Search Results (278)

Recent preclinical and clinical studies have confirmed the essential role of interferons in the host’s immune response against malignant cells. Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer strongly associated with Merkel cell polyomavirus (MCPyV). Despite progress in understanding MCC pathogenesis, the role of innate immune signaling, particularly interferon-γ (IFN γ) and its downstream pathways, remains underexplored. This review summarizes recent findings on IFN-γ in MCC, highlighting its dual role in promoting both antitumor immunity and immune evasion. IFN-γ enhances cytotoxic T cell responses, upregulates MHC class I/II expression, and induces tumor cell apoptosis. Transcriptomic studies have shown that IFN-γ treatment upregulates immune-regulatory genes including PD-L1, HLA-A/B/C, and IDO1 by over threefold; it also activates APOBEC3B and 3G, contributing to antiviral defense and tumor editing. Clinically, immune checkpoint inhibitors (ICIs) such as pembrolizumab and avelumab yield objective response rates of 30–56% and two-year overall survival rates exceeding 60% in advanced MCC. However, approximately 50% of patients do not respond, in part due to IFN-γ signaling deficiencies. This review further discusses IFN-γ’s crosstalk with the STAT1/3/5 pathways and emerging combination strategies aimed at restoring immune sensitivity. Understanding these mechanisms may inform personalized immunotherapeutic approaches and guide the development of IFN-γ–based interventions in MCC. Full article

The function of NK cells in cancer and viral infections is well documented and understood. NK cell activity, including cytokine secretion, cytotoxic activity, and the coordination of inhibitory and activating receptors, linking innate and adaptive immunity, among others, has been examined for numerous pathogens, including parasites, bacteria, and viruses. The emergence of the SARS-CoV-2 health crisis has exposed a deficiency in understanding the previously elucidated mechanisms; the rationale for the reported variability in symptomatology among COVID-19 patients is extensive and intricate. It is evident that NK cells exert a significant influence on symptom severity, and their absence, with the presence or absence of their surface receptors, elicits a tailored response to the virus. This overview examines the impact of NK cells on the progression of several viral diseases, emphasizing their involvement in the pathogenesis of SARS-CoV-2 via the activation of surface receptors. Full article

Background: Vaccines represent one of the most affordable and efficient tools for controlling infectious diseases; however, the development of efficacious vaccines against complex pathogens remains a major challenge. Adjuvants play a relevant role in enhancing vaccine-induced immune responses. One such molecule is interferon-stimulated gene 15 (ISG15), a key modulator of antiviral immunity that acts both through ISGylation-dependent mechanisms and as a cytokine-like molecule. Methods: In this study, we assessed the immunostimulatory potential of ISG15 as an adjuvant in Modified Vaccinia virus Ankara (MVA)-based vaccine candidates targeting Zika virus (ZIKV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Early innate responses and immune cell infiltration were analyzed in immunized mice by flow cytometry and cytokine profiling. To elucidate the underlying mechanism of action of ISG15, in vitro co-infection studies were performed in macrophages. Finally, we evaluated the magnitude and functional quality of the elicited antigen-specific cellular immune responses in vivo. Results: Analysis of early innate responses revealed both platform- and variant-specific effects. ISG15AA preferentially promoted natural killer (NK) cell recruitment at the injection site, whereas ISG15GG enhanced myeloid cell infiltration in draining lymph nodes (DLNs), particularly when delivered via MVA. Moreover, in vitro co-infection of macrophages with MVA-based vaccine vectors and the ISG15AA mutant led to a marked increase in proinflammatory cytokine production, highlighting a dominant role for the extracellular, ISGylation-independent functions of ISG15 in shaping vaccine-induced immunity. Notably, co-infection of ISG15 with MVA-ZIKV and MVA-SARS-CoV-2 vaccine candidates enhanced the magnitude of antigen-specific immune responses in both vaccine models. Conclusions: ISG15, particularly in its ISGylation-deficient form, acts as a promising immunomodulatory adjuvant for viral vaccines, enhancing both innate and adaptive immune responses. Consistent with previous findings in the context of Human Immunodeficiency virus type 1 (HIV-1) vaccines, this study further supports the potential of ISG15 as an effective adjuvant for vaccines targeting viral infections such as ZIKV and SARS-CoV-2. Full article

Stereotactic body radiotherapy (SBRT) delivers ablative radiation doses with sub-millimeter precision. Radiogenomic studies, meanwhile, provide insights into how tumor-intrinsic genetic factors influence responses to such high-dose treatments. This review explores the radiobiological mechanisms underpinning SBRT efficacy, emphasizing the roles of DNA damage response (DDR) pathways, tumor suppressor gene alterations, and inflammatory signaling in shaping tumor radiosensitivity or resistance. SBRT induces complex DNA double-strand breaks (DSBs) that robustly activate DDR signaling cascades, particularly via the ATM and ATR kinases. Tumors with proficient DNA repair capabilities often resist SBRT, whereas deficiencies in key repair genes can render them more susceptible to radiation-induced cytotoxicity. Mutations in tumor suppressor genes may impair p53-dependent apoptosis and disrupt cell cycle checkpoints, allowing malignant cells to evade radiation-induced cell death. Furthermore, SBRT provokes the release of pro-inflammatory cytokines and activates innate immune pathways, potentially leading to immunogenic cell death and reshaping the tumor microenvironment. Radiogenomic profiling has identified genomic alterations and molecular signatures associated with differential responses to SBRT and immune activation. These insights open avenues for precision radiotherapy approaches, including the use of genomic biomarkers for patient selection, the integration of SBRT with DDR inhibitors or immunotherapies, and the customization of treatment plans based on individual tumor genotypes and immune landscapes. Ultimately, these strategies aim to enhance SBRT efficacy and improve clinical outcomes through biologically tailored treatment. This review provides a comprehensive summary of current knowledge on the genetic determinants of response to stereotactic radiotherapy and discusses their implications for personalized cancer treatment. Full article

Coagulation factor XII (FXII), the initiator of the intrinsic coagulation pathway, is not involved in hemostasis but is associated with pathological thrombosis. Bacterial infections activate coagulation cascades, although the underlying mechanisms remain not fully understood. Here, we revealed that FXII exhibits antibacterial activity through its heavy chain (hFXII) against Pseudomonas aeruginosa (P. aeruginosa), a Gram-negative bacterium. We constructed an FXII-deficient (FXII^−/−) mouse model and demonstrated that FXII plays a critical role in antibacterial functions. FXII and hFXII significantly reduced bacterial loads via intravenous injection, confirming their antibacterial activity in FXII^−/−. To further investigate the pathophysiological implications of FXII in the P. aeruginosa-induced disseminated intravascular coagulation (DIC) mouse model, FXII and hFXII effectively reduced DIC-related bacterial infections, alleviated organ damage, and decreased fibrin deposition, consequently improving survival rates. This study indicates that FXII exhibits both in vitro and in vivo antibacterial activity, primarily mediated through its heavy chain. In thrombotic diseases triggered by Gram-negative bacterial infections, the antibacterial functions of FXII may influence the progression of the disease. These results not only redefine the critical role of the intrinsic coagulation pathway in innate immune defense but also provide novel insights into the prevention and treatment of severe infection-related diseases. Full article

Macrophages participate in cutaneous wound healing by adopting M1 pro-inflammatory and M2 immunoregulatory/pro-repair phenotypes. Chronic wounds associated with a deficient macrophage response could benefit from treatments that restore an acute inflammatory response and promote healing. Calcium-alginate dressings release calcium ions, which are potent bioactivators of macrophage function in wounds. Here, the effects of two calcium-alginate dressings, Algosteril^® (ALG, pure Ca²⁺ alginate) and Biatain^® Alginate (BIA, Ca²⁺ alginate with carboxymethyl cellulose), and a 3 mM CaCl₂ solution were compared in human macrophages polarized to M1 or M2. ALG and CaCl₂ preserved monocyte viability, and BIA reduced it. Both alginates and CaCl₂ reinforced the M1 pro-inflammatory transcriptional profile and phenotype, with significant increases in IL-6 and TNF-α secretion by ALG only. In M2 macrophages, all conditions increased the M1-specific gene expression and reduced M2 markers, suggesting an orientation toward an inflammatory profile. Only ALG significantly increased the secretion of CCL18 and VEGF, suggesting pro-repair activity. All conditions increased M2 phagocytic activity. This work demonstrates the interest in calcium alginates for stimulating macrophage subtypes, which could help restore wound healing, especially in patients with compromised innate immunity. It highlights the differences among the calcium-alginate dressings. The pure alginate shows higher stimulation of macrophage pro-inflammatory and pro-repair functions. Full article

Mouse models serve as a means of examining immune changes when genes of interest are knocked out (KO). One group of immune gene-producing cells that have been identified is type 2 innate lymphoid cells (Ilc2). These cells are involved in the production of Th2 equivalent immune responses and signal cytokine production during the resolution of Nippostrongylus brasiliensis parasite infection in mice lungs. However, many questions about Ilc2 activity in the gut remain. To study this, retinoic acid receptor (RAR)-related orphan receptor alpha (RORα)-deficient mice were infected with adult N. brasiliensis and arranged into four treatment groups. Ten days post-infection (dpi), mouse ileum tissue was extracted for RNA-Seq. The RORα-deficient mice showed little change in gene expression at 10 dpi (N = 51) when compared to the WT mice at 10 dpi (N = 915), displaying dysregulation within the mouse gut. Based on the results, the gene expression in the gut of Ilc2-deficient mice denoted that the inability to craft Ilc2 cells left the mice unable to mount classical helminth immune responses involving humoral, mast cell, and antibody Th2-driven reactions. Overall, the results showed the importance of Ilc2 in the gut during N. brasiliensis infections and the effect that the lack of these cells had on immunity. Full article

Probiotics play a pivotal role in animal production by promoting growth, enhancing gut health, and modulating immune responses. Bacillus subtilis, a widely utilized probiotic, forms robust spores that exhibit exceptional resistance, making it ideal for feed applications. While B. subtilis spores have been shown to stimulate innate immune signaling, the specific contributions of spore coat proteins to immune modulation remain poorly characterized. In this study, we investigated the immunostimulatory effects of spores deficient in six key coat proteins: SpoIVA, SafA, CotE, CotX, CotZ, and CgeA. These proteins are essential for the assembly and structural integrity of the spore’s multi-layered coat, and are involved in recruiting other coat components. Deletion of these genes result in defects in spore coat architecture, potentially altering spore–host interactions. Using porcine alveolar macrophages (MΦ3D4/2), we assessed cytokine responses to each mutant strain. Our findings demonstrate that the absence of specific structural proteins significantly impacts immune activation, particularly through Toll-like receptor pathways. This work provides novel insights into the immunomodulatory functions of spore coat proteins and lays the foundation for the rational design of next-generation B. subtilis-based probiotics with enhanced immunological properties for agricultural applications. Full article

Deficiencies in immune function increase susceptibility to infections and chronic diseases by impairing immune surveillance and tolerance mechanisms, especially in children with immature immune systems. Chronic inflammation associated with immune dysfunction can impair childhood by suppressing the GH–IGF-1. HT042 is composed of Astragalus mongholicus, Eleutherococcus senticosus, and Phlomis umbrosa, which are medicinal herbs that are traditionally utilized in East Asia to promote growth and enhance immune function; thus, HT042 itself holds potential as an immunomodulator. We evaluated the immunomodulatory effects of HT042 in a cyclophosphamide (CYP)-induced immunosuppressed mouse model, as well as in ex vivo primary splenocytes and RAW 264.7 macrophages. HT042 demonstrated remarkable immune-enhancing effects, including the restoration of weight loss and hematological parameters, as well as enhancing NK cell activity. Primary splenocytes treated with HT042 showed increased expression of CD3, CD4, and CD8, along with Th subset transcription factors (T-bet, GATA3, RORγt, Foxp3) and corresponding cytokines (IFN-γ, IL-4, IL-17, IL-10). In RAW 264.7 macrophages, HT042 increased nitric oxide production and upregulated NOS2, COX-2, and inflammatory cytokines (IL-6, IL-1β, TNF-α). It is noteworthy that HT042 enhances both innate and adaptive immune pathways, particularly via T cell modulation and macrophage activation, as this study is among the first to demonstrate such effects in the context of CYP-induced immunosuppression. Full article

Vitamin D has emerged as a potential modulator of immune responses, sparking interest in its role in COVID-19 susceptibility and clinical outcomes. This review synthesizes current clinical evidence and explores immunological insights into the relationship between vitamin D levels and COVID-19 infection severity. Epidemiological studies indicate an inverse correlation between vitamin D deficiency and an increased risk of severe disease, hospitalization, and mortality in COVID-19 patients. Immunologically, vitamin D exerts regulatory effects on both innate and adaptive immunity, enhancing antimicrobial defense mechanisms, reducing excessive inflammatory responses, and potentially mitigating cytokine storm events observed in severe COVID-19 cases. Despite promising observational data, clinical trials evaluating vitamin D supplementation have shown mixed results, underscoring the need for standardized dosing regimens and patient stratification. Future research should focus on large-scale randomized controlled trials to conclusively determine the therapeutic potential and optimal supplementation strategies for vitamin D in managing COVID-19. Full article

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in infants, young children, and immunocompromised individuals. Currently, FDA-approved monoclonal antibody therapies are limited to infants and young children with severe RSV disease. As a result, there is an urgent need for comprehensive studies of RSV pathogenesis to support the development of new therapeutic strategies. Exchange proteins directly activated by cAMP (EPAC) have recently emerged as key regulators in various viral infections. Our previous work identified EPAC isoform 2 (EPAC2) as a critical factor in RSV replication and host innate immune responses. However, the molecular mechanisms underlying EPAC2’s role in RSV infection remain unclear. In this study, we investigated EPAC2-mediated RSV infection by identifying EPAC2-interacting proteins. Proteomics and immunoprecipitation analyses revealed that junction plakoglobin (JUP) interacts with EPAC2 in both mock- and RSV-infected cells, with this interaction notably enhanced during RSV infection. To determine JUP’s role in RSV infection, we compared viral replication in JUP-deficient and control cells. JUP downregulation significantly reduced the production of infectious RSV particles, likely by impairing viral budding and viral gene transcription. Moreover, our findings indicate that JUP is essential for an effective cellular immune response to RSV infection. Together, these results suggest that EPAC2 and JUP may cooperatively regulate RSV replication and dissemination. Full article

Cullin 2 (Cul2), a core component of the Cullin-RING E3 ubiquitin ligase complex, is integral to regulating distinct biological processes. However, its role in innate immune defenses remains poorly understood. In this study, we investigated the functional significance of Cul2 in the immune deficiency (IMD) signaling-mediated antimicrobial immune reactions in Drosophila melanogaster (fruit fly). We demonstrated that loss-of-function of Cul2 led to a marked reduction in antimicrobial peptide induction following bacterial infection, which was associated with increased fly mortality and bacterial load. The proteomic analysis further revealed that loss-of-function of Cul2 reduced the expression of Effete (Eff), a key E2 ubiquitin-conjugating enzyme during IMD signaling. Intriguingly, ectopic expression of eff effectively rescued the immune defects caused by loss of Cul2. Taken together, the results of our study underscore the critical role of Cul2 in ensuring robust IMD signaling activation, highlighting its importance in the innate immune defense against microbial infection in Drosophila. Full article

A significant portion of adolescents suffer from mental illnesses and persistent pain due to repeated stress. The components of the nervous system that link stress and pain in early life remain unclear. Prior studies in adult mice implicated the innate immune system, specifically Toll-like receptors (TLRs), as critical for inducing long-term anxiety and pain-like behaviors in social defeat stress (SDS) models. In this work, we investigated the pain and anxiety behavioral phenotypes of wild-type and TLR4-deficient juvenile mice subjected to repeated SDS and evaluated the engagement of TLR4 by measuring dimerization in the spinal cord, dorsal root ganglia, and prefrontal cortex. Male juvenile (4-week-old) mice (C57BL/6J or Tlr4^-/-) underwent six social defeat sessions with adult aggressor (CD1) mice. In WT mice, SDS promotes chronic mechanical allodynia and thermal hyperalgesia assessed via von Frey testing and the Hargreaves test, respectively. In parallel, the stressed WT mice exhibited transient anxiety-like behavior and long-lasting locomotor activity reduction in the open-field test. Tlr4^-/--stressed animals were resistant to the induction of pain-like behavior but had a remnant of anxious behavior, spending less time in the center of the arena. In WT SDS, there were concordant robust increases in TLR4 dimerization in dorsal root ganglia macrophages and spinal cord microglia, indicating TLR4 activation. These results suggest that the chronic pain phenotype and locomotor impairment induced by SDS in juvenile mice depends on TLR4 engagement evidenced by dimerization in immune cells of the dorsal root ganglia and spinal cord. Full article

T and B cell-deficient rag1^−/− mutant zebrafish develop protective immunity mediated by trained immunity. In mammals, trained immune responses can be induced by Toll-like receptor (TLR) ligands. This study evaluated protective trained immunity in rag1^−/− zebrafish through exposure to TLR ligands (beta glucan, R848, poly I:C), RE33^® (a live-attenuated Edwardsiella ictaluri vaccine), or combinations thereof, followed by wild-type E. ictaluri challenge one month later. Survival analyses revealed that all TLR ligands and vaccine treatments provided significantly higher protection than the control, with beta glucan inducing significantly greater protection than RE33^®, while R848 and poly I:C were equivalent to the vaccine. Survivals for the treatments were beta glucan 70%, beta glucan + RE33^® 60%, R848 + RE33^® 54%, poly I:C + RE33^® 50%, R848 49%, poly I:C 32%, RE33^® 24%, and control 0%. Gene expression analysis of kidney and liver tissues post challenge revealed that beta glucan training elicited early and strong increased expressions of nklb (5536 fold @ 6 hpi), nkld (147 fold @ 12 hpi), and ifng (575 fold @ 12 hpi) in the kidney, and ifng (1369 fold @ 6 hpi), nkla (250 fold @ 6 hpi), nklb (734 fold @ 6 hpi), nklc (2135 fold @ 6 hpi) and nkld (589 fold @ 6 hpi) in the liver. Principal component analysis (PCA) revealed that early kidney gene expressions at 6–12 h post secondary infection (nkla @ 12 hpi, nklb @ 6 and 12 hpi, nklc @ 6 and 12 hpi, nkld @ 6 and 12 hpi, ifng @ 6 and 12 hpi, t-bet @ 6, 12 and 48 hpi, and nitr9 @24 hpi) in the kidney and liver (nkla, nklb, nklc, nkld, ifng, t-bet and nitr9 @ 6 hpi) were associated with the highest survival. This study highlights that TLR ligand-induced trained immunity boosts innate immunity and survival, with NK cell subpopulations in kidney and liver tissues responding differently to mediate protective responses. Full article

Innate immunity is critical for insects to adjust to complicated environments. Studying the insect immune system can aid in identifying novel insecticide targets and provide insights for developing novel pest control strategies. Insects recognize environmental pathogens through pattern recognition receptors, thus activating the innate immune system to eliminate pathogens. The innate immune system of insects primarily comprises cellular immunity and humoral immunity. Toll, immune deficiency, and Janus kinase/signal transducers and activators of transcription are the main signaling pathways regulating insect humoral immunity. Nevertheless, increasing research has revealed that immune signaling activated by microbes also performs non-immune roles while exerting immune roles, and insulin signaling performs a key role in mediating the connection between the immune system and non-immune physiological activities. Therefore, this paper first briefly reviews the main innate immune signaling and insulin signaling of insects, then summarizes the relationship between immune signaling activated by microbes and insect growth and development, reproduction, pesticide resistance, chemical communication, cell turnover, lifespan, sleep, energy generation pathways and their possible underlying mechanisms. Future research directions and methodologies are also proposed, aiming to provide insights into further study on the physiological mechanism linking microbes and insect hosts. Full article