Search Results (142)

The mitogen-activated protein kinase (MAPK) pathways, ERK, JNK, and p38, are key regulators of immune responses during viral infections. These signaling cascades control cytokine production, T cell activity, and antigen presentation. However, many viruses can hijack MAPK pathways to avoid immune detection, promote their replication, and establish chronic infection. In this review, we discuss how different viruses, including HSV-1, HBV, HCMV, and SARS-CoV-2, manipulate MAPK signaling to alter host cell functions. A particular focus is given to the CD1d–iNKT cell axis, which plays a critical role in early antiviral responses but is often disrupted through MAPK-dependent mechanisms. We explore how changes in MAPK signaling affect antigen-presenting cells, drive T cell exhaustion, and reprogram immune cell metabolism, factors that contribute to viral immune evasion. The review also examines therapeutic strategies aimed at targeting MAPKs to improve antiviral immunity. These include small-molecule inhibitors and immune modulators that may enhance antiviral responses while limiting side effects. We emphasize the importance of context, as MAPK-targeted therapies must be carefully timed and tailored to avoid suppressing protective immunity or triggering unwanted inflammation. Overall, this review highlights the therapeutic potential and challenges of targeting MAPK pathways in viral infections and encourages further research into selective, host-directed antiviral strategies. Full article

Plastic pollutants, including phthalates, bisphenol A (BPA), per- and polyfluoroalkyl substances (PFAS), and microplastics (MPs), are increasingly recognized as emerging environmental cofactors that intersect with infectious disease dynamics. These compounds, once considered inert, can alter immune function, reshape host–pathogen interactions, and directly influence viral survival and transmission. In this review, we compile current evidence on the chemistry, environmental occurrence, and biological activity of major plastic-associated pollutants with emphasis on their role in viral infections. Phthalates such as di(2-ethylhexyl) phthalate (DEHP) and its metabolite MEHP modulate innate immune signaling and have been shown to exacerbate infections, including Dengue and Coxsackievirus B3. Other DEHP-like phthalates, such as dibutyl phthalate (DBP), exhibit consistent infection-enhancing effects, while high molecular weight or cyclical phthalates such as polyvinyl acetate phthalate (PVAP) display conflicting results in their modulation of viral infections. BPA, widely detected in human tissues, acts through endocrine and immune disruption, worsening viral myocarditis, and altering influenza outcomes. PFAS, persistent “forever chemicals,” reshape adaptive immune responses and are associated with increased susceptibility, viral persistence, or severity of infection of herpesvirus (HCMV, EBV, HSV-1), hepatitis virus, and influenza infection. Microplastics represent a distinct risk by acting as physical carriers for viruses and bacteria, stabilizing viral RNA, enhancing host cell uptake, and skewing immune responses. Together, these pollutants extend beyond toxicology into virology, providing novel insights into how environmental exposures converge with viral pathogenesis. We highlight mechanistic advances and critical knowledge gaps and propose future directions for integrating environmental health and infectious disease research. Full article

Human cytomegalovirus (HCMV) and Human Immunodeficiency Virus (HIV) are two pathogens known to have dramatic consequences when contracted early in life. In addition to having a significant impact when acquired individually, these two viruses are known to frequently cause coinfections. Indeed, also in the modern era, HCMV remains one of the most prevalent coinfections in newborns of mothers living with HIV, including both HIV-positive children regardless of their immune status, and those exposed to HIV but uninfected (HEU). In children with HIV infection, HCMV coinfection has historically been associated with AIDS-defining disease, high mortality, and prolonged, elevated HCMV viral load. Although timely administration of antiretroviral therapy prevents immunodeficiency in people living with HIV and thus reduces the incidence of full-blown HCMV disease in cases of coinfection, emerging data suggest that HCMV-induced immune activation and aging persist, potentially contributing to long-term, non-AIDS-related comorbidities. Growing evidence indicates that also HCMV amplifies HIV susceptibility, disease progression, and immune dysregulation through multiple synergistic mechanisms. Moreover, congenital and early postnatal HCMV infections occur at significantly higher rates in HEU newborns than in HIV-unexposed children and are associated with worse clinical outcomes, particularly when HCMV viral loads are high. This review summarizes current knowledge on the epidemiology, clinical impact, and immunopathogenetic interactions of early HCMV–HIV coinfection in pediatric populations. By integrating recent findings with historical evidence, it highlights critical mechanistic and epidemiological gaps that warrant further investigation. Full article

(1) Background: Sepsis is characterized by profound heterogeneity of immune responses, complicating biomarker-based prediction of clinical outcomes. Latent human cytomegalovirus (HCMV) infection is one of the strongest modulators of the human immune system and may influence cytokine-mediated signaling during sepsis. (2) Methods: In this post hoc analysis of 331 patients from the prospective multicenter SepsisDataNet.NRW cohort (German Clinical Trial Registry No. DRKS00018871), we quantified 13 serum cytokines on day 1 after sepsis diagnosis and determined HCMV IgG serostatus via ELISA. Using nested cross-validated logistic regression with exhaustive feature selection, we identified cytokine panels predictive of 30-day survival in the total cohort and in subgroups stratified by HCMV serostatus. (3) Results: In the total cohort, a four-cytokine panel (IL-6, IL-10, TNF-α, IL-12p70) predicted 30-day survival with a cross-validated area under the curve (AUC) of 0.66 [95% CI: 0.59–0.72]. Stratification by HCMV serostatus revealed distinct predictive profiles: in HCMV-seropositive patients, a two-cytokine model (IL-10, IL-23) achieved an AUC of 0.69 [95% CI: 0.61–0.77], whereas in seronegative patients, a model based on IL-8 and IL-17A failed to generalize (AUC = 0.47 [95% CI: 0.33–0.61]). Kaplan–Meier analysis confirmed a significant separation of survival curves for the HCMV-seropositive group (p < 0.001) but not for seronegative patients (p = 0.282). (4) Conclusions: HCMV serostatus defines an immunological context in which cytokine-based prediction of sepsis outcome becomes feasible. These data suggest that viral serostatus should be systematically incorporated into biomarker discovery and immunophenotyping approaches to improve the reproducibility and biological interpretability of sepsis endotyping. Full article

Glioblastoma (GB) is a highly aggressive brain tumor with a very poor prognosis. Treatment usually consists of surgery, followed by radiotherapy and chemotherapy, but the prognosis remains poor due to its resistance to therapies and a high recurrence rate. Multiple studies have reported the presence of human cytomegalovirus (HCMV) proteins and/or nucleic acids in GB tissues, suggesting its possible implication. These findings have led to the hypothesis that HCMV may contribute to tumor progression, immune evasion, angiogenesis, and resistance to therapy. Clinical trials using anti-HCMV therapies have shown promising preliminary results, indicating a potential therapeutic benefit. This review aims to provide a comprehensive overview of the current evidence linking HCMV to GB and the therapeutic implications. A deeper understanding of this complex interaction could unveil novel strategies for GB treatment. Full article

The complex relationship between human cytomegalovirus (HCMV) and cancer has been of interest since the 1960s. As a highly prevalent human β-herpesvirus, HCMV establishes lifelong latency in CD34+ myeloid progenitor cells and has been implicated as an oncomodulatory virus in various cancers, including glioblastoma multiforme, breast, prostate, colorectal, and ovarian cancer (OC). Recently, discussions have emerged regarding the classification of HCMV as an eighth oncovirus due to the persistence of its nucleic acids and proteins in many tumour types. As one of the deadliest gynaecological cancers, OC is often characterised as the ‘silent killer’ with less than half of women surviving for 5 years, a rate that drops below 20% when detected at advanced stages. Reported effects of HCMV vary between cancers, likely due to differences in tumour type, viral strain, and disease stage. While HCMV infection has been linked to poor OC patient outcomes, its impact on the OC tumour microenvironment (TME) and immune system remains less understood. Investigating HCMV’s potential oncogenic role could provide critical insights into OC progression. This review discusses recent developments on HCMV’s multifaceted roles in OC, including strain heterogeneity, immunomodulation of the TME, dysregulation of inflammatory signalling pathways, and potential therapeutic approaches targeting HCMV in anti-cancer immunotherapies. Full article

Human cytomegalovirus (HCMV) establishes lifelong latency following primary infection, residing within myeloid progenitor cells and monocytes. To achieve this, the virus employs multiple immune evasion strategies. It suppresses innate immune signaling by inhibiting Toll-like receptor and cGAS-STING pathways. In addition, the virus suppresses major histocompatibility complex (MHC)-dependent antigen presentation to evade T cell recognition. As the downregulation of MHC molecules may trigger NK cell activation, the virus compensates for this by expressing proteins such as UL40 and IL-10, which engage inhibitory NK cell receptors and block activating signals, thereby suppressing NK cell immune surveillance. Viral proteins like UL36 and UL37 block host cell apoptosis and necroptosis, allowing HCMV to persist undetected and avoid clearance. In settings of profound immunosuppression, such as after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or solid organ transplantation, slow immune reconstitution creates a window for viral reactivation. Likewise, immunosenescence and chronic low-grade inflammation during aging increases the risk of reactivation. Once reactivated, HCMV triggers programmed cell death, releasing viral PAMPs (pathogen-associated molecular patterns) and host-derived DAMPs (damage-associated molecular patterns). This release fuels a potent inflammatory response, promoting further viral reactivation and exacerbating tissue damage, creating a vicious cycle. This cycle of inflammation and reactivation contributes to both transplant-related complications and the decline of antiviral immunity in the elderly. Therefore, understanding the immune regulatory mechanisms that govern the switch from latency to reactivation is critical, especially within the unique immune landscapes of transplantation and aging. Elucidating these pathways is essential for developing strategies to prevent and treat HCMV-related disease in these high-risk populations. Full article

Human cytomegalovirus (HCMV) is a complex pathogen that encodes a diverse array of proteins essential for its survival and replication within host organisms. Among these proteins, a noteworthy group comprises four chemokine-like G protein-coupled receptors (cellular GPCRs), which play pivotal roles in the virus’s evasion of the host immune response and the establishment of persistent infections. Of particular interest is pUS28, recognized as one of the most extensively studied viral GPCRs (vGPCRs). This receptor has attracted significant attention for its potential as a target for innovative antiviral therapies aimed at addressing HCMV-related diseases. In contrast, pUS27 has not been as thoroughly characterized, presenting a potentially promising avenue for antiviral intervention. The relative scarcity of research surrounding pUS27 underscores an exciting opportunity for further exploration, as a deeper understanding of its functions and mechanisms may reveal novel strategies for combating HCMV infections. This review seeks to synthesize recent advancements in our understanding of pUS27, elucidating its biological roles, interactions, and potential implications for therapeutic development. We will also highlight critical gaps in the existing literature that warrant further investigation, underscoring the need for a more comprehensive understanding of this understudied receptor. By delving into the complexities of pUS27, we aim to inspire future research initiatives that could lead to the development of novel antiviral treatments, thereby enhancing our overall understanding of HCMV pathogenesis. Importance: The study of vGPCRs is essential for understanding how viruses like HCMV manipulate host cell signaling and evade immune responses. While pUS28 has been extensively studied due to its broad chemokine binding and signaling activity, its lesser-known homolog, pUS27, warrants closer attention. Likely arising from a gene duplication event, pUS27 shares approximately 31% sequence identity with pUS28 and is conserved across HCMV strains, suggesting an important functional role. By focusing on pUS27, we may uncover shared mechanisms that allow therapies to effectively target both pUS28 and pUS27, potentially leading to more potent antiviral treatments. The implications of studying pUS27 are profound, as it could play a pivotal role in improving our approaches to combating HCMV and enhancing our overall understanding of immune evasion strategies. Full article

Congenital human cytomegalovirus (HCMV) infection is the most common vertically transmitted viral infection, and it affects 1 in 200 live births worldwide. While neonates are often asymptomatic at birth, congenital HCMV infection can result in long-term complications, including microcephaly, sensorineural hearing loss, and neurodevelopmental abnormalities. Developing antiviral strategies for the treatment and prevention of congenital HCMV infections is a global public health priority. However, licensed anti-HCMV vaccines are not yet available, and therapeutic options for use during pregnancy remain limited. The complement system is a crucial component of the innate immune system that plays essential roles in both fetal development and maternal defense against infectious pathogens. In cases of congenital HCMV infection, complement may contribute to the successful containment of the virus, but dysregulation and overactivation could concurrently drive tissue-damaging inflammation. This review discusses the known roles of the complement system in fetal development and in HCMV pathogenesis and synthesizes existing research to develop the hypothesis that a dysregulated complement system is a key mechanism in the development of congenital HCMV-related pathogenesis and neurodevelopmental sequelae. We explore how HCMV may perturb the complement system during pregnancy and use one inhibitor example to illustrate the broader potential of targeting complement in limiting disease. Full article

Human cytomegalovirus (HCMV) is the leading viral cause of congenital infections and causes substantial morbidity and mortality in neonates and immunosuppressed people. Generating an anti-HCMV vaccine is required for preventing viral-associated diseases and infections. Oral vaccines based on attenuated Salmonella are an attractive solution, since these vaccines can be applied orally and easily for mass immunization. In this report, we constructed an attenuated Salmonella strain for the expression of the murine cytomegalovirus (MCMV) M43 protein and studied its ability as an oral vaccine candidate to stimulate antiviral immunity in mice. In orally immunized mice, the constructed vaccine, Sal-M43, elicited both serum IgG and mucosal IgA levels as well as T cell responses that were specific against the MCMV M43 protein. Moreover, the Sal-M43 immunization substantially inhibited the viral growth and infection in various organs and tissues and offered complete immune protection against both intraperitoneal and intranasal MCMV challenges. Thus, the Salmonella-based vaccine expressing the M43 antigen is effective in inducing anti-MCMV immunity. These findings also reveal the promise of developing oral anti-CMV vaccines based on attenuated Salmonella vectors expressing different viral antigens. Full article

Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus that establishes lifelong latent infection in CD34⁺ haematopoietic stem and progenitor cells. A unique subset of viral genes is expressed during latency, which functions to modulate cellular mechanisms without supporting viral replication. One potential function of these genes is to regulate the differentiation state of latently infected CD34⁺ cells, thereby preventing their progression into antigen-presenting cells, e.g., dendritic cells. In this study, we first compared CD34⁺ cells that supported productive and latent infections using the RV-TB40-BAC_KL7-SE-EGFP virus. Over a seven-day time course, the proportion of latently infected CD34⁺ cell subsets within the myeloid progenitor population remained similar to that in the mock-infected control. However, starting from day 3 post-infection, there was an increase in the proportion of the early progenitor subsets, including haematopoietic stem cells (HSCs) and multipotent progenitors (MPPs). In contrast, productively infected cells, which constituted less than 1% of the population, only accounted for a small portion of the myeloid progenitors. Importantly, our data revealed that the innate immune STING/p-TBK1/p-IRF3 pathway was activated in latently infected CD34⁺ cells, yet type I interferon (IFN) expression was decreased. This decrease was attributed to impaired p-IRF3 nuclear translocation, limiting the induction of an autocrine type I IFN response. However, treatment with IFN-β could induce myelopoiesis in latently infected cells. In summary, HCMV modulates a key component of the STING pathway to inhibit antiviral immune responses by decreasing the type I IFN-mediated cell differentiation of CD34⁺ progenitor cells. This study uncovered a new mechanism of latent HCMV-mediated regulation of the host cell differentiation response. Full article

Human cytomegalovirus (HCMV) establishes lifelong latency in the host, with the bone marrow (BM) CD34+ cells serving as a key reservoir. To investigate tissue-specific immune responses to CMV, we analysed paired peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMNCs) from HCMV-seropositive donors using multiparametric flow cytometry and cytokine FluroSpot assays. We assessed immune cell composition, memory T cell subsets, cytokine production, cytotoxic potential, activation marker expression, and checkpoint inhibitory receptor (CIR) profiles, both ex vivo and following stimulation with lytic and latent HCMV antigens. BMMNCs were enriched in CD34+ progenitor cells and exhibited distinct T cell memory subset distributions. HCMV-specific responses were compartmentalised: IFN-γ responses predominated in PBMCs following lytic antigen stimulation, while IL-10 and TNF-α responses were more prominent in BMMNCs, particularly in response to latent antigens. US28-specific T cells in the BM showed elevated expression of CD39, PD-1, BTLA, CTLA-4, ICOS, and LAG-3 on CD4+ T cells and increased expression of PD-1, CD39, BTLA, TIGIT, LAG-3, and ICOS on CD8+ T cell populations, suggesting a more immunoregulatory phenotype. These findings highlight functional and phenotypic differences in HCMV-specific T cell responses between blood and bone marrow, underscoring the role of the BM niche in shaping antiviral immunity and maintaining viral latency. Full article

Human cytomegalovirus (HCMV) is a ubiquitous member of the herpesvirus family, of significant clinical importance, and highly adapted to its host, resulting from millions of years of co-evolution. As a result, the virus systematically subverts almost all aspects of antiviral immune defence to successfully establish a lifelong persistent infection, and in the process, dramatically reshapes the phenotype and function of host immunity to both HCMV and other diseases. Natural killer (NK) cells are a critical component of successful herpesvirus control. Here, we discuss their role in modulating HCMV disease and the multitude of ways that HCMV has evolved to prevent and manipulate this process. We also consider how antibody-dependent cellular cytotoxicity by NK cells directed against HCMV might overcome NK immune evasion mechanisms and be useful therapeutically. Full article

Human cytomegalovirus (HCMV) coinfection is associated with a faster HIV disease progression and adverse clinical outcomes. HCMV-encoded miRNA expression, in individuals acutely infected with HIV (AHI), compared to those with HCMV monoinfection, was investigated in relation to viral replication and inflammation/immune activation. Sixteen individuals with AHI coinfected with HCMV were analyzed at serodiagnosis (T0) and after 6 (T1) and 12 (T2) months of antiretroviral therapy initiated within one week from serodiagnosis. Fourteen HCMV monoinfected subjects were also studied. Plasma RNA was reverse-transcribed and amplified with a panel designed to detect 14 different HCMV-microRNAs (miRNAs). VEGF-A and IP-10 plasma levels were quantified using ELISA. Except for hcmv-miR-70-3p, detected in all subjects, hcmv-miR-UL112-3p, hcmv-miR-US25-1-5p, hcmv-miR-US25-2-3p, hcmv-miR-US4-5p, hcmv-miR-US5-1, hcmv-miR-US5-2-3p, hcmv-miR-UL36-3p, and hcmv-miR-UL36-5p were significantly more frequently detected when HCMV DNA was present (lytic infection). In latent HCMV infection, hcmv-miR-UL22A-5p and hcmv-miR-UL148D were more frequently observed in HIV/HCMV-coinfected individuals, compared to mono-HCMV infection. Hcmv-miR-UL22A-5p and hcmv-miR-US33-5p showed a direct correlation with HIV-1 RNA. Notable positive correlations between hcmv-miR-UL22A-5p and the interferon-gamma-inducible protein 10 (IP-10), as well as between hcmv-miR-UL148D and the vascular endothelial growth factor A (VEGF-A), were also observed. HCMV-miRNA expression varies between lytic and latent infection and differs in HIV coinfection. In HCMV/HIV coinfection, increased levels of hcmv-miR-UL148D, associated with VEGF-A production, seem to be less linked to HIV viremia with respect to hcmv-miR-UL22A-5p and hcmv-miR-US33-5p. A deeper understanding of HCMV-encoded miRNA biology may facilitate the comprehension of HCMV/HIV coinfection pathogenetic mechanisms. Full article

Periodontal disease (PD) is an inflammatory condition that can contribute to the development of oral cancer. Chronic inflammation from PD can lead to the release of inflammatory mediators and growth factors that promote tumorigenesis. Porphyromonas gingivalis (P. gingivalis) is one of several pathogens implicated in PD and its potential link to oral cancer. However, other viral infections, such as human cytomegalovirus (HCMV), can also contribute to chronic inflammation, creating a favorable environment for oral cancer development. Objectives: The present literature review tries to investigate the possible influence of P. gingivalis and HCMV co-infection in fostering the development of oral cancer and chronic periodontitis. Methods: A comprehensive search was conducted in PubMed and Google Scholar, focusing on the relevance and significance of articles that examine the role of P. gingivalis and HCMV in periodontal disease and oral cancer. Results: The evidence suggests that P. gingivalis and HCMV may act synergistically to modulate host immunity, disrupt epithelial integrity, and interfere with key cellular pathways. These interactions may enhance tissue destruction and foster a microenvironment conducive to malignant transformation. However, most of these findings stem from in vitro models and small-scale clinical studies, limiting the generalizability and clinical relevance of current conclusions. Conclusions: Although the proposed interaction between P. gingivalis and HCMV provides a compelling framework for understanding how microbial co-infections may influence oral cancer, the evidence remains preliminary and largely associative. To support these mechanistic hypotheses, future studies should give top priority to in vivo models, bigger patient cohorts, and longitudinal clinical studies. Full article