Merkel Cell Polyomavirus Research Articles

Novel Human Polyomaviruses Discovered From 2007 to the Present: An Update of Current Knowledge.

Human polyomaviruses (HPyVs) are a diverse group of viruses that typically establish asymptomatic persistent infections in healthy individuals. However, they can lead to severe diseases in immunocompromised patients. The past 15years have witnessed significant advancements in understanding HPyVs, leading to the discovery of several novel and highly divergent strains. This surge in knowledge raises critical questions about their evolution, tropism, and potential contributions to various diseases. Although HPyVs are generally benign, certain strains can lead to significant health issues under immunocompromised conditions. Since 2007, several novel PyVs have been isolated from humans: Karolinska Institute Polyomavirus (KIPyV), Washington University Polyomavirus (WUPyV), Merkel cell Polyomavirus (MCPyV), HPyV6, HPyV7, Trichodisplasia spinulosa polyomavirus (TSPyV), HPyV9, HPyV10, Saint Louis polyomavirus (STLPyV), HPyV12, New Jersey Polyomavirus (NJPyV), Lyon IARC polyomavirus (LIPyV), HPyV16 and Quebec polyomavirus (QPyV). This review summarises the available data regarding the biology, tissue tropism, epidemiology, and associated diseases of novel HPyVs discovered from 2007 to the present. While some HPyVs are well-characterised with clear associations to specific diseases, others remain enigmatic, warranting additional investigation into their biology and clinical implications.

NSD3::FGFR1: A Novel Gene Fusion First to Be Described in Merkel Cell Carcinoma.

Merkel cell carcinomas (MCCs) exhibit diverse molecular profiles, often categorized by their association with Merkel cell polyoma virus (MCPyV). MCPyV-associated MCCs typically display a low tumor mutational burden (TMB), lacking both somatic mutations and ultraviolet signature. By contrast, MCPyV-negative MCCs commonly arise in sun-exposed skin and frequently exhibit a high TMB, along with TERT promoter mutation (TPM) and somatic mutations, particularly in TP53 and RB1. Gene fusions are exceedingly rare in MCCs, and their specific frequency and fusion transcripts remain largely unexplored. Here, we present a unique case of MCPyV-associated MCC characterized by NSD3::FGFR1 fusion, representing a novel fusion transcript not previously reported in MCCs. A 72-year-old White man presented with a cyst-like nodule on the left elbow, which had progressively increased in size over a span of 6 months. Excisional biopsy specimen revealed a neuroendocrine carcinoma diffusely expressing CK20 (perinuclear dot-like), synaptophysin, CD56, NSE, and MCPyV, consistent with MCC. Next-generation sequencing identified a NSD3::FGFR1 fusion without any additional somatic mutations, including TP53 and RB1 mutations, or TPM. Although NSD3::FGFR1 fusion has been sporadically reported in other solid tumors, such as pulmonary squamous cell carcinoma, its identification in an MCC is unprecedented to our knowledge. This novel finding not only underscores the uniqueness of our case but also contributes to the evolving understanding of the molecular landscape of MCCs, particularly MCPyV-associated MCCs.

What is the predominant etiological factor for Merkel cell carcinoma in Turkey: viral infection or sun exposure?

BackgroundMerkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin carcinoma. The pathogenesis involves Merkel cell polyomavirus (MCPyV) and ultraviolet radiation exposure. Studies on MCC in Turkey are scarce, with essential data on local etiopathogenic and prognostic factors still lacking. We aimed to analyze the clinical and histopathologic features, biomarkers, and to evaluate these findings alongside Turkish literature to infer the etiopathogenesis, prognosis, and possible treatment options for the disease.MethodsWe analyzed the clinicopathologic features of 7 MCC patients diagnosed at the Pathology Department of Pamukkale University between 2003 and 2024 in this retrospective study. Clinical data was retrieved from the hospital’s electronic records. Formalin-fixed, paraffin-embedded tumor specimens stained with hematoxylin-eosin were examined microscopically. MCPyV, Retinoblastoma 1 (RB1), p53, PRAME, PD-L1, and MMR proteins were evaluated immunohistochemically. Research on MCC from Turkey was sourced from Turkish databases (ULAKBIM, Turkiye Atif Dizini, DergiPark, Turk Medline) and international databases (Pubmed, Google Scholar, Scopus, Embase). The literature review identified original research, case reports, theses, and conference presentations.ResultsThe patients in our series, all aged over 50 (mean age 76.1 ± 14.8), with a slight predominance of one gender (F: M = 1.33:1). During a mean follow-up of 16.1 months, 42.9% (3/7) had lymph node metastases, and 57.1% (4/7) showed distant metastases. PRAME was positive in 42.9% of the cases (3/7). The total number of MCC cases reported from Turkey was estimated at 227 ± 46, with MCPyV status available in a subset, showing a positivity rate of 70.3%. PD-L1 expression was observed in the tumor microenvironment in 55% of virus-positive MCC cases from Turkey.ConclusionsThe 9% incidence of gluteal localization in Turkish MCC cases, considering its geographical significance, is noteworthy. Notably, all MCC cases from Turkey in which microsatellite instability status has been assessed were found to be microsatellite stable. PRAME should be investigated in larger series for its potential role in the shared oncogenic pathways of MCC.

High-throughput screening identifies Aurora kinase B as a critical therapeutic target for Merkel cell carcinoma

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer. Most MCCs contain Merkel cell polyomavirus (virus-positive MCC; VP-MCC), and the remaining are virus-negative (VN-MCC). Immune checkpoint inhibitors are the first-line treatment for metastatic MCC, but durable responses are achieved in less than 50% of patients. To identify new treatments, we screen ~4,000 compounds for their ability to reduce MCC viability and demonstrate that VP-MCC and VN-MCC exhibit distinct response profiles. Aurora kinase inhibitors selectively reduce VP-MCC viability, with RNAi screening independently identifying AURKB as an essential gene for MCC survival, especially in VP-MCC. AZD2811, a selective AURKB inhibitor, induces mitotic dysregulation and apoptosis in MCC cells, with greater efficacy in VP-MCC. In mice, AZD2811 nanoparticles inhibit tumor growth and increase survival in both VP-MCC and VN-MCC xenograft models. Overall, our unbiased screens identify AURKB as a promising therapeutic target and AZD2811NP as a potential treatment for MCC.

Integrative analysis reveals therapeutic potential of pyrvinium pamoate in Merkel cell carcinoma.

Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine cutaneous malignancy arising from either ultraviolet-induced mutagenesis or Merkel cell polyomavirus (MCPyV) integration. Despite extensive research, our understanding of the molecular mechanisms driving the transition from normal cells to MCC remains limited. To address this knowledge gap, we assessed the impact of inducible MCPyV T antigens on normal human fibroblasts by performing RNA sequencing. Our data uncovered changes in expression and regulation of Wnt signaling pathway members. Building on this observation, we bioinformatically evaluated various Wnt pathway perturbagens for their ability to reverse the MCC gene expression signature and identified pyrvinium pamoate, an FDA-approved anthelminthic drug known for its anti-tumor activity in other cancers. Leveraging transcriptomic, network, and molecular analyses, we found that pyrvinium targets multiple MCC vulnerabilities. Pyrvinium not only reverses the neuroendocrine features of MCC by modulating canonical and non-canonical Wnt signaling but also inhibits cancer cell growth by activating p53-mediated apoptosis, disrupting mitochondrial function, and inducing endoplasmic reticulum stress. Finally, we demonstrated that pyrvinium reduces tumor growth in an MCC mouse xenograft model. These findings offer a new understanding of the role of Wnt signaling in MCC and highlight the utility of pyrvinium as a potential treatment for MCC.

Merkel Cell Polyomavirus Co-Infection in HIV/AIDS Individuals: Clinical Diagnosis, Consequences and Treatments.

Merkel cell polyomavirus (MCV) was named for its role as the causative agent of Merkel cell carcinoma (MCC), which is MCV positive in approximately 80% of cases. MCV is classified as a Group 2A carcinogen, which promotes carcinogenesis by integrating T-antigen into the cell genome. The prevalence of anti-MCV antibodies in the general population can be as high as 90%. MCV typically promotes cancer by integrating T-antigen genes into the host cell genome, and 80% of MCC cases are attributed to MCV activation. In immunocompetent individuals, MCV usually remains latent after infection. However, the incidence of MCC increases significantly in immunocompromised or immunodeficient patients, such as those who have undergone organ transplantation, have chronic lymphocytic leukemia, or are living with human immunodeficiency virus (HIV) infection. Acquired immunodeficiency is a particular feature of people living with HIV. Currently, research on HIV/AIDS patients with MCV infection, clinical outcomes, and treatments is quite limited. This paper reviews previous research and systematically examines the relationship between HIV/AIDS and MCV-associated diseases, with the aim of providing valuable information for the prevention, diagnosis, and treatment of MCV in vulnerable populations.

Genetic and molecular profiling in Merkel Cell Carcinoma: Focus on MCPyV oncoproteins and emerging diagnostic techniques.

Genetic and molecular profiling in Merkel Cell Carcinoma: Focus on MCPyV oncoproteins and emerging diagnostic techniques.

Characterization of different clinical presentation of Merkel cell carcinomas and their potential prognostic implications.

Recent studies analyzed the impact of Merkel cell polyomavirus (MCPyV) on the prognosis of Merkel cell carcinoma (MCC) patients. No data on specific morphological clinical differences of MCPyV+ or MCPyV- are currently available neither on the possible prognostic implication of different clinical presentation of MCC. 1) to describe clinicopathological characteristics of MCC patients and the prevalence of MCPyV infection in an Italian cohort of patients; 2) to define possible differences in clinicopathological and prognostic features among MCPyV+ and MCPyV- MCCs. Retrospective, multicenter, cohort study conducted in two Italian tertiary referral centers. MCPyV presence was detected by immunohistochemistry (IHC) and PCR with two different primers amplifying VP1 (VP1-PCR) and LT viral region (LT-PCR). Clinicopathological features were compared between MCPyV+ and MCPyV- tumors and between red exophytic nodules and subcutaneous cyst-like MCCs. 62 MCCs were included, presenting as red exophytic nodules (69.3%) or with a subcutaneous cyst-like appearance (19.3%); MCPyV was detected in 40.3% of cases by IHC, 56.4% by VP1-PCR and 79% by LT-PCR. No correlation was found between clinical morphology and viral status. Mortality rate was 40.8% for MCPyV- and 23.1% for MCPyV+ (p-value 0.239) and 69.8% for red nodules and 25% for cyst-like lesions (p-value 0.005). By multivariable analysis, age at diagnosis, ki67 and treatment with surgery/radiotherapy remained the only factors significantly affecting the OS. This study highlights the potential impact of clinical morphology of MCCs on prognosis. Subcutaneous cyst-like morphology may provide a survival benefit to the patients, regardless the presence of MCPyV.

Evaluating CK20 and MCPyV Antibody Clones in Diagnosing Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is diagnosed through histopathological and immunohistochemical examination of biopsies from skin or other organs. Its distinguishing features include perinuclear dot-like staining with Cytokeratin 20 (CK20) and detection of Merkel cell polyomavirus (MCPyV) using various methods. However, CK20 and MCPyV negative MCC cases have been reported at varying rates. In this single center cross-sectional study, we aimed to determine which clones are more effective in diagnosing MCC by comparing the performance of CK20 antibody clones Ks20.8 and SP33, as well as MCPyV antibody clones Ab3 and CM2B4. Fifty-four patients diagnosed with MCC were included. Among these, 42 cases were primary cutaneous, and 12 cases were nodal MCC. Fifty-two (96.3%) cases were positive with both CK20 clones, while two cases were negative. Clone SP33 stained areas of necrosis, whereas Ks20.8 showed no aberrant staining. MCPyV was detected in 44 cases (81.5%) using clone Ab3 and 39 cases (72.2%) using clone CM2B4. Staining with MCPyV clone Ab3 was diffuse and strong in most cases, while approximately 30% of CM2B4-positive cases exhibited low percentages and/or weak staining, complicating the evaluation. The two CK20-negative cases were also negative with both MCPyV clones. Our data demonstrated that CK20 clone Ks20.8 may be preferred for MCC diagnosis due to its consistent performance and lack of aberrant staining. Similarly, MCPyV clone Ab3 appears superior to CM2B4 for identifying MCPyV-positive cases.

Sustained Release of HIF-2α Inhibitors Using Biodegradable Porous Silicon Carriers for Enhanced Immunogenic Cell Death of Malignant Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer with limited treatment options, often associated with Merkel cell polyomavirus (MCPyV) and marked by hypoxic tumor microenvironments that promote resistance to therapies. Belzutifan, an FDA-approved hypoxia-inducible factor-2α (HIF-2α) inhibitor, has shown promise in inhibiting tumor growth; however, its clinical efficacy is hindered by its low solubility, rapid clearance, and limited bioavailability. In this study, we present a strategy using porous silicon (pSi) microparticles and nanoparticles as carriers for the sustained delivery of benzoate to MCC cells. The pSi carriers were engineered to securely encapsulate and gradually release belzutifan, overcoming the limitations of free drug administration. Microparticles provided sustained extracellular release, while nanoparticles enabled efficient intracellular delivery, enhancing HIF-2α inhibition. Moreover, the use of biodegradable silicon particles enables long-term consistent release of belzutifan over 10 days in vitro with a single dose administration in the tumor microenvironment, while free belzutifan is rapidly deactivated within 1 day postadministration. In vitro studies demonstrated significant immunogenic cell death (ICD) in MCC cells, marked by the cytosolic localization of HMGB1 and elevated expression of pro-inflammatory cytokines as well as strong upregulation of TLR9. Particularly, the increased TLR9 expression in both MCC cell lines with pSi carrier treatment reinforces immune activation through toll-like receptor signaling, enhancing both innate and adaptive immune responses within the tumor microenvironment. These findings indicate that pSi carriers not only enhance belzutifan's stability and release profile but also amplify antitumor immune responses within the tumor microenvironment. Our results suggest that belzutifan-loaded pSi carriers offer a potent and targeted therapeutic strategy for MCC, potentially addressing key challenges in cancer immunotherapy by combining HIF-2α inhibition with robust immune activation. This platform highlights the universal utility of pSi-based delivery systems to advance MCC treatment with implications for broader cancer therapies.

Herpesviruses mimic zygotic genome activation to promote viral replication

Zygotic genome activation (ZGA) is crucial for maternal to zygotic transition at the 2-8-cell stage in order to overcome silencing of genes and enable transcription from the zygotic genome. In humans, ZGA is induced by DUX4, a pioneer factor that drives expression of downstream germline-specific genes and retroelements. Here we show that herpesviruses from all subfamilies, papillomaviruses and Merkel cell polyomavirus actively induce DUX4 expression to promote viral transcription and replication. Analysis of single-cell sequencing data sets from patients shows that viral DUX4 activation is of relevance in vivo. Herpes-simplex virus 1 (HSV-1) immediate early proteins directly induce expression of DUX4 and its target genes, which mimics zygotic genome activation. Upon HSV-1 infection, DUX4 directly binds to the viral genome and promotes viral transcription. DUX4 is functionally required for infection, since genetic depletion by CRISPR/Cas9 as well as degradation of DUX4 by nanobody constructs abrogates HSV-1 replication. Our results show that DNA viruses including herpesviruses mimic an embryonic-like transcriptional program that prevents epigenetic silencing of the viral genome and facilitates herpesviral gene expression.

Non-Genetic Biomarkers in Merkel Cell Carcinoma: Prognostic Implications and Predictive Utility for Response to Anti-PD-(L)1 Immune Checkpoint Inhibitors.

Merkel cell carcinoma (MCC) is a skin cancer that arises due to either Merkel cell polyomavirus infection (MCPyV) or ultraviolet (UV)radiation exposure, presenting primarily in the head and neck region of fair-skinned males. The recent success of PD-(L)1 immune checkpoint inhibitors (ICIs) in locally advanced/metastatic MCC, with an objective response rate (ORR) around 50% and improved survival, as a first-line treatment has moved ICIs to the forefront of therapy for MCC and generated interest in identifying biomarkers to predict clinical response. The MCC tumour microenvironment (TME) contains various components of the adaptive and innate immune system. These components can contribute to tumour immune escape through immunosuppression by preventing entrance of other immune cells or by aiding in the cytotoxic clearance of tumour cells. We aim to combine information from studies of baseline and on-treatment monitoring of the TME to help predict the success of ICIs in MCC. This review enhances the understanding of how CD8 T cells, γδ T cells and macrophages may impact predictions of response rates to ICIs in MCC patients. These immune cells are non-genetic biomarkers that can also be used to determine prognosis in MCC treatment.

Integrative analysis reveals therapeutic potential of pyrvinium pamoate in Merkel cell carcinoma.

Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine cutaneous malignancy arising from either ultraviolet-induced mutagenesis or Merkel cell polyomavirus (MCPyV) integration. Despite extensive research, our understanding of the molecular mechanisms driving the transition from normal cells to MCC remains limited. To address this knowledge gap, we assessed the impact of inducible MCPyV T antigens on normal human fibroblasts by performing RNA sequencing. Our data uncovered changes in expression and regulation of Wnt signaling pathway members. Building on this observation, we bioinformatically evaluated various Wnt pathway perturbagens for their ability to reverse the MCC gene expression signature and identified pyrvinium pamoate, an FDA-approved anthelminthic drug known for its anti-tumor activity in other cancers. Leveraging transcriptomic, network, and molecular analyses, we found that pyrvinium targets multiple MCC vulnerabilities. Pyrvinium not only reverses the neuroendocrine features of MCC by modulating canonical and non-canonical Wnt signaling but also inhibits cancer cell growth by activating p53-mediated apoptosis, disrupting mitochondrial function, and inducing endoplasmic reticulum stress. Finally, we demonstrated that pyrvinium reduces tumor growth in an MCC mouse xenograft model. These findings offer a new understanding of the role of Wnt signaling in MCC and highlight the utility of pyrvinium as a potential treatment for MCC.

Characteristics of Spontaneous Regression in Merkel Cell Carcinoma: A Retrospective Analysis of Patient and Tumor Features.

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine neoplasia. MCC complete spontaneous regression (CRS) has been linked to good prognosis. We conducted a retrospective review of a single-center cohort of MCC patients to analyze the characteristics of patients and tumors that exhibited regression. The calculated incidence of regressión was 4.5% (5/112). Median age at diagnosis was 69 years (RIQ 31), tumors were primarily located on the head and neck and patients had low rates of immunosuppression. After a median following-up of 4 years none of the patients showed recurrence or distant metastases. Merkel cell polyomavirus (MCPyV) positivity was associated with regression (P=0.045). Despite limited understanding of regression mechanisms, biopsy-induced immune responses linked with host and tumor factors such as age,immunosuppression or MCPyV positivity may play an important role. More research in this field is crucial for the comprehension of this rare phenomenon.

Merkel cell carcinoma in Taiwan: a subset is chronic arsenicism-related, and the Merkel cell polyomavirus-negative cases are pathologically distinct from virus-related cases with a poorer outcome.

Merkel cell carcinoma in Taiwan: a subset is chronic arsenicism-related, and the Merkel cell polyomavirus-negative cases are pathologically distinct from virus-related cases with a poorer outcome.

Merkel Cell Carcinoma and Immunosuppression, UV Radiation, and Merkel Cell Polyomavirus

Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer. Quantifying the contribution of major potentially modifiable risk factors to the burden of MCC may inform prevention efforts. To estimate the population attributable fraction of MCC cases in the US that were attributable to major immunosuppressing conditions (eg, HIV, solid organ transplant, chronic lymphocytic leukemia [CLL]), ambient UV radiation [UVR] exposure, and Merkel cell polyomavirus [MCPyV]). This epidemiological assessment combined data from population-based registries and case series and included cases of MCC that were diagnosed from January 2001 to December 2019 diagnosed in people with HIV, solid organ transplant recipients, and patients with CLL who were identified through population-based cancer registries and linkages with HIV and transplant registries. UVR-based on cloud-adjusted daily ambient UVR irradiance was merged with cancer registry data on the county of residence at diagnosis. Studies reporting the prevalence of MCPyV in MCC specimens collected in the US were combined via a meta-analysis. HIV, solid organ transplant, CLL, UVR, and MCPyV. Population attributable fraction of MCC cases attributable to major risk factors. A total of 38 020 MCCs were diagnosed in the US among xx patients (14 325 [38%] female individuals; 1586 [4%] Hispanic, 561 [1%] non-Hispanic Black, and 35 171 [93%] non-Hispanic White individuals). Compared with the general US population, MCC incidence was elevated among people with HIV (standardized incidence ratio [SIR], 2.78), organ transplant recipients (SIR, 13.1), and patients with CLL (SIR, 5.75). Due to the rarity of these conditions, only 0.2% (95% CI, 0.1%-0.3%) of MCC cases were attributable to HIV, 1.5% (95% CI, 1.4%-1.7%) to solid organ transplant, and 0.8% (95% CI, 0.5%-1.3%) to CLL. Compared with individuals of racial and ethnic minority groups, MCC incidence was elevated among non-Hispanic White individuals at lower and higher ambient UVR exposure levels (incidence rate ratios: 4.05 and 4.91, respectively, for MCC on the head and neck). Overall, 65.1% (95% CI, 63.6%-66.7%) of MCCs were attributable to UVR. Based on a meta-analysis of 19 case series, 63.8% (95% CI, 54.5%-70.9%) of MCCs were attributable to MCPyV. Studies were identified from a MEDLINE search performed on October 12, 2023. The results of this study suggest that most MCC cases in the US were attributable to ambient UVR exposure or MCPyV, with a small fraction due to immunosuppressive conditions. Efforts to lower MCC incidence could focus on limiting UVR exposure.

Novel polyomavirus in the endangered garden dormouse Eliomys quercinus

BackgroundThe garden dormouse (Eliomys quercinus) has experienced a significant population decline across Europe in recent decades. While habitat loss and climate change are often cited as primary factors, pathogen exposure, either to novel or to previously known, may play a role in such a decline. This study aimed to investigate the presence of polyomaviruses in garden dormice, given that these viruses are highly prevalent and can cause disease, particularly in immunocompromised individuals.MethodsThe carcasses of garden dormice (n = 89) were collected throughout Germany. Kidney samples were tested for the presence of polyomavirus DNA using nested degenerate and specific diagnostic PCRs. Seroprevalence was assessed from chest cavity fluid samples through an enzyme-linked immunosorbent assay using polyomavirus VP1 virus-like particles produced in yeast.ResultsA new polyomavirus, related to chimpanzee (Pan troglodytes) polyomaviruses 4 and 5 and human Merkel cell polyomavirus, was identified in the garden dormouse. Two 5,380 bp-length complete viral genomes were sequenced from dormice kidney samples (sequences PQ246041 and PQ246042). Genes encoding the putative structural proteins VP1, VP2, and VP3, as well as the Large, Middle, and small T antigens, containing conserved functional domains were identified. Polyomavirus DNA was detected in 2 of 74 dormice (2.7%, 95% confidence interval: 0-6.4%) through PCR, while 12 of 69 animals (17.4%, 95% confidence interval: 8.4-26.3%) tested positive for polyomavirus-specific antibodies.ConclusionsIn conclusion, here we describe a novel polyomavirus in the garden dormouse with molecular and serological detection. Pairwise sequence comparison and phylogenetic analysis suggest that this novel virus may represent a novel species within the genus Alphapolyomavirus. Future work should examine if this virus is garden dormouse-specific and whether it is associated with disease in dormice.

Unveiling the truth: Pathogen infections linked to miscarriage: A STROBE-Compliant Mendelian randomization study.

Miscarriage represents a prevalent yet insufficiently studied adverse pregnancy outcome. The definitive causal links between various pathogens and miscarriage remain to be established. To investigate the causal connections between pathogen infections and miscarriage, we utilized a two-sample bidirectional Mendelian randomization (MR) analysis. We sourced genome-wide association studies data on pathogen infections from the UK Biobank, which included serological markers for infectious diseases and comprehensive whole-genome genetic information from approximately 10,000 individuals. Additionally, genome-wide association studies data on miscarriages were collected from 3 distinct European populations for our analysis. The MR analysis was primarily conducted using the inverse variance weighted method, complemented by Bayesian weighted MR and the weighted median method for robustness. To ensure the reliability of our findings, we performed heterogeneity and pleiotropy tests, leave-one-out sensitivity analyses, and a meta-analysis. Our extensive research has identified a causal association between miscarriage and infections by several human herpesviruses (HHV-1, HHV-3, HHV-4, HHV-6, and HHV-7), polyomaviruses (BK, JC, and Merkel cell polyomaviruses), and Chlamydia trachomatis (inverse variance weighted, P < .05). Notably, a meta-analysis of the integrated data highlighted the particularly high accuracy and consistency of the association with Merkel cell polyomavirus. Our MR analysis has clarified the causal relationships between specific pathogen infections and miscarriage, providing a critical foundation for the prevention and treatment of this adverse pregnancy outcome.

ASO Author Reflections: Impact of Merkel Cell Polyomavirus Antibody in Tumor and Plasma Specimens

ASO Author Reflections: Impact of Merkel Cell Polyomavirus Antibody in Tumor and Plasma Specimens

Intra-host genomic diversity and integration landscape of human tissue-resident DNA virome.

The viral intra-host genetic diversitiesand interactions with the human genome during decades of persistence remain poorly characterized. In this study, we analyzed the variability and integration sites of persisting viruses in nine organs from thirteen individuals who died suddenly from non-viralcauses. The viruses studiedincluded parvovirus B19, six herpesviruses, Merkel cell (MCPyV) and JC polyomaviruses, totaling 127 genomes. The viral sequences across organs were remarkably conserved within each individual, suggesting that persistence stems from single dominant strains. This indicates that intra-host viral evolution, thus far inferred primarily from immunocompromised patients, is likely overestimated in healthy subjects. Indeed, we detected increased viral subpopulations in two individuals with putative reactivations, suggesting that replication status influences diversity. Furthermore, we identified asymmetrical mutationpatternsreflectingselective pressures exerted by the host. Strikingly, our analysis revealed non-clonal viral integrations even in individuals without cancer. These included MCPyV integrations and truncations resembling clonally expanded variants inMerkel cell carcinomas, as well as novel junctions between herpesvirus 6B and mitochondrial sequences, the significance of which remains to be evaluated. Our work systematically characterizes the genomic landscape of the tissue-resident virome, highlighting potential deviations occurring during disease.