Search Results (669)

Infectious diseases constitute a major public health concern and a leading cause of morbidity and mortality worldwide. The eye, by virtue of its rich vascularity and unique immunological microenvironment, is susceptible to involvement by a broad spectrum of bacterial, viral, fungal, and parasitic systemic infections, which may lead to diverse ocular and visual manifestations through direct pathogen invasion, immune-mediated mechanisms, or complications of therapy. Notable systemic infections with potential ocular involvement include tuberculosis; the spirochetal illnesses syphilis, Lyme disease, and leptospirosis; brucellosis; cat-scratch disease; leprosy; infective endocarditis; human immunodeficiency virus, cytomegalovirus, West Nile virus, and adenovirus infections; rubeola; dengue fever; candidiasis; cryptococcosis; aspergillosis; mucormycosis; toxoplasmosis; malaria; onchocerciasis; and cysticercosis. Ocular manifestations can serve as early diagnostic clues to underlying systemic infections, whereas, conversely, systemic features can help interpret ocular findings. Effective investigation and management of systemic infections benefit from a multidisciplinary approach, in which ophthalmologists can contribute substantially and help optimize both visual and overall health outcomes. Full article

Background/Objectives: Cytomegalovirus (CMV) retinitis remains a significant opportunistic infection in patients with advanced human immunodeficiency virus (HIV) infection, particularly with late HIV diagnoses. This three-case series aimed to describe HIV-associated CMV retinitis in newly diagnosed advanced HIV infection with documented concurrent and/or prior infectious conditions, and to highlight the importance of bord systemic screening and multidisciplinary management. Methods: We retrospectively reviewed three male patients diagnosed with HIV-associated CMV retinitis at a tertiary ophthalmology referral center. Clinical findings, CD4-positive T-cell counts, HIV-RNA levels, aqueous humor CMV-DNA results, systemic infectious conditions, treatment and ocular outcomes were summarized. Results: All patients had marked cellular immunodeficiency, with CD4-positive T-cell counts ranging from 46 to 141 cells/µL, and CMV-DNA was detected in aqueous humor in all cases. The infectious burden was substantial: all three patients had syphilis and hepatitis B virus infection, two had oral candidiasis, and individual patients had chlamydia infection, tuberculosis, amebic colitis, or a history of herpes zoster. One patient was initially suspected of having syphilitic uveitis, which illustrates how coinfections may obscure the diagnosis of CMV retinitis. Retinal detachment occurred in two cases and was surgically repaired with anatomical recovery. Conclusions: These cases emphasize that CMV retinitis in newly diagnosed advanced HIV infection should prompt broad infection screening and multidisciplinary evaluation, particularly in the setting of delayed HIV diagnosis and severe immunosuppression. Comprehensive screening for opportunistic and sexually transmitted infections, prompt ocular virological confirmation, and multidisciplinary management are essential in patients with HIV-associated CMV retinitis. Full article

Multiple sclerosis is an immune-driven neurological disease that affects myelinated axons in the central nervous system. However, the trigger of the (dysregulated) immune reactions is not known. According to Wilkin’s primary lesion theory, myelin-reactive T cells present in the immune repertoire hyper-react to myelin antigens that are released from idiopathic lesions within the central nervous system. However, neither the cause of the primary lesion nor the cause of the immune hyper-reactivity is known. We investigated whether these unknown activation signals may be relayed by common herpesviruses. In this concept paper, we propose the novel paradigm that the trigger of autoimmunity in MS comprises a conspiracy of three common herpesviruses: human herpesvirus-6A as a potential trigger of primary lesions due to its proven capacity to cause oligodendrogliopathy, cytomegalovirus as a trigger for the formation of effector memory cytotoxic T cells with proven capacity to induce multiple sclerosis pathology in a non-human primate MS model and Epstein-Barr Virus due to its capacity to render B cells capable to effectively present a critical myelin antigen to these effector memory cytotoxic T cells. Full article

Cytomegalovirus (CMV) is a major determinant of post-transplant morbidity in solid organ transplant recipients, not only through direct viral disease but also through a broad spectrum of indirect effects that may adversely influence graft and patient outcomes. This review summarizes current clinical and mechanistic evidence regarding the mechanisms of CMV-associated indirect injury in transplantation, drawing on human observational studies together with supporting in vitro and animal-model data. CMV establishes lifelong latency with intermittent reactivation and exerts sustained immunomodulatory effects on both innate and adaptive immunity, which may persist even during low-level viral replication. The mechanisms discussed include monocyte reprogramming, altered antigen presentation, T-cell and natural killer cell dysregulation, endothelial activation and dysfunction, chronic inflammatory signaling, impaired antimicrobial defense, and disturbances in metabolic regulation. The review considers how these mechanisms have been proposed to translate into major post-transplant complications, including acute rejection, chronic allograft dysfunction, cardiovascular and thrombotic disease, post-transplant diabetes, and increased susceptibility to secondary bacterial, fungal, and viral infections. It also addresses current preventive strategies, although evidence regarding their effectiveness in reducing indirect clinical outcomes remains limited and largely observational. Much of the supporting evidence is associative, and the contribution of CMV is often difficult to separate from that of the overall immunosuppressive burden and the comorbidities of transplant recipients. With these considerations, the available evidence supports regarding CMV not merely as an opportunistic pathogen, but as a persistent immunobiological driver of long-term transplant injury. Improved understanding of these indirect effects may enhance risk stratification, support biomarker-guided prevention, and inform future strategies aimed at reducing long-term graft dysfunction and patient morbidity after transplantation. Full article

The diversity and abundance of the brain virome is an active field of investigation. However, how the brain virome relates to the presence of viruses outside of the nervous system remains unclear. The rationale for this study is that analyses across multiple biologically linked compartments within the same individuals provide an important opportunity to evaluate virome discordance and viral burden. To characterize viral prevalence and burden across anatomical compartments, we applied the targeted viral enrichment method ViroFind to matched postmortem brain (n = 66), cerebrospinal fluid (CSF; n = 24), and peripheral samples (spleen, peripheral blood mononuclear cells, and lymph nodes; n = 66) from individuals with and without human immunodeficiency virus (HIV) infection and substance use disorder (SUD) in the National NeuroAIDS Tissue Consortium. We detected nucleic acids from 27 viruses representing 12 taxa. Several viruses, including adenovirus, torque teno virus, Epstein–Barr virus, human herpesvirus 6 and 7, cytomegalovirus, parvovirus, and JC polyomavirus, showed significant inter-compartment differences in prevalence or burden. CSF exhibited lower overall viral diversity than brain or peripheral samples, whereas peripheral samples showed the highest viral burden. CNS viral detection was more likely when the same virus was also detected in the periphery. We also detected HBV and HCV in CNS samples despite them not being classically regarded as neurotropic. Broader virome profiling showed greater peripheral viral burden and diversity in HIV-positive than HIV-negative individuals, whereas SUD was not associated with overall viral burden differences. These findings highlight important cross-compartment differences in viral detection, including occurrence of occult HBV infection within the CNS, and support the value of CNS–periphery comparisons in virome studies. These findings can contribute to improved diagnosis and management of viral infections. Full article

Herpesvirus infections belong to major pathogens in the human population. This study aimed at evaluating diagnostic data for eight human herpesviruses, based on datasets derived from a large European tertiary care center. Specifically, we analyzed 118,692 herpesvirus submittals to the Diagnostic Division of the Virological Institute, University Hospital Erlangen (UKER), Germany, between July 2014 and June 2024. Our points of focus were the following: (i) the frequencies of herpesvirus diagnostic results with positivity rates, (ii) departments representing main sample submitters, (iii) the specific importance of intensive care units (ICUs), (iv) the COVID-19 pandemic period, and (v) distinct properties of sample types. Overall, we are stating the highest frequencies of diagnostic assessment for herpes simplex virus (HSV), human cytomegalovirus (HCMV), and Epstein–Barr virus (EBV) infections, pointing to their dominant relevance for clinical practice. Notably, HCMV submittals (46.6% of total), together with EBV (26.2%) and HSV (15.7), accounted for almost 90% of all herpesviral diagnostic samples during this period. Within these key groups, HCMV, EBV and HSV showed positivity rates of 14.5%, 35.0%, and 18.5%, respectively. Concerning a main input of sample submittals, two departments were predominant in our center, i.e., the Departments of Haematology–Oncology and Anaesthesiology. These included patients under multifold types of treatment associated with an increased risk of herpesvirus reactivation or primary infection. Furthermore, another high portion of submittals was noted for ICUs and external sources. In addition, a numerical, transient increase in herpesvirus diagnostic submittals, from various sources, was shown for the COVID-19 pandemic years (mostly 2021) as compared to other periods. Combined, these data underlined the importance of clinical monitoring of herpesvirus infections, particularly for high-risk patients, and the steady need of improvements in preventive measures, therapeutic options, and safe diagnostic tools. Full article

Background: Previous work from our group demonstrated an association between immunohistochemical detection of Human cytomegalovirus (HCMV) late antigen and poor event-free survival (EFS) in pediatric medulloblastoma. Whole-genome sequencing (WGS) further identified increased abundance of HCMV-aligned reads at the UL88 locus, particularly in Group 3 tumors, a molecular subgroup associated with aggressive clinical behavior and poor prognosis. Methods: We performed an integrated multi-omics analysis of pediatric medulloblastoma using WGS (n = 39) and RNA sequencing (RNA-seq; n = 28) datasets. RNA-seq data were filtered using stringent alignment criteria (MAPQ ≥ 20) and compared with fetal brain (n = 12), adult brain (n = 12), and HCMV-infected cell culture controls (n = 3). Only high-confidence uniquely aligned reads were retained to reduce nonspecific and multi-mapped viral alignments. Sequencing reads were aligned to the HCMV Merlin reference genome (NC_006273.2) using a standardized analytical pipeline. A subset of 28 cases with matched tumor WGS, tumor RNA-seq, and germline WGS data was used for integrated multi-omics analyses. Orthogonal validation analyses were performed in Group 3 tumors using independent genomic and transcriptomic approaches. Exploratory survival analyses were conducted in a combined cohort (n = 84) integrating genomic and immunohistochemical datasets. Results: Recurrent low-level HCMV-aligned molecular signals were identified across medulloblastoma datasets. Reads aligning to UL76, UL88, and UL99 were the most consistently detected HCMV-associated late-gene signals across RNA-seq and WGS datasets. A composite HCMV late-gene signature (UL76–UL88–UL99) showed higher levels in Group 3 tumors than in other molecular subgroups (p < 0.05 in WGS analyses). Orthogonal analyses demonstrated concordant low-level HCMV-associated genomic and transcriptomic signals enriched in tumors with MYC-associated activation and chromosome 17 imbalance. In the combined cohort (n = 84), elevated HCMV-associated signal assessed by immunohistochemistry and genomic profiling was associated with reduced EFS (median 55 vs. 147 months; log-rank p < 0.001). The subgroup classified as HCMV-high Group 3 demonstrated the strongest association with adverse outcome in exploratory multivariable analyses (HR = 6.43, p = 0.002). Conclusions: This study identifies recurrent low-level HCMV-associated genomic and transcriptomic signals across pediatric medulloblastoma datasets, with preferential enrichment in biologically aggressive Group 3 tumors. Although the extremely low abundance of viral-aligned reads precludes definitive evidence of productive viral infection, the reproducible detection of HCMV-associated molecular signatures across independent sequencing platforms supports further investigation into a potential oncomodulatory association in pediatric medulloblastoma. Additional validation using optimized viral detection methodologies, independent cohorts, and mechanistic studies will be necessary to clarify the biological and clinical significance of these findings. Full article

Programmed cell death (PCD) pathways of innate immunity serve to protect host cells from invading viruses. Parthanatos is a novel form of PCD triggered by excessive host cell DNA damage that leads to overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) which in turn stimulates poly(ADP-ribose) (PAR) polymer formation. PAR translocates to the cytoplasm, where it induces release of apoptosis-inducing factor (AIF) from mitochondria, that then travels back to the nucleus, where it mediates large-scale DNA fragmentation and cell death. Little information is available regarding parthanatos as a cell death mechanism to dampen herpesvirus replication at the host cell level. A series of studies were therefore performed to clarify a possible role for parthanatos during productive replication of murine cytomegalovirus (MCMV) and herpes simplex virus type 1 (HSV-1) in diverse cell types. These included mouse embryo fibroblasts, mouse lung fibroblasts, mouse microglial (BV-2) cells, and human retinal pigment epithelial (ARPE-19) cells. We report that PAR protein production is surprisingly cell type specific. Moreover, MCMV or HSV-1 infection may suppress parthanatos as observed for other PCD pathways, such as apoptosis, necroptosis, and pyroptosis, in a dose-dependent and cell type-specific manner. We conclude that the operation of parthanatos at the host cell level during herpesvirus replication is more complex than originally thought but offers new targets for possible therapeutic interventions. Full article

Viral infections of the central nervous system produce memory impairment through mechanisms that extend beyond acute neuronal injury. Herpes simplex virus type 1, human immunodeficiency virus, varicella zoster virus, cytomegalovirus, Epstein–Barr virus, influenza, SARS-CoV-2, West Nile virus, and Zika virus each enter or engage the brain through distinct routes, yet converge on four shared molecular pathways that selectively damage hippocampal circuits: mitochondria-associated membrane (MAM) dysfunction, chronic neuroinflammation, blood–brain barrier (BBB) disruption, and impaired CREB-BDNF signaling. These pathways specifically compromise the dentate gyrus, CA3, and CA1 subfields, producing predictable deficits in pattern separation, associative retrieval, and temporal memory binding. Antiretroviral and antiviral therapies suppress viral replication but fail to reverse organelle-level dysfunction, leaving most hippocampal injury unaddressed. Emerging plasma biomarkers, p-tau217, neurofilament light chain, and GFAP, combined with hippocampal subfield MRI, now enable mechanistic stratification before irreversible circuit loss occurs. This review proposes, as a unifying hypothesis, that virus-associated memory impairment represents a convergent hippocampal syndrome driven by shared downstream pathways, and that combination therapies targeting these pathways simultaneously offer greater therapeutic promise than pathogen-specific approaches alone. The evidentiary basis for this framework varies across pathogens and conditions; direct mechanistic evidence, mechanistic analogy, and preclinical data are distinguished throughout. Full article

Human cytomegalovirus (HCMV) remains an important medical problem in multiple patient settings despite the availability of antivirals. In part, this is linked to resistance, cost and restrictions on use in several patient settings. More generally, it remains attractive to increase our arsenal of anti-viral approaches to target HCMV. We previously characterized a potent inhibitor of HCMV infection, DIDS, that displays cysteine reactivity, allowing it to bind virions and neutralize HCMV infection of fibroblasts. We now show that DIDS is inhibitory to cell-free and cell-associated infection of multiple cell types, including cells of the haematopoietic lineage—cells important for latency and dissemination. Consistent with this broad activity, DIDS partially inhibited gB (but not SARS-CoV-2 spike) fusion activity. Intriguingly, further characterization of DIDS activity in myeloid cells revealed that, unlike in all other cell types, DIDS blocked a post-entry event in CD14+ monocytes and also dendritic cell derivatives. Despite viral entry, entry was largely silent, with a failure to activate innate immunity and cell survival pathways known to be activated by HCMV. In contrast, HCMV infection was observed to activate host miRNA expression in CD14+ cells, suggesting a DIDS-insensitive viral function was responsible or, alternatively, that host miRNA expression is a potential anti-viral response to viral internalization. Thus, we report the further characterization of a broad-acting inhibitor of HCMV infection, which may also prove a useful tool to study unique events for the infection of monocytic cells by HCMV—a cell type that is crucial for HCMV dissemination and pathogenesis in vivo. Full article

Background: Emerging evidence suggests that antiviral treatment targeting human cytomegalovirus (HCMV) may improve outcomes in patients with glioblastoma (GBM). In this study, we analyzed serological data from the placebo-controlled VIGAS1 trial (Eudra number 2006-002022-29), which assessed the effect of valganciclovir (VGCV) on GBM progression in 42 patients, for impact of VGCV in preventing HCMV reactivation. Methods: VIGAS1 patients had undergone radical surgery and were randomized to receive either VGCV (n = 22) or placebo (n = 20) alongside standard radiochemotherapy. Blood was prospectively collected at baseline and 3-, 12- and 24-week follow-up visits. GBM cell lines and a cytomegalovirus-infected murine brain cancer model were used to validate the clinical findings. Results: Over the 24-week study period, we found that HCMV reactivation, as inferred from IgM seropositivity, occurred in 58.3% of patients in the placebo group, whereas this was completely prevented in the VGCV-treated group except for one patient with no treatment compliance (p = 0.0005). HCMV reactivation was linked to early recurrence. IgG-positive patients treated with VGCV showed a significantly longer time to progression (TTP) than those receiving placebo (6.7 vs. 3.7 months, p = 0.0408). We found a significant association between higher steroid doses and enhanced reactivation in the placebo group. In vitro and murine studies confirmed that corticosteroids, combined with radiation therapy, enhanced cytomegalovirus reactivation, which was mitigated by antiviral treatment. Conclusions: These findings suggest that preventing HCMV reactivation with antiviral therapy may improve patient outcomes, especially in HCMV-seropositive GBM patients, and further support the hypothesis that HCMV is a tumor-promoting virus. Full article

Adenoviruses have been implicated in childhood cancers, primarily leukemia, yet prior neonatal investigations have rarely examined other pediatric tumor types. This study evaluated whether adenoviral early region (E1A) sequences can be detected in archival neonatal Guthrie cards from children who later developed diverse pediatric tumors and in corresponding paraffin-embedded tissues. DNA extraction was optimized for long-stored dried blood spots, and PCR conditions were refined for both Guthrie card and paraffin-derived DNA. Adenoviral E1A was analyzed using conventional and nested PCR, and sequencing of representative amplicons confirmed correspondence to human adenovirus species C. E1A PCR positivity was found in 43% of Guthrie cards from cases (n = 54) and 34% of controls (n = 32), and in 41% of tumor tissues (n = 75) compared with 5% of non-tumor paraffin controls (n = 20). Detection occurred across multiple tumor categories without a clear association with tumor type. Partial concordance was observed between paired neonatal and tumor samples, and cytomegalovirus markers were detected in a subset of E1A-positive specimens. These findings confirm the suitability of Guthrie cards for retrospective viral DNA detection and extend previous leukemia-focused neonatal studies to broader pediatric tumors. The data suggest a potential association between birth-stage adenoviral detection and childhood cancer, though a causal link remains unproven and requires further longitudinal investigation. Full article

The rectal mucosa houses a large number of viruses with important roles in shaping the local microbial communities and modulating immune responses, which could influence host susceptibility to infection and other diseases. Unique composition of the gut microbiome, including the predominance of clinically significant eukaryotic viruses like herpesviruses, cytomegalovirus, and human papillomavirus, has been described in both people with HIV (PWH) and men who have sex with men (MSM) vulnerable to HIV. Despite these insights, the rectal virome and the clinical implications of virome–bacteriome–immune interactions in the rectal mucosa remain poorly understood. In this review, we synthesize existing data on the composition of the rectal virome, its interactions with the bacteriome and the immune system, and implications on clinical outcomes in people living with or vulnerable to HIV. We also highlight the gaps and research needed to further explore and unravel these relationships. Full article

Human cytomegalovirus (HCMV) remains a significant cause of morbidity in immunocompromised patients, necessitating the development of improved antivirals. Using an integrated in silico and in vitro approach, we identified a novel ligand (NL) as a letermovir analog with enhanced binding affinity and reduced cytotoxicity. A pUL56 terminase subunit model generated with AlphaFold 3 was used for the virtual screening of a 15,000-compound library. Among the 73 candidates with structural similarity to letermovir (Tanimoto ≥ 0.6), NL exhibited superior predicted binding affinity (ΔG_bind = −10.7 kcal/mol). In silico toxicity prediction (ProTox 3.0) classified NL as having low toxicity (class 4, LD50 ≈ 1000 mg/kg), which was confirmed in vitro, where NL demonstrated 158-fold less toxic (CC50 = 2.69 mg/mL) in MRC-5 cells than letermovir (0.017 mg/mL). Molecular dynamics simulations over 500 ns revealed that the pUL56-NL complex forms a more thermodynamically stable interaction, with a lower calculated free energy of binding (MMGBSA: −40.89 ± 7.40 kcal/mol vs. −32.76 ± 4.96 kcal/mol) and a narrower free energy landscape. These results establish NL as a promising, low-cytotoxicity candidate with enhanced target engagement, warranting further investigation as a potential anti-HCMV therapeutic. Full article