搜索结果：Pathogens & immunity

Lung tissue-resident memory T (TRM) cells are critical for frontline immunity, yet they undergo rapid attrition in the mouse lung. Whether this paradigm applies to humans has remained unknown. Here we present a comprehensive analysis of T cells from human lungs, characterizing the prevalence and properties of lung TRM cells specific to a broad spectrum of pathogens. Using a T cell receptor-guided approach that integrates single-cell transcriptomics with paired T cell receptor repertoire profiling, we mapped the pathogen specificity of more than 87,000 lung T cells across 40 individuals, the majority of whom harbored TRM cells specific to multiple pathogens. We confirmed that a large fraction of lung TRM clones persist in the lung for many months to years. Thus, in contrast to those of mice, human lungs retain a stable and varied pool of pathogen-specific TRM cells, suggesting that strategies to bolster these responses could provide durable protection against severe lung infections.

Non-invasive biomarkers of immune function are increasingly important for assessing health, welfare and disease risk in zoo and wild mammals, particularly because they support repeated monitoring while minimizing handling-related disturbance. Secretory immunoglobulin A (IgA), a key component of mucosal immunity, can be quantified from faecal samples and provides a practical measure of gut-associated immune activity without invasive sampling. We conducted a systematic literature review of 21 peer-reviewed studies that quantified faecal IgA across diverse mammalian taxa and ecological contexts. Across species, faecal IgA was technically measurable and biologically responsive, but its interpretation was strongly context dependent. Reported patterns reflected interactions among pathogen exposure, physiological stress, nutritional state, life-history stage and management conditions. In captive settings, faecal IgA frequently varied with individual heterogeneity and management factors and showed inconsistent alignment with endocrine stress markers. In free-ranging populations, faecal IgA more commonly tracked parasite burden, reproductive investment, seasonal variation and host-microbiome dynamics. However, most ecological and welfare-associated patterns were derived from observational designs, which limit causal inference. Additionally, methodological heterogeneity in assay validation, sample processing and preservation limited direct quantitative comparison among studies. Overall, faecal IgA does not function as a unidimensional indicator of stress or welfare, but rather as a context-sensitive marker of mucosal immune allocation. We integrate these findings into a conceptual framework linking external pressures, mucosal immune dynamics, complementary biomarkers and health-related outcomes to guide interpretation across zoo and wild settings. When embedded within longitudinal and multi-marker approaches supported by species-specific validation, faecal IgA has potential to contribute meaningfully to non-invasive health assessment in conservation physiology.

Influenza-associated pulmonary aspergillosis (IAPA) is a severe complication of influenza infection associated with substantial mortality. Influenza disrupts pulmonary host defenses and alters innate immune responses, predisposing patients to invasive fungal infection. Interleukin-27 (IL-27) is an immunoregulatory cytokine with context-dependent antiviral and antifungal effects; however, its role during IAPA remains undefined. A mouse model of IAPA was established by infecting wild-type and IL-27 receptor α-deficient ( Il27ra - / - ) mice with influenza A, followed by Aspergillus fumigatus challenge. IL-27 and IL-27Rα expression were increased during IAPA. Single-cell RNA sequencing identified monocytes as the primary source of IL-27 and T cells as major IL-27rα-expressing cells. Il27ra - / - mice exhibited significantly increased pulmonary fungal and influenza viral burden, enhanced type 2 immune responses characterized by elevated IL-4, IL-5, IL-9, IL-13, eosinophils, Th2 cells, pathogenic Th2 cells, and ILC2s. Despite increased eosinophil abundance, eosinophil-mediated conidial killing was impaired in Il27ra - / - mice. IL-27Rα deficiency also reduced macrophage abundance and impaired macrophage conidial uptake. Conversely, timed administration of rIL-27 enhanced fungal clearance, improved survival, and increased macrophage conidial uptake and augmented eosinophil killing capacity during IAPA. IL-27 signaling is a protective immunoregulatory cytokine during IAPA that limits pathological type 2 inflammation and enhances antifungal effector function of both eosinophils and macrophages. These findings identify IL-27 as a potential therapeutic in IAPA.

Bovine leukaemia virus (BLV) and Coxiella burnetii are important infectious pathogens of dairy cattle with potential implications for animal health, productivity and zoonotic transmission (in the case of C. burnetii). Because BLV may alter immune function, we hypothesize that infection with the virus could increase cattle susceptibility to C. burnetii. This cross-sectional study aimed to estimate the seroprevalence of BLV and C. burnetii in dairy cattle herds in the Emirate of Abu Dhabi (EAD) and to assess any association between the positive serostatus of the two pathogens. Sera from 492 adult Holstein-Friesian cattle were screened by ELISA for antibodies to both pathogens, and associations were evaluated using logistic regression. The overall seroprevalences of BLV and C. burnetii were 47.0% and 49.4%, respectively, with 24.2% of cattle being dually seropositive. BLV seroprevalences across farms were 27.6%, 56.3% and 50.9%, while C. burnetii seroprevalences were 42.9%, 29.2% and 53.8% for Farms 1, 2 and 3, respectively. Logistic regression showed that BLV-positive cattle had higher odds of C. burnetii seropositivity (OR = 1.25, 95% CI [0.88-1.79]), even though the association was not statistically significant (p = 0.2258). The relatively high seroprevalences compared with previous reports suggest ongoing intra-herd transmission of both pathogens, likely exacerbated by the absence of targeted control strategies. Although no causal relationship was established, the observed trend may reflect BLV-associated immunosuppression that could enhance susceptibility to C. burnetii. Further large-scale studies are warranted, and livestock health authorities in the UAE are encouraged to implement targeted surveillance and biosecurity measures.

Plant immune responses rely on mitogen-activated protein kinase (MAPK) cascade that integrates pattern-triggered immunity and effector-triggered immunity. How fungal pathogens suppress this central signaling hub remains poorly understood. Here, we identify a secreted effector from phytopathogenic fungus Verticillium dahliae, VdHCE1, that is required for full virulence and directly targets host MAPK signaling. VdHCE1 interacts with the MAPK kinase MKK5 and is phosphorylated at threonine 166 in planta. Biochemical analyses demonstrated that VdHCE1 competes with MPK3 and MPK6 as a substrate of MKK5, thereby attenuating downstream MAPK activation. Consistently, VdHCE1 suppresses elicitor- and NLR-triggered immune responses, while deletion of VdHCE1 compromises fungal virulence in Arabidopsis and cotton. Genetic disruption of MKK5 restores the virulence of VdHCE1-deficient strains, establishing MKK5 as the functional target of VdHCE1. These findings reveal a strategy by which a filamentous fungal pathogen suppresses plant immunity by acting as a decoy substrate within the MAPK cascade and provide a molecular framework for engineering resistance to vascular wilt disease.

Mucosal chemokines (eg, CCL25, CCL28, CXCL14, and CXCL17) play key roles in protecting mucosal surfaces against invading infectious pathogens. However, their specific contributions to protection against genital herpes remain to be fully elucidated. Here, we investigated the role of CXCL14 as a mediator of mucosal immunity against genital HSV-2 infection and disease. CXCL14 expression was analyzed in HSV-specific CD8+ T cells from HSV-2-infected asymptomatic and symptomatic women, in primary human vaginal epithelial cells, and in a murine genital HSV-2 infection model. CXCL14(-/-) deficient mice and wild-type (WT) mice were compared for genital disease severity, vaginal viral loads, survival, immune cell recruitment, and T-cell effector function following intravaginal HSV-2 infection. Chromatin immunoprecipitation assays were performed to identify transcription factors binding to the CXCL14 promoter after HSV-2 infection. CXCL14 was homeostatically expressed at the genital tract mucosal surface, and HSV-specific CD8+ T cells from HSV-2-infected asymptomatic women expressed significantly higher levels of CXCL14 than those from symptomatic women. HSV-2 infection rapidly induced CXCL14 transcription and production in primary human vaginal epithelial cells and in murine vaginal mucocutaneous tissue. CXCL14(-/-) mice developed more severe genital lesions, higher vaginal viral loads, and lower survival compared to WT mice. In addition, CXCL14 deficiency impaired the recruitment of natural killer (NK) cells, neutrophils, and CD44+CD62L- effector memory CD4+ and CD8+ T cells to the infected vaginal mucosa. It reduced T cell effector functions, including production of IFN-γ, TNF-α, and Granzyme B. Mechanistically, NF-κB and OCT-1 transcription factors bound to the CXCL14 promoter within hours of HSV-2 infection. Our findings demonstrate that NF-κB- and OCT-1-driven CXCL14 expression is crucial for orchestrating early innate and T-cell responses that protect against genital HSV-2 infection and disease. These results suggest that CXCL14 is an important immunoregulatory chemokine triggered early after epithelial viral infection, facilitating the induction of effective mucosal protective immunity against genital herpes.

Effective vaccines against sexually transmitted pathogens must elicit protective immunity at mucosal surfaces, particularly within the female reproductive tract. Caprine herpesvirus 1 (CpHV-1) causes genital disease, reproductive failure, and neonatal mortality in goats and provides a biologically relevant large-animal model for human genital herpesvirus infection. Here, we evaluated a mucosal vaccination strategy based on a bovine herpesvirus 4 (BoHV-4) vector expressing the CpHV-1 immunodominant glycoprotein D (BoHV4-A-gD(cp)gD(106)ΔTK). Goats were immunized via the intravaginal or intranasal route using a prime-boost regimen and subsequently challenged intravaginally with virulent CpHV-1. Ex vivo tissue analyses showed efficient transduction of nasal mucosa and limited vaginal transduction restricted to the cervical region. Despite these differences, both immunization routes conferred complete protection against disease. Vaccinated animals showed no fever or genital pathology following challenge, in contrast to unvaccinated controls. Viral shedding was significantly reduced in vaccinated goats, with intravaginal immunization providing superior control of genital virus excretion. Both routes induced CpHV-1-specific systemic antibody responses, including functional neutralizing antibodies, with higher neutralizing titers observed after intranasal vaccination. These findings demonstrate that BoHV-4-based vectors can induce robust protective immunity against genital herpesvirus infection when delivered via either local or distal mucosal routes. The results highlight the importance of mucosal vaccination strategies and support the versatility of BoHV-4 as a vaccine platform for sexually transmitted infections. This study further establishes the goat-CpHV-1 model as a valuable translational system for the preclinical evaluation of mucosal herpesvirus vaccines.

The outer membranes (OMs) of bacterial pathogens are potent virulence factors and serve as the first line of defense against host immunity. Their striking bilayer asymmetry is essential for function but poses an exceptional challenge for reconstitution in vitro , limiting structure-activity analysis to artificial non-native platforms that can interfere with structure and function. Here, we describe bacterial OM vesicles (OMVs), natively secreted from the cellular OM during bacterial cell growth and development, as an effective vehicle for structure-activity analysis in situ based on solid-state nuclear magnetic resonance (NMR). We show that E. coli OMVs may be engineered to express a range of isotopically labeled target OM proteins, and isolated for solid-state NMR magic angle spinning (MAS) experiments. High resolution NMR spectra are obtained for three bacterial virulence factors: the adhesion invasion locus (Ail) and plasminogen activator protease (Pla) from Yersinia pestis , and the major porin (OmpF) from E. coli . The spectra reflect the native protein structures, report on the specific OMV membrane environment, and may be used to map protein interactions with their human host ligands, specifically the multifunctional glycoprotein Vitronectin (Vn) which binds Ail as part of its serum protection activity. Notably, OMVs support protein functionality, enabling structure and activity to be correlated in situ . OMVs expressing plasmid-encoded Ail recruit human Vn and confer serum protection to wild-type E. coli cells, while OMVs expressing plasmid-encoded Pla support the proteolytic activity of Pla. Taken together, the data establish OMVs as a robust new platform for structure-activity analysis of OM proteins in situ , offer new insights about the complexity of the bacterial OM, and reveal additional functional aspects of OMVs as key ancillary units of bacterial infection.

An 8-year-old spayed female American Shorthair cat was evaluated for refractory perioral nodules and respiratory distress persisting for 9 months. The patient had a history of feline atopy and chronic gingivostomatitis managed with long-term immunosuppressive therapy, including cyclosporine A and prednisolone. Pre-surgical computed tomography (CT) revealed a 2.1 cm nasolabial mass without osteolysis, later diagnosed as a mycobacterial infection. This unusual infection was tentatively attributed to pharmacological suppression of cell-mediated immunity, potentially impairing both granuloma formation and inflammatory bone resorption. Fine-needle aspiration (FNA) and Ziehl-Neelsen (ZN) staining demonstrated a high burden of acid-fast bacilli (AFB). However, conventional cultures, including inoculation on 3% Ogawa medium, failed due to rapid overgrowth of Klebsiella pneumoniae (K. pneumoniae). Post-mortem multi-target real-time PCR and whole genome sequencing (WGS), together with internal transcribed spacer (ITS) sequencing and phenotypic antimicrobial testing, identified a fatal co-infection comprising Mycobacterium tuberculosis complex (MTBC), Mycobacterium kansasii, K. pneumoniae, and multidrug-resistant Pseudomonas aeruginosa. This report describes a rare feline case of a fatal polymicrobial infection involving both MTBC and non-tuberculous mycobacteria (NTM) in conjunction with opportunistic gram-negative pathogens. The findings suggest that chronic iatrogenic immunosuppression may alter or obscure classical diagnostic features of mycobacteriosis and facilitate complex co-infections. This case highlights the importance of high-sensitivity molecular diagnostics and suggests that immunocompromised companion animals may, in rare instances, serve as cautious indicators of possible household mycobacterial exposure within a One Health framework.

Bacterial pathogens modulate host cell physiology by secreting effector proteins that rewire host signaling pathways. A subset of these effectors directly modify host chromatin to reprogram gene expression and promote infection. While these enzymes are thought to function autonomously, the extent to which the host epigenetic landscape regulates their activity remains largely unknown. RomA and its homolog LegAs4 are Set domain-containing lysine methyltransferases from Legionella pneumophila that methylate histone H3 at lysine 14 (H3K14) to suppress host immune responses and enhance intracellular bacterial replication. Here, we demonstrate that RomA activity is constrained by pre-existing host histone post-translational modifications (PTMs) through multiple layers of histone PTM crosstalk. RomA selectively binds and methylates unmodified histone H3 tails and is inhibited by histone PTMs associated with active transcription, including H3K4 trimethylation, H3K4 acetylation, and H4K12 mono-methylation. We identify both cis- and trans-histone regulatory mechanisms, whereby unmodified H3K4 and H3K14 must reside on the same H3 tail to support RomA activity, while H4K12me1 inhibits RomA across the nucleosome. Notably, cryo-EM analysis and biochemical data reveal that RomA does not engage the nucleosome acidic patch but instead associates flexibly through histone tails. Together, these findings establish the host epigenetic regulation of bacterial effectors as a fundamental and previously unrecognized layer of host-pathogen interactions. Bacterial pathogens reprogram host gene expression by delivering effector proteins that modify chromatin, but it is not known how the host epigenetic environment impacts effector function. Here, we show that the Legionella effector RomA senses and responds to the host's existing epigenetic landscape and is selectively active only in specific chromatin contexts through mechanisms resembling those used by eukaryotic chromatin regulators. Notably, we uncover that RomA utilizes cis-histone and trans-histone crosstalk mechanisms previously observed only in eukaryotic systems. These reveals an unexpected form of host-pathogen crosstalk in which bacterial effector activity can be constrained by host epigenetic modifications.

Neutrophils are central mediators of kidney immunity and injury, exerting both protective and pathogenic functions on tissue compartment, inflammatory response, and disease state. During urinary tract infection and pyelonephritis, neutrophils protect the host through phagocytosis, granule release, reactive oxygen species (ROS) production, and neutrophil extracellular trap (NET) formation. In contrast, dysregulated neutrophil activation contributes to sterile and autoimmune kidney disease, including cholesterol crystal embolism, anti-neutrophil cytoplasmic antibody -associated vasculitis (AAV), ischemic acute kidney injury, and progression to chronic kidney disease. Emerging evidence indicates that neutrophil function in the kidney is highly compartment-specific and shaped by local metabolic and inflammatory cues. Persistent neutrophil activation promotes thromboinflammation, endothelial injury, autoimmunity, and fibrogenic remodeling through release of cytokines, S100A8/A9, proteases, ROS, and NET-associated mediators. In chronic kidney disease, uremic toxins and metabolites, such as uric acid, further alter neutrophil function by impairing antimicrobial responses while sustaining inflammatory activation. This review summarizes current insights into neutrophil biology across infection, sterile, and autoimmune kidney diseases, with focus on complement-specific neutrophil functions and effector mechanisms. In addition, we discuss emerging therapeutic strategies targeting neutrophil activation pathways and highlight recent advances in spatial transcriptomics, single-cell technologies, and intravital imaging that are reshaping our understanding of neutrophil-mediated kidney injury.

Copper is an essential nutrient that at high levels is toxic to life. Mammalian hosts can accumulate copper in phagolysosomes to restrict a variety of pathogens, including Mycobacterium tuberculosis. However, pathogens have evolved various mechanisms to counter copper stress. While several pathways that mitigate copper-derived toxicity have been described in Mycobacterium tuberculosis, the Mycobacterium tuberculosis lab strain H37Rv is significantly more sensitive to copper than other lab strains, including CDC1551 and Erdman. Here, we determine a cause of this sensitivity in H37Rv is due to a single amino acid substitution in CysK2 (Rv0848), which is encoded in the copper-inducible RicR regulon required for robust copper resistance and virulence. H37Rv CysK2 was previously reported as a S-sulfocysteine synthase. However, we found CysK2 is a cysteine synthase, the activity of which is required for resistance to copper. This study is the first to link de novo cysteine biosynthesis with copper resistance in Mycobacterium tuberculosis. Copper is a proposed component of the host immune response against Mycobacterium tuberculosis; thus, an understanding of how this pathogen mitigates copper stress may yield new targets for therapeutics. Cysteine synthesis is implicated in copper responses in other bacterial species, but had not been shown in mycobacterial copper resistance. This study demonstrates for the first time that the Mycobacterium tuberculosis cysteine synthase CysK2 and, by extension, cysteine biosynthesis, can promote copper resistance.

Bacterial membranes, in their natural and engineered forms, including outer membrane vesicles, bacterial ghosts, engineered membrane fragments, and hybrid scaffolds, are emerging as multifunctional immunotherapeutic platforms that merge antigen presentation with intrinsic adjuvanticity. By codisplaying tumor antigens and conserved pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide, flagellin, and CpG motifs, bacterial membranes activate dendritic cells, drive crosspresentation, and elicit durable cytotoxic T-cell memory. Advances in genetic fusion systems (Lpp-OmpA, ClyA, Ag43, and SpyTag/SpyCatcher), lipid A detoxification, and tumor membrane hybridization have transformed bacterial membranes from empirical immunostimulants into programmable vaccine scaffolds. Preclinical studies across melanoma, lung, breast, and glioblastoma models show that these systems reprogram the tumor microenvironment, inducing Th1-polarized immunity, pyroptotic tumor death, and synergy with checkpoint blockade, chemotherapy, and phototherapy. Beyond vesicular formats, membrane fragments and engineered ghosts demonstrate equivalent potential for safe, modular, and scalable vaccine design. Integrating AI-driven antigen discovery, CRISPR-based strain engineering, and automated biofoundries now offers a path toward clinical translation. Collectively, these developments position bacterial membranes as a unifying platform that bridges innate and adaptive immunity for next-generation cancer immunotherapy.

Subtle mechanical forces (such as cellular stretching, shear stress, tissue pressure, ultrasound, and acupuncture, which are lower than the tissue and cell damage thresholds but can be sensed and transduced by cells) can regulate the physiological functions of immune cells through mechanosensitive ion channels (MSCs). When being sensed by MSCs on the surface of immune cells, these subtle mechanical stimuli are converted into biochemical signals that trigger cellular activation, migration, phagocytosis, and cytokine release. Under pathological conditions such as inflammation, infection, and cancer, mechanical signals are transmitted through mechanosensitive channels-including Piezo, TRPV, MRTFA-SRF, Hippo-YAP/TAZ, and integrins-to modulate both innate and adaptive immune responses. The "subtle mechanical force-MSC-immunity" axis plays a crucial role in inflammation modulation, pathogen clearance, and antitumor immunity, holding significant potential for translational applications. This review summarizes the mechanisms by which subtle mechanical forces mediate immune modulation through MSCs and outlines the functions and signal transduction mechanisms of subtle mechanical forces and MSCs, with a particular focus on the roles of Piezo, TRPV, MRTFA-SRF, Hippo-YAP/TAZ, and integrin channels in various immune cells. It further elaborates on the immunomodulatory effects and the potential application prospects of exogenous subtle mechanical stimuli in physical therapy, aiming to provide new insights for understanding the regulation of immune responses by subtle mechanical forces and offer a theoretical basis for developing novel immunotherapies based on subtle mechanical forces. 机械力(如细胞牵张、剪切力、组织压力、超声波及针刺等低于组织和细胞结构损伤阈值、但足以被细胞感知并转导的物理刺激)可通过机械力敏感离子通道(mechanosensitive ion channel, MSCs)调控免疫细胞的生理功能。当机械力被免疫细胞表面的机械力敏感离子通道感知后，可将其转化为生化信号，从而触发免疫细胞的激活、迁移、吞噬和炎症因子释放等。在炎症、感染、肿瘤等疾病状态下，机械信号通过Piezo、TRPV、MRTFA-SRF和Hippo-YAP/TAZ通路以及整合素等机械敏感通道影响先天和适应性免疫反应。“机械力-机械力敏感离子通道-免疫”轴在炎症调控、病原清除和抗肿瘤免疫中发挥重要作用，具有显著的临床应用前景。本文综述了机械力通过机械力敏感离子通道介导的免疫调节机制，概述了机械力与机械力敏感离子通道的功能与信号传导机制，进一步阐述了机械力敏感离子通道在不同免疫细胞(T细胞、巨噬细胞、树突状细胞及肥大细胞)中的作用，分析了“机械力-机械敏感通道-免疫”轴在炎症等疾病中的免疫调控效应，并探讨了物理疗法中外源微弱机械刺激的免疫调节作用及其潜在应用前景。本文为理解机械力调控免疫反应提供了新思路，并为基于机械力的新型免疫疗法提供了理论基础。.

Bats are major reservoirs of viruses that can be transmitted to humans in zoonotic outbreaks. Antibody-mediated immunity plays an important role in shaping viral evolution and immune evasion but remains understudied in bats. All known mammals have a single immunoglobulin heavy chain (IgH) gene locus and up to two light chain loci. We have identified dual IgH loci on separate chromosomes in 26 bat species, highlighting extreme variation of immunogenetic architecture in order Chiroptera. In a model species, Eptesicus fuscus, we leveraged single-cell transcriptomes to confirm functional rearrangement and expression of both loci, but with different mechanisms for generating antibody diversity and function. These results provide a foundation for analysis of humoral immunity and pathogen response in bats.

The perinatal period represents a unique immunological window of opportunity, in which γδ T cells play a central role. New methods, including single-cell and high-resolution TCR repertoire analyses, have transformed our understanding of how γδ T cells develop, diversify, and function from fetal life into adulthood. Early γδ T cell waves display TCRs shaped by low TdT activity, biased V(D)J recombination, and favored V-J and V-D pairings that give rise to public, near germline-encoded TCRs with preprogrammed effector functions. These fetal-derived populations contribute to rapid pathogen responses and unique pathogen-driven expansions during congenital infections, revealing fundamental differences between perinatal and adult γδ T cell immunity. However, it is less clear how pre- and perinatal γδ T cells persist and influence individual immune responses later in life. This review synthesizes current insights into ontogeny, effector programming, and repertoire dynamics of γδ T cells in early life. We focus on deciphering the evident changes in the γδ T cell compartment during gestation, birth, and early life in humans.

Ascoviruses, as obligate insect pathogens that exclusively infect lepidopteran hosts, are highly reliant on the precise modulation of key host physiological processes, including metabolism, developmental signaling, and immune homeostasis, to facilitate successful infection, subsequent viral replication and transmission. The corazonin signaling pathway serves as a key regulatory pathway in insect development and molting. Herein, we found that ascoviruses modulate the Corazonin signaling pathway to affect the host molting process, thereby influencing viral replication. Therefore, understanding the molecular mechanisms between ascovirus and the corazonin signaling pathway is of particular importance. In this study, we found that corazonin (HaCrz) and the receptor (HaCrzR) were essential for promoting the molting process in response to HvAV infection. Silencing of HaCrz or HaCrzR via RNAi extended larval instar stages, elevated host mortality, reduced transcript levels of downstream molting-related genes (HaTH and HaDDC), and substantially enhanced viral replication. In contrast, exogenous injection of synthetic mature HaCrz peptide, which interacts structurally with HaCrzR as validated by molecular docking, accelerated host molting and improved antiviral responses. These findings not only revealed the mechanism by which viruses manipulate the host molting process but more importantly, demonstrated that viruses create favorable conditions for viral replication and transmission by interfering with host developmental behaviors.

The epidermis relies on collagen-rich extracellular matrices (ECMs) to maintain barrier integrity against pathogens. Lysosomes regulate cuticle collagen turnover, yet how neuronal signaling modulates epidermal lysosomal function and collagen organization during infection remains unclear. Using Pseudomonas aeruginosa PA14- Caenorhabditis elegans infection model, we demonstrate that pathogen-induced neuronal signaling disrupts epidermal lysosomal activity and collagen remodeling. PA14 infection triggers neurons to secrete NSIF-1 (Neuronal Secreted Immune Factor 1), which translocates to the epidermis and impairs lysosomal acidification, maturation, and degradation by suppressing the transcription factor ELT-3. This disruption leads to disorganized collagen structure, compromising cuticle integrity and host resistance. Genetic mutation of nsif-1 restores lysosomal function, enhances collagen density, and improves survival, while neuron-specific nsif-1 knockdown confirms its neuronal origin. Moreover, NSIF-1 inhibits ELT-3 nuclear localization, blocking its role in lysosomal-dependent ECM repair. Our study reveals a neuro-epidermal axis wherein pathogens exploit neuronal signals to disrupt lysosomal function and collagen homeostasis, identifying NSIF-1 and ELT-3 as potential targets to counteract infection-driven ECM dysregulation.

In polymicrobial infections, how the host recognizes and responds to pathogens influences which species will persist to cause chronic infections. The human respiratory tract is a common anatomical site for viral-bacterial co-infections, where primary viral infections predispose to secondary bacterial infections, leading to increased morbidity and mortality. Additionally, co-infections are disproportionately prevalent in people with chronic lung diseases, such as chronic obstructive pulmonary disease and cystic fibrosis. We previously reported that primary viral infections and antiviral interferon (IFN) signaling stimulate Pseudomonas aeruginosa (PA) biofilm formation on airway epithelial cells (AECs). IFN signaling induces aerobic glycolysis in AECs and generates lactate as a cellular byproduct. Given that innate immune systems play an integral role in co-infection dynamics, we investigated the role of host-secreted metabolites (i.e. lactate) on innate immune cell activity during respiratory co-infections. We found that exposure to the apical secretions from IFNβ-treated AECs significantly compromised macrophage antibacterial activity, with the soluble metabolite lactate playing an important role. Macrophages used monocarboxylate transporters and G-protein receptors to transport and/or sense lactate, respectively, and this exposure to lactate diminished their bacterial-killing activity in a time-exposure dependent manner. Lactate exposure particularly reprogrammed macrophage cellular metabolism towards an anti-inflammatory state by increasing oxidative phosphorylation and fatty acid oxidation. Collectively, these findings provide insight into metabolites as complex regulators of trans-kingdom interactions and epithelial-macrophage crosstalk during respiratory co-infections.