Crucially, dominant features related to sites competition for gRNA, and local geometric properties varied across systems, highlighting the strong context dependence of Cas9 efficiency and arguing against a universal model. Interestingly, codon usage bias-based features also emerged as informative predictors, as they are proxies for chromatin accessibility. In contrast, trends in repair outcomes remained conserved. This work provides essential resources for more generalizable CRISPR guide design.

synthetic biology↗

bioRxiv2026

Alternative exon splicing reveals hidden mitochondrial targeting of PLIN3

Perilipin 3 (PLIN3) is a lipid droplet-associated protein implicated in cellular lipid metabolism. We characterize a previously unrecognized alternative splicing event in human PLIN3. The generated transcript PLIN3B is detectable at the RNA level across human tissues and is modulated by antisense oligonucleotide-mediated splicing. Despite clear evidence for PLIN3B transcript expression, endogenous PLIN3B protein could not be detected using multiple complementary state-of-the-art detection strategies. When expressed exogenously, PLIN3B coding sequence encodes an unstable protein that localizes predominantly within mitochondria, in contrast to canonical PLIN3. Using super-resolution microscopy, correlative light-electron microscopy, and interaction proteomics, we show that PLIN3B accumulates intramitochondrially and engages protein quality control machinery. Mitochondrial targeting depends on residues shared by both isoforms, not altered by alternative splicing, indicating that mitochondrial targeting is normally repressed. Together, these results show that alternative exon splicing in PLIN3 reveals latent mitochondrial targeting without producing detectable endogenous protein, underscoring the need to distinguish transcript diversity from stable protein expression.

cell biology↗

bioRxiv2026

Tubulin acetylation governs organelle remodeling and lysosomal reformation during neuronal differentiation

A functional nervous system depends on neuronal morphology established during differentiation. The microtubule (MT) cytoskeleton supports neuronal differentiation by organizing organelle positioning and facilitating transport. The dynamics and properties of MTs are regulated by a variety of post-translational modifications (PTMs), with many organelle interactions occurring preferentially on modified MTs. Here we find that tubulin acetylation is enriched at specific subcellular locations during differentiation of human induced neurons. We apply a quantitative multispectral imaging pipeline to simultaneously analyze eight membrane-bound organelles and define how tubulin acetylation reshapes organelle architecture and interaction networks during neuronal differentiation. We find that loss of tubulin acetylation broadly alters organelle morphology, spatial distribution, and inter-organelle interactions, with lysosome-organelle interactions most affected. Loss of acetylated MTs leads to enlarged, highly acidified lysosomes, impaired lysosomal fission, and accumulation of autolysosomes, consistent with defective lysosomal reformation. Super-resolution microscopy further reveals that lysosome-endoplasmic reticulum (ER) contacts preferentially associate with acetylated MTs. Together, our data support a model in which tubulin acetylation coordinates lysosome-ER interactions to facilitate lysosome remodeling and turnover. This work establishes tubulin acetylation as a key cytoskeletal regulator that links organelle interactions to organelle homeostasis important for neuronal differentiation.

cell biology↗

bioRxiv2026

Loss of dispersal via ice nucleation activity constrains microbial evolution

The ability to disperse over long distances through the atmosphere is a common trait across the tree of life, facilitating resource access and increasing long-range gene flow. Loss of dispersal mechanisms, viz. flight, can occur in animals found on islands where documented phenotypic changes like loss of wingspan impedes longer distance travel to mate with the metapopulation. Bacteria also experience atmospheric flight and descend via bioprecipitation by catalyzing the freezing of cloud droplets with protein InaZ. InaZ triggers ice nucleation at temperatures near 0{circ}C(1). This ice nucleation activity (INA), a biophysical trait, enhances bacterial deposition through precipitation. The role of InaZ-mediated ice nucleation on bacterial dispersal is well documented, but the impact of loss of INA and thus reduction or loss of atmospheric dispersal on bacterial ecology and evolution has not been described. Here we show that the loss of the ancestral inaZ gene restricts bacterial dispersal and leads to significant genetic and ecological isolation across multiple genera. Through the analysis of available complete genomes, we demonstrate that lineages lacking functional inaZ experience major gene loss events, reduced recombination rates and a marked dependence on human-mediated or insect transmission. These INA-lacking bacteria exhibit an increased ecological signature of isolation that parallels the distribution of geographically isolated animals. Our results establish InaZ as a keystone biophysical trait that defines microbial dispersal strategies. We anticipate these findings will provide a framework for understanding how shifts in biophysical traits drive niche differentiation and changes in dispersal with downstream consequences for Earth system processes. Significance StatementSome microorganisms catalyze freezing of cloud droplets near 0{degrees}C via ice nucleation activity (INA) enhancing their deposition. We determined that loss of the gene encoding the INA protein in Gammaproteobacteria restricts bacterial dispersal. Bacteria that lost this ancestral trait compared to relatives with INA experienced distinct, major gene loss events, altered gene flow and marked dependence on transmission by plant tissues or insects and an increased ecological signature of isolation paralleling the geographically isolated plants and animals. We posit that gene loss for biophysical traits such as INA is a keystone example of the consequences of a biological trait defining microbial dispersal.

evolutionary biology↗

bioRxiv2026

Organelle communication networks rewire to support lipid metabolism during neuronal differentiation

Cell fate transitions require coordinated remodeling of intracellular organelles, but how organelle morphology and interactions rewire during neurogenesis remains unclear. Here we combine multispectral imaging with quantitative organelle signature analysis to simultaneously map eight organelles as human induced pluripotent stem cells differentiate into forebrain-like neurons. We find compartment and time-specific rescaling of organelles and a progressive increase in higher-order membrane contacts, with mitochondria emerging as an early interaction hub. Later, endoplasmic reticulum (ER)-organelle contacts dominate with ER-peroxisome contacts promoting ether lipid biosynthesis, membrane homeostasis and synapse formation. Disrupting this contact impairs plasmalogen production, synaptic organization, and neuronal activity, identifying the ER-peroxisome axis as a key regulator of neuronal maturation.

cell biology↗

bioRxiv2025

Lymphotoxin-driven cancer cell eradication by tumoricidal CD8+ tumor-infiltrating lymphocytes

Tumor-infiltrating lymphocyte (TIL) therapy is FDA-approved for patients with treatment-resistant advanced melanoma, but the TIL subpopulations critical for tumor eradication remains incompletely understood. Using patient-derived TIL-melanoma co-cultures, we identified and characterized a novel subset of CD8+ TIL, capable of class I HLA-independent cancer cell lysis. The lymphotoxin {beta} receptor (LT{beta}R) and interferon (IFN) sensing pathways were nominated as key determinants of TIL-mediated cancer cell killing from a whole-genome, loss-of-function CRISPR screen. Validation studies confirmed that dual LT{beta}R and IFN sensing is necessary and sufficient for cancer cell lysis, and that expanded CD8+ TIL express high lymphotoxin {beta} (LTB) and upregulate lymphotoxin (LTA) upon coculture with cancer cells. Leveraging paired scRNA-seq and scTCR-seq data, we confirmed that enrichment of LTB+CD8+ T cells is associated with clinical response to TIL, and that LTB+CD8+ TIL are expanded from putative neoantigen-reactive, LTBlo CD8+ T cells in resected tumors. SignificanceWe have uncovered a previously unrecognized mechanism of TIL-mediated tumor eradication, providing mechanistic insights into the role of LTBR/IFN signaling in TIL-mediated cancer cell killing, and potentially offering insights into novel strategies to isolate, enrich, and expand tumoricidal TIL or augment specific TIL functions to enhance tumor control.

cancer biology↗

bioRxiv2025

The anti-virus T cell response dominates the anti-cancer response in oncolytic virus therapy

Oncolytic viruses have strong potential as immunotherapies. By causing cancer cells to die and relieve antigens, these viruses can stimulate robust, systemic immune responses that may eliminate disseminated disease and prevent recurrence. Unfortunately, clinical trials using oncolytic viruses have not induced clearance of metastasis or protection from recurrence. Likewise, the combination of the only FDA-approved oncolytic virus-- Talimogene laherparapvec--with immune checkpoint blockade did not improve progression-free or overall survival. Because of these disappointing clinical trials, we sought to measure the ability of oncolytic viruses to induce cancer antigen presentation and the elicitation of cancer antigen-specific immune responses. Our data revealed that despite improved antigen presentation by dendritic cells, priming of cancer antigen-specific T cells was limited. However, viral antigen-specific T cells did develop and were in a phenotypic state to induce an effective response against virally infected cells. These preclinical results were mirrored in human peripheral blood samples. Overall, these data show that oncolytic virus treatment induces a response against the virus itself, but not cancer antigen, explaining the lack of response in metastatic disease. These interesting findings identify a critical mechanism that needs to be overcome to increase the efficacy of oncolytic virus therapy.

immunology↗

bioRxiv2025

Overcoming impaired antigen presentation in tumor draining lymph nodes facilitates immunotherapy

Immunotherapies have revolutionized cancer care in recent decades, but approved therapies often fail and currently only target specific steps in the generation of anti-cancer immune responses. Notably, the majority of approved immunotherapies do not target antigen processing and presentation, which are key steps in the development of immune responses and harbor potential as targets to improve immunotherapy. Here, we demonstrate that breast tumors induce locoregional lymph node impairment in antigen presentation--but not in antigen processing--which limits anti-cancer antigen- specific T cell responses. Inhibition of the locoregional T cell response was due to a tumor-mediated reduction of the cytokine IL1{beta} in tumor draining lymph nodes, which impaired antigen presentation. Further, we tested the ability of dendritic cells in lymph nodes at various distances from the primary tumor to be activated utilizing an antigen- agnostic adjuvant delivery strategy. We observed improved anti-tumor T cell responses when the adjuvant was delivered to cancer antigen-positive lymph nodes distant from the tumor, suggesting these lymph nodes can be targeted to improve anti-cancer immune responses. When combined with immune checkpoint blockade, delivery of the adjuvant to distant lymph nodes led to long-term survival and protection from recurrence. Antigen presentation and T cell responses could also be recovered by exogenous delivery of IL1{beta} via intratumoral injection, with improved survival when combined with immune checkpoint blockade. Our study demonstrates that tumor- induced locoregional impairment of antigen presentation can be overcome by the appropriate introduction of immunological adjuvant to tumor-distant lymph nodes or by restoring IL1{beta} to the tumor-draining lymph node. These strategies can induce high- quality, durable immune responses and have clinical implications for expanding the efficacy of immunotherapies. SummaryBreast tumors induce locoregional lymph node impairments in antigen presentation, which can be remedied via either IL1{beta} delivery or antigen-agnostic adjuvant therapies to distant lymph nodes, facilitating better immunotherapy responses.

cancer biology↗

bioRxiv2025

Akkermansia muciniphila Impacts Group B Streptococcus Vaginal Colonization

Streptococcus agalactiae or Group B Streptococcus (GBS) is an opportunistic pathogen that asymptomatically colonizes the vaginal tract of up to 30% of healthy individuals. However, during pregnancy it is associated with adverse pregnancy outcomes, and GBS can be transmitted to the fetus in utero, or the newborn during vaginal birth, resulting in invasive neonatal disease. Previously we identified that Akkermansia muciniphila alters the dynamics of GBS vaginal colonization. However, the global effect of A. muciniphila in the female genital tract remains largely unknown, as it has predominantly been studied in the context of gastrointestinal health. Here we determine that A. muciniphila promotes GBS aggregation and attachment to human vaginal epithelial cells (hVECs). RNA-sequencing analysis revealed that A. muciniphila changed expression of 258 unique GBS genes during hVEC colonization, with many involved in cell wall/membrane/envelope biogenesis. We demonstrate that A. muciniphila-mediated increases in GBS aggregation and attachment to hVECs are dependent on GBS capsule and pili, respectively. Lastly, we found that A. muciniphila promoted GBS aggregation in the murine vaginal lumen and continual treatment with A. muciniphila reduced GBS vaginal persistence. Our results highlight the dynamic impact of A. muciniphila on GBS gene expression and vaginal colonization, as well as demonstrate the probiotic potential of A. muciniphila in the vaginal environment. IMPORTANCEGroup B Streptococcus (GBS) is a frequent colonizer of the vaginal tract of healthy people, however during pregnancy, maternal colonization is associated with adverse pregnancy outcomes. GBS is a leading cause of neonatal sepsis and meningitis and can be transmitted to a newborn during vaginal delivery or by ascension into the uterus during pregnancy. Influence of the vaginal microbiota on GBS pathogenesis remains greatly underappreciated. We have found that GBS is associated with the mucin-degrading intestinal commensal Akkermansia muciniphila, a newly identified colonizer of the vaginal tract. Significance of our research is in identifying the mechanistic impact of this commensal organism on GBS aggregation, cell adherence, and gene expression, as well as its therapeutic potential during GBS vaginal colonization. Unraveling relationships between GBS and the vaginal microbiota will improve maternal and fetal health and may enterprise the development of alternative methods to reduce GBS in utero complications and neonatal disease.

microbiology↗

bioRxiv2025

A fungal pathobiont promotes Streptococcus agalactiae vaginal persistence and pathogenesis through physical and metabolic interactions

Complex polymicrobial interactions at the host interface can shape the mucosal landscape and tip the scales between commensalism and pathogenicity. Here, we use a newly adapted murine model of vaginal colonization to show that the human pathobiont Candida albicans (Ca) supports Group B Streptococcus (GBS) fitness in the vaginal tract and ascension to the uterus. GBS frequently colonizes the vagina asymptomatically; however, during pregnancy, colonization can lead to adverse outcomes and neonatal invasive infection. Using human vaginal isolates of Ca and GBS, we demonstrate that physical interactions contribute to persistence. Triple RNA sequencing of Ca, GBS, and a physiologically relevant model of the human vaginal epithelium reveals that GBS induces arginine biosynthesis in Ca. This drives the expression of bacterial virulence factors and primes GBS for adhesion to the epithelium. We show that interkingdom nutrient exchange can increase GBS pathogenic potential and identify a new target for preventative therapies.

microbiology↗