RESUMEN
We present a challenging clinical case of a 68-year-old female kidney transplant recipient who had a complicated posttransplant course marked by borderline T-cell-mediated rejection and BK virus nephropathy. The treatment for borderline rejection with steroids resulted in overimmunosuppression, and the patient acquired cytomegalovirus infection manifesting as colitis and SARS-CoV-2 infection. This progressed rapidly to collapsing glomerulopathy and allograft failure. This study also highlights the challenges in surveillance with donor-derived cell-free DNA in the setting of allograft injury by multiple viral infections.
Asunto(s)
Virus BK , COVID-19 , Infecciones por Citomegalovirus , Rechazo de Injerto , Trasplante de Riñón , Infecciones por Polyomavirus , Infecciones Tumorales por Virus , Humanos , Femenino , COVID-19/complicaciones , COVID-19/inmunología , COVID-19/diagnóstico , Anciano , Trasplante de Riñón/efectos adversos , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/virología , Infecciones por Polyomavirus/diagnóstico , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/virología , Infecciones por Citomegalovirus/tratamiento farmacológico , Rechazo de Injerto/inmunología , Rechazo de Injerto/virología , Virus BK/patogenicidad , Virus BK/inmunología , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/virología , Infecciones Tumorales por Virus/diagnóstico , Progresión de la Enfermedad , Resultado del Tratamiento , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , CoinfecciónRESUMEN
While Merkel cell polyomavirus (MCPyV or MCV) is an abundant virus frequently shed from healthy skin, it is one of the most lethal tumor viruses in immunocompromised individuals, highlighting the crucial role of host immunity in controlling MCPyV oncogenic potential. Despite its prevalence, very little is known about how MCPyV interfaces with the host immune response to maintain asymptomatic persistent infection and how inadequate control of MCPyV infection triggers MCC tumorigenesis. In this study, we discovered that the MCPyV protein, known as the Alternative Large Tumor Open Reading Frame (ALTO), also referred to as middle T, effectively primes and activates the STING signaling pathway. It recruits Src kinase into the complex of STING downstream kinase TBK1 to trigger its autophosphorylation, which ultimately activates the subsequent antiviral immune response. Combining single-cell analysis with both loss- and gain-of-function studies of MCPyV infection, we demonstrated that the activity of ALTO leads to a decrease in MCPyV replication. Thus, we have identified ALTO as a crucial viral factor that modulates the STING-TBK1 pathway, creating a negative feedback loop that limits viral infection and maintains a delicate balance with the host immune system. Our study reveals a novel mechanism by which a tumorigenic virus-encoded protein can link Src function in cell proliferation to the activation of innate immune signaling, thereby controlling viral spread, and sustaining persistent infection. Our previous findings suggest that STING also functions as a tumor suppressor in MCPyV-driven oncogenesis. This research provides a foundation for investigating how disruptions in the finely tuned virus-host balance, maintained by STING, could alter the fate of MCPyV infection, potentially encouraging malignancy.
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Poliomavirus de Células de Merkel , Infecciones por Polyomavirus , Proteínas Serina-Treonina Quinasas , Infecciones Tumorales por Virus , Proteínas Serina-Treonina Quinasas/metabolismo , Infecciones por Polyomavirus/metabolismo , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/virología , Humanos , Infecciones Tumorales por Virus/metabolismo , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/virología , Carcinoma de Células de Merkel/virología , Carcinoma de Células de Merkel/metabolismo , Proteínas de la Membrana/metabolismo , Transducción de Señal , Proteínas Virales/metabolismo , Replicación Viral , Neoplasias Cutáneas/virología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/inmunología , AnimalesRESUMEN
OBJECTIVES: BK virus is a major cause of chronic renal allograft failure.Transplant ureteral stent use has been reported as a risk factorfor BK virus infection. Recently, the use of a new type of ureteral stent (Magnetic Black Star) was reported in kidney transplant recipients. The aim ofthis preliminary report was to compare BK virus viremia and viruria occurrence depending on the type of double-J stent (standard versus Magnetic Black Star). MATERIALS AND METHODS: We included all kidney transplants performed in our center from January to December 2022. Each case had double-J stent placement. Indwelling stents were either a 6- or 7-Fr standard double-J stent or a 6-Fr Magnetic Black Star double-J stent. The type of double-J stent was chosen according to the surgeon's preference. A standard BK virus screening protocol was followed during the study period, which consisted of routine polymerase chain reaction examination of plasma and urine samples during monthly follow-ups. RESULTS: We assessed 120 patients without missing data: 92 patients received standard double-J stents and 28 patients received Magnetic Black Star stents. Patients were mostly male in the standard group (70.7%) versus the Magnetic Black Star group (42.9%) (P = .01). ABO- and HLA-incompatible transplant rates were similar in both groups. BK viremia occurrence and BK viruria occurrence were similar between groups at 1 month, 3 months, and 6 months. CONCLUSIONS: This preliminary study showed no differences concerning BKvirus infection depending on the type of double-J stents used during kidney transplant.
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Virus BK , Trasplante de Riñón , Infecciones por Polyomavirus , Diseño de Prótesis , Stents , Infecciones Tumorales por Virus , Viremia , Humanos , Trasplante de Riñón/efectos adversos , Virus BK/patogenicidad , Virus BK/inmunología , Masculino , Viremia/diagnóstico , Viremia/virología , Femenino , Persona de Mediana Edad , Infecciones por Polyomavirus/virología , Infecciones por Polyomavirus/diagnóstico , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/orina , Factores de Riesgo , Resultado del Tratamiento , Adulto , Infecciones Tumorales por Virus/virología , Infecciones Tumorales por Virus/diagnóstico , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/orina , Factores de Tiempo , Datos Preliminares , Estudios RetrospectivosRESUMEN
BACKGROUND: Immunosuppression reduction for BK polyoma virus (BKV) must be balanced against risk of adverse alloimmune outcomes. We sought to characterize risk of alloimmune events after BKV within context of HLA-DR/DQ molecular mismatch (mMM) risk score. METHODS: This single-center study evaluated 460 kidney transplant patients on tacrolimus-mycophenolate-prednisone from 2010-2021. BKV status was classified at 6-months post-transplant as "BKV" or "no BKV" in landmark analysis. Primary outcome was T-cell mediated rejection (TCMR). Secondary outcomes included all-cause graft failure (ACGF), death-censored graft failure (DCGF), de novo donor specific antibody (dnDSA), and antibody-mediated rejection (ABMR). Predictors of outcomes were assessed in Cox proportional hazards models including BKV status and alloimmune risk defined by recipient age and molecular mismatch (RAMM) groups. RESULTS: At 6-months post-transplant, 72 patients had BKV and 388 had no BKV. TCMR occurred in 86 recipients, including 27.8% with BKV and 17% with no BKV (p = .05). TCMR risk was increased in recipients with BKV (HR 1.90, (95% CI 1.14, 3.17); p = .01) and high vs. low-risk RAMM group risk (HR 2.26 (95% CI 1.02, 4.98); p = .02) in multivariable analyses; but not HLA serological MM in sensitivity analysis. Recipients with BKV experienced increased dnDSA in univariable analysis, and there was no association with ABMR, DCGF, or ACGF. CONCLUSIONS: Recipients with BKV had increased risk of TCMR independent of induction immunosuppression and conventional alloimmune risk measures. Recipients with high-risk RAMM experienced increased TCMR risk. Future studies on optimizing immunosuppression for BKV should explore nuanced risk stratification and may consider novel measures of alloimmune risk.
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Virus BK , Rechazo de Injerto , Supervivencia de Injerto , Pruebas de Función Renal , Trasplante de Riñón , Infecciones por Polyomavirus , Infecciones Tumorales por Virus , Viremia , Humanos , Trasplante de Riñón/efectos adversos , Virus BK/inmunología , Virus BK/aislamiento & purificación , Femenino , Masculino , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/virología , Infecciones por Polyomavirus/complicaciones , Persona de Mediana Edad , Rechazo de Injerto/etiología , Rechazo de Injerto/inmunología , Estudios de Seguimiento , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/virología , Viremia/inmunología , Viremia/virología , Pronóstico , Factores de Riesgo , Tasa de Filtración Glomerular , Adulto , Complicaciones Posoperatorias , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Estudios Retrospectivos , Fallo Renal Crónico/cirugía , Fallo Renal Crónico/inmunología , Enfermedades Renales/virología , Enfermedades Renales/inmunología , Enfermedades Renales/cirugía , Receptores de TrasplantesRESUMEN
BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive cancer with often poor outcomes. Limited biomarkers exist for predicting clinical outcomes. The Merkel cell polyomavirus (MCPyV) serum antibody test (AMERK) has shown potential for indicating better recurrence-free survival in a single-institution study. The study aimed to evaluate the link between initial AMERK serostatus and survival. Secondary objectives included examining the relationship between initial AMERK titer levels and tumor burden. METHODS: A retrospective cohort study across two institutions analyzed patients tested with AMERK within 90 days of MCC diagnosis. Regression models assessed the association of survival outcomes with serostatus, considering various factors. The relationship between AMERK titer and tumor burden indicators was evaluated using ANOVA. Significance testing was exploratory, without a fixed significance level. RESULTS: Of 261 MCC patients tested, 49.4% were initially seropositive (titer ≥75). Multivariable analysis showed that seropositivity improved recurrence, event-free, overall, and MCC-specific survival rates. Strong associations were found between initial AMERK titer and clinical, tumor, and nodal stages, tumor size, and disease extent. Notably, improved survival with seropositivity was observed only in patients with localized disease at initial presentation. CONCLUSION: Circulating antibodies to MCPyV oncoproteins, as indicated by the AMERK test, are linked with better survival in MCC patients with localized disease at presentation. This could enhance patient risk profiling and treatment personalization. The study's retrospective nature and exploratory analysis are key limitations. PLAIN LANGUAGE SUMMARY: Merkel cell carcinoma (MCC) is a potentially aggressive skin cancer, and tools to predict patient outcomes are limited. A blood test called anti-Merkel cell panel (AMERK), which checks for specific antibodies related to this cancer, might give us some clues. In this study, we looked at 261 MCC patients who took the AMERK test within 90 days of diagnosis. We found that patients with an initial positive AMERK result tended to have better outcomes, especially if their cancer was in the early stages. However, it is important to note that this study has limitations, including using retrospective data and exploratory analyses.
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Anticuerpos Antivirales , Carcinoma de Células de Merkel , Poliomavirus de Células de Merkel , Neoplasias Cutáneas , Humanos , Carcinoma de Células de Merkel/virología , Carcinoma de Células de Merkel/sangre , Carcinoma de Células de Merkel/mortalidad , Carcinoma de Células de Merkel/diagnóstico , Carcinoma de Células de Merkel/inmunología , Poliomavirus de Células de Merkel/inmunología , Poliomavirus de Células de Merkel/aislamiento & purificación , Femenino , Masculino , Estudios Retrospectivos , Anciano , Pronóstico , Persona de Mediana Edad , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/virología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Anticuerpos Antivirales/sangre , Anciano de 80 o más Años , Infecciones Tumorales por Virus/virología , Infecciones por Polyomavirus/sangre , Infecciones por Polyomavirus/diagnóstico , Infecciones por Polyomavirus/virología , Infecciones por Polyomavirus/inmunologíaRESUMEN
OBJECTIVES: Modern immunosuppressive regimens have reduced rejection episodes in renal allograft recipients but have increased the risk of opportunistic infections. Infections are considered to be the second leading cause of death after cardiovascular complications in renal allograft recipients. Data on opportunistic infections affecting the allograft itself are scarce. The present study describes the spectrum of renal opportunistic infections and their outcomes diagnosed on renal allograft biopsies and nephrectomy specimens. MATERIALS AND METHODS: Our retrospective observational study was conducted from December 2011 to December 2021. We analyzed infectious episodes diagnosed on renal allograft biopsies or graft nephrectomy specimens. We obtained clinical, epidemiological, and laboratory details for analyses from hospital records. RESULTS: BK virus nephropathy was the most common opportunistic infection affecting the allograft, accounting for 47% of cases, followed by bacterial graft pyelonephritis (25%). Mucormycosis was the most common fungal infection. The diagnosis of infection from day of transplant ranged from 14 days to 39 months. Follow-up periods ranged from 1 to 10 years. Mortality was highest among patients with opportunistic fungal infection (62%), followed by viral infections, and graft failure rate was highest in patients with graft pyelonephritis (50%). Among patients with BK polyomavirus nephropathy, 45% had stable graft function compared with just 33% of patients with bacterial graft pyelonephritis. CONCLUSIONS: BK polyoma virus infection was the most common infection affecting the renal allograft in our study. Although fungal infections caused the highest mortality among our patients, bacterial graft pyelonephritis was responsible for maximum graft failure. Correctly identifying infections on histology is important so that graft and patient life can be prolonged.
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Trasplante de Riñón , Nefrectomía , Infecciones Oportunistas , Humanos , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/mortalidad , Estudios Retrospectivos , Masculino , Femenino , Nefrectomía/efectos adversos , Persona de Mediana Edad , Adulto , Biopsia , Resultado del Tratamiento , Factores de Tiempo , Factores de Riesgo , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/mortalidad , Infecciones Oportunistas/diagnóstico , Infecciones Oportunistas/microbiología , Infecciones Oportunistas/virología , Infecciones Oportunistas/epidemiología , Aloinjertos , Donadores Vivos , Supervivencia de Injerto , Turquía/epidemiología , Anciano , Pielonefritis/microbiología , Pielonefritis/diagnóstico , Pielonefritis/mortalidad , Infecciones por Polyomavirus/diagnóstico , Infecciones por Polyomavirus/mortalidad , Infecciones por Polyomavirus/virología , Infecciones por Polyomavirus/epidemiología , Infecciones por Polyomavirus/inmunologíaAsunto(s)
Anticuerpos Neutralizantes , Virus BK , Infecciones por Polyomavirus , Replicación Viral , Humanos , Virus BK/inmunología , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/virología , Infecciones por Polyomavirus/prevención & control , Anticuerpos Neutralizantes/inmunología , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/prevención & control , Infecciones Tumorales por Virus/virología , Animales , Anticuerpos Antivirales/inmunologíaRESUMEN
Merkel cell polyomavirus (MCPyV) has been associated with approximately 80% of Merkel cell carcinoma (MCC), an aggressive and increasingly incident skin cancer. The link between host innate immunity, viral load control, and carcinogenesis has been established but poorly characterized. We previously established the importance of the STING and NF-κB pathways in the host innate immune response to viral infection. In this study, we further discovered that MCPyV infection of human dermal fibroblasts (HDFs) induces the expression of type I and III interferons (IFNs), which in turn stimulate robust expression of IFN-stimulated genes (ISGs). Blocking type I IFN downstream signaling using an IFN-ß antibody, JAK inhibitors, and CRISPR knockout of the receptor dramatically repressed MCPyV infection-induced ISG expression but did not significantly restore viral replication activities. These findings suggest that IFN-mediated induction of ISGs in response to MCPyV infection is not crucial to viral control. Instead, we found that type I IFN exerts a more direct effect on MCPyV infection postentry by repressing early viral transcription. We further demonstrated that growth factors normally upregulated in wounded or UV-irradiated human skin can significantly stimulate MCPyV gene expression and replication. Together, these data suggest that in healthy individuals, host antiviral responses, such as IFN production induced by viral activity, may restrict viral propagation to reduce MCPyV burden. Meanwhile, growth factors induced by skin abrasion or UV irradiation may stimulate infected dermal fibroblasts to promote MCPyV propagation. A delicate balance of these mutually antagonizing factors provides a mechanism to support persistent MCPyV infection. IMPORTANCE Merkel cell carcinoma is an aggressive skin cancer that is particularly lethal to immunocompromised individuals. Though rare, MCC incidence has increased significantly in recent years. There are no lasting and effective treatments for metastatic disease, highlighting the need for additional treatment and prevention strategies. By investigating how the host innate immune system interfaces with Merkel cell polyomavirus, the etiological agent of most of these cancers, our studies identified key factors necessary for viral control, as well as conditions that support viral propagation. These studies provide new insights for understanding how the virus balances the effects of the host immune defenses and of growth factor stimulation to achieve persistent infection. Since virus-positive MCC requires the expression of viral oncogenes to survive, our observation that type I IFN can repress viral oncogene transcription indicates that these cytokines could be explored as a viable therapeutic option for treating patients with virus-positive MCC.
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Carcinoma de Células de Merkel , Interferones , Infecciones por Polyomavirus , Transducción de Señal , Infecciones Tumorales por Virus , Poliomavirus de Células de Merkel/inmunología , Interferones/fisiología , Transducción de Señal/inmunología , Infecciones por Polyomavirus/inmunología , Infecciones Tumorales por Virus/inmunología , Carcinoma de Células de Merkel/inmunología , Inmunidad Innata/inmunología , Interacciones Microbiota-Huesped/inmunología , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Expresión Génica/inmunología , Replicación Viral/genéticaRESUMEN
BACKGROUND: BK virus associated nephropathy (BKVAN) is one of the common causes of graft loss among kidney transplanted recipients (KTRs). The current treatment for BKV nephropathy is decreasing the immunosuppressive regimen in KTRs. Interleukin-27 (IL-27) is a multifunctional cytokine that might be the front-runner of an important pathway in this regard. Therefore, in current study it is tried to evaluate the changes in the expression level of IL-27 and some related molecules, resulting from BKV reactivation in KTR patients. METHODS: EDTA-treated blood samples were collected from all participants. Patients were divided into two groups, 31 kidney transplant recipients with active and 32 inactive BKV infection, after being monitored by Real time PCR (Taq-Man) in plasma. Total of 30 normal individuals were considered as healthy control group. Real time PCR (SYBR Green) technique is used to determine the expression level of studied genes. RESULTS: The results of gene expression comparisons showed that the expression level of IL-27, IFN-γ, TNF-α, TNFR2 and IRF7 genes was significantly higher in inactive group in comparison to active group. The expression level of TLR4 was lower in both active and inactive groups in comparison to control group. ROC curve analysis showed that IL-27 and IRF7 are significantly different amongst other studied genes. Finally, the analyses revealed that the expression level of most of the studied genes (except for TNF-α and TLR4) have significant correlation with viral load. CONCLUSIONS: Our findings revealed that IL-27, IFN-γ, TNF-α, TNFR2 and IRF7 expression level is higher in inactive group and TLR4 expression level is lower in patients' groups in comparison to control group. Also, ROC curve analysis showed IL-27 and IRF7 can significantly differentiate studied groups (BKV active vs. inactive). Therefore, these results might help elucidating the pattern in charge of BKV reactivation in kidney transplanted patients.
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Virus BK/fisiología , Citocinas/fisiología , Enfermedades Renales/virología , Trasplante de Riñón , Infecciones por Polyomavirus/inmunología , Complicaciones Posoperatorias/inmunología , Complicaciones Posoperatorias/virología , Infecciones Tumorales por Virus/inmunología , Activación Viral , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenAsunto(s)
Linfocitos T CD8-positivos/inmunología , Carcinoma de Células de Merkel/inmunología , Poliomavirus de Células de Merkel/fisiología , Infecciones por Polyomavirus/inmunología , Neoplasias Cutáneas/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos Virales de Tumores/inmunología , Células Cultivadas , Mapeo Epitopo , Epítopos de Linfocito T/inmunología , Femenino , Antígenos HLA/metabolismo , Humanos , Vigilancia Inmunológica , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Péptidos/inmunologíaRESUMEN
The human BK polyomavirus (BKPyV) is latent in the kidneys of most adults, but can be reactivated in immunosuppressed states, such as following renal transplantation. If left unchecked, BK polyomavirus nephropathy (PyVAN) and possible graft loss may result from viral destruction of tubular epithelial cells and interstitial fibrosis. When coupled with regular post-transplant screening, immunosuppression reduction has been effective in limiting BKPyV viremia and the development of PyVAN. Antiviral drugs that are safe and effective in combating BKPyV have not been identified but would be a benefit in complementing or replacing immunosuppression reduction. The present study explores inhibition of the host DNA damage response (DDR) as an antiviral strategy. Immunohistochemical and immunofluorescent analyses of PyVAN biopsies provide evidence for stimulation of a DDR in vivo. DDR pathways were also stimulated in vitro following BKPyV infection of low-passage human renal proximal tubule epithelial cells. The role of Chk1, a protein kinase known to be involved in the replication stress-induced DDR, was examined by inhibition with the small molecule LY2603618 and by siRNA-mediated knockdown. Inhibition of Chk1 resulted in decreased replication of BKPyV DNA and viral spread. Activation of mitotic pathways was associated with the reduction in BKPyV replication. Chk1 inhibitors that are found to be safe and effective in clinical trials for cancer should also be evaluated for antiviral activity against BKPyV.
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Virus BK/genética , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Infecciones por Polyomavirus/tratamiento farmacológico , Virus BK/patogenicidad , Células Cultivadas , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/fisiología , Daño del ADN/fisiología , Reparación del ADN/fisiología , Humanos , Riñón/patología , Riñón/virología , Trasplante de Riñón , Compuestos de Fenilurea/farmacología , Infecciones por Polyomavirus/genética , Infecciones por Polyomavirus/inmunología , Pirazinas/farmacología , Infecciones Tumorales por Virus/tratamiento farmacológico , Infecciones Tumorales por Virus/genética , Replicación Viral/efectos de los fármacos , Replicación Viral/fisiologíaAsunto(s)
Anticuerpos Antivirales/sangre , Hipersensibilidad Inmediata/inmunología , Inmunoglobulina G/sangre , Poliomavirus/inmunología , Asma/inmunología , Asma/patología , Asma/virología , Eccema/inmunología , Eccema/patología , Eccema/virología , Humanos , Hipersensibilidad Inmediata/patología , Hipersensibilidad Inmediata/virología , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/patología , Rinitis Alérgica/inmunología , Rinitis Alérgica/patología , Rinitis Alérgica/virologíaRESUMEN
It has been reported that polyomaviruses are the microbes which can be a cause of several human pathological conditions including cancers, nephropathy, progressive multifocal leukoencephalopathy and gynaecological disease. Although investigators proposed some mechanisms used by the viruses to induce the disorders, the roles played by chemokines in the pathogenesis of polyomaviruses infections are yet to be clarified. This review article investigated recent studies regarding the roles played by chemokines in the pathogenesis of the polyomaviruses infections. The research in the literature revealed that CXC chemokines, including CXCL1, CXCL5, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12 and CXCL16, significantly participate in the pathogenesis of polyomaviruses. CC chemokines, such as CCL2, CCL5 and CCL20 also participate in the induction of the pathological conditions. Therefore, it appears that CXC chemokines may be considered as the strategic factors involved in the pathogenesis of polyomaviruses.
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Quimiocinas CC/inmunología , Quimiocinas CXC/inmunología , Infecciones por Polyomavirus/inmunología , Poliomavirus , Humanos , Poliomavirus/patogenicidadRESUMEN
The mechanism by which DNA viruses interact with different DNA sensors and their connection with the activation of interferon (IFN) type I pathway are poorly understood. We investigated the roles of protein 204 (p204) and cyclic guanosine-adenosine synthetase (cGAS) sensors during infection with mouse polyomavirus (MPyV). The phosphorylation of IFN regulatory factor 3 (IRF3) and the stimulator of IFN genes (STING) proteins and the upregulation of IFN beta (IFN-ß) and MX Dynamin Like GTPase 1 (MX-1) genes were detected at the time of replication of MPyV genomes in the nucleus. STING knockout abolished the IFN response. Infection with a mutant virus that exhibits defective nuclear entry via nucleopores and that accumulates in the cytoplasm confirmed that replication of viral genomes in the nucleus is required for IFN induction. The importance of both DNA sensors, p204 and cGAS, in MPyV-induced IFN response was demonstrated by downregulation of the IFN pathway observed in p204-knockdown and cGAS-knockout cells. Confocal microscopy revealed the colocalization of p204 with MPyV genomes in the nucleus. cGAS was found in the cytoplasm, colocalizing with viral DNA leaked from the nucleus and with DNA within micronucleus-like bodies, but also with the MPyV genomes in the nucleus. However, 2'3'-Cyclic guanosine monophosphate-adenosine monophosphate synthesized by cGAS was detected exclusively in the cytoplasm. Biochemical assays revealed no evidence of functional interaction between cGAS and p204 in the nucleus. Our results provide evidence for the complex interactions of MPyV and DNA sensors including the sensing of viral genomes in the nucleus by p204 and of leaked viral DNA and micronucleus-like bodies in the cytoplasm by cGAS.
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ADN Viral/inmunología , Inmunidad Innata/inmunología , Proteínas de la Membrana/metabolismo , Proteínas Nucleares/metabolismo , Nucleotidiltransferasas/metabolismo , Fosfoproteínas/metabolismo , Infecciones por Polyomavirus/inmunología , Poliomavirus/inmunología , Infecciones Tumorales por Virus/inmunología , Animales , ADN Viral/genética , Interacciones Huésped-Patógeno , Interferón beta/metabolismo , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/genética , Ratones , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/genética , Nucleotidiltransferasas/antagonistas & inhibidores , Nucleotidiltransferasas/genética , Fosfoproteínas/antagonistas & inhibidores , Fosfoproteínas/genética , Fosforilación , Poliomavirus/genética , Infecciones por Polyomavirus/virología , Infecciones Tumorales por Virus/virologíaRESUMEN
BACKGROUND: Evidence suggests a complex interplay between infections and allergic diseases. OBJECTIVE: To explore the association of 14 common viruses with eczema, asthma, and rhinoconjunctivitis in childhood. METHODS: We used cross-sectional (n = 686) and prospective (n = 440) data from children participating in the Rhea birth cohort. Immunoglobulin G to polyomaviruses (BK polyomavirus, JC polyomavirus, KI polyomavirus [KIPyV], WU polyomavirus [WUPyV], human polyomavirus 6, human polyomavirus 7, Trichodysplasia spinulosa polyomavirus, Merkel cell polyomavirus, human polyomavirus 9, and human polyomavirus 10) and herpesviruses (Epstein-Barr virus, Cytomegalovirus, Herpes simplex virus-1, Herpes simplex virus-2) were measured at age 4 years by fluorescent bead-based multiplex serology. Definitions of eczema, asthma, and rhinoconjunctivitis at ages 4 and 6 years were based on questionnaires. Mediation of the associations by immune biomarkers was tested. RESULTS: Less likely to have eczema at age 4 years were KIPyV-seropositive (odds ratio [OR], 0.47; 95% confidence interval [CI], 0.27-0.82) and human polyomavirus 6 (OR, 0.44; 95% CI, 0.26-0.73) compared with their seronegative counterparts. Seropositivity to Epstein-Barr virus was negatively associated with eczema at age 4 years (OR, 0.39; 95% CI, 0.22-0.67) and 6 years (OR, 0.50; 95% CI, 0.25-0.99). Children with a higher burden of herpesviruses or of skin polyomaviruses had the lowest odds of eczema at age 4 years. Higher odds for asthma at age 4 years were found for WUPyV-seropositive children (OR, 3.98; 95% CI, 1.38-11.51), and for children seropositive to both respiratory polyomaviruses (KIPyV and WUPyV) (OR, 7.35; 95% CI, 1.66-32.59) compared with children seronegative to both. No associations were observed for rhinoconjunctivitis. There was no evidence of mediation by immune biomarkers. CONCLUSION: A heterogeneous pattern of infections and allergic diseases was observed with common infections associated with a decreased eczema risk and an increased asthma risk in children.
Asunto(s)
Asma/epidemiología , Eccema/epidemiología , Infecciones por Virus de Epstein-Barr/epidemiología , Infecciones por Polyomavirus/epidemiología , Asma/inmunología , Niño , Preescolar , Eccema/inmunología , Infecciones por Virus de Epstein-Barr/inmunología , Herpesvirus Humano 4/inmunología , Humanos , Poliomavirus/inmunología , Infecciones por Polyomavirus/inmunologíaRESUMEN
Merkel cell polyomavirus (MCPyV) infects most of the human population asymptomatically, but in rare cases it leads to a highly aggressive skin cancer called Merkel cell carcinoma (MCC). MCC incidence is much higher in aging and immunocompromised populations. The epidemiology of MCC suggests that dysbiosis between the host immune response and the MCPyV infectious cycle could contribute to the development of MCPyV-associated MCC. Insufficient restriction of MCPyV by normal cellular processes, for example, could promote the incidental oncogenic MCPyV integration events and/or entry into the original cell of MCC. Progress toward understanding MCPyV biology has been hindered by its narrow cellular tropism. Our discovery that primary human dermal fibroblasts (HDFs) support MCPyV infection has made it possible to closely model cellular responses to different stages of the infectious cycle. The present study reveals that the onset of MCPyV replication and early gene expression induces an inflammatory cytokine and interferon-stimulated gene (ISG) response. The cGAS-STING pathway, in coordination with NF-κB, mediates induction of this innate immune gene expression program. Further, silencing of cGAS or NF-κB pathway factors led to elevated MCPyV replication. We also discovered that the PYHIN protein IFI16 localizes to MCPyV replication centers but does not contribute to the induction of ISGs. Instead, IFI16 upregulates inflammatory cytokines in response to MCPyV infection by an alternative mechanism. The work described herein establishes a foundation for exploring how changes to the skin microenvironment induced by aging or immunodeficiency might alter the fate of MCPyV and its host cell to encourage carcinogenesis. IMPORTANCE MCC has a high rate of mortality and an increasing incidence. Immune-checkpoint therapies have improved the prognosis of patients with metastatic MCC. Still, a significant proportion of the patients fail to respond to immune-checkpoint therapies or have a medical need for iatrogenic immune-suppression. A greater understanding of MCPyV biology could inform targeted therapies for MCPyV-associated MCC. Moreover, cellular events preceding MCC oncogenesis remain largely unknown. The present study aims to explore how MCPyV interfaces with innate immunity during its infectious cycle. We describe how MCPyV replication and/or transcription elicit an innate immune response via cGAS-STING, NF-κB, and IFI16. We also explore the effects of this response on MCPyV replication. Our findings illustrate how healthy cellular conditions may allow low-level infection that evades immune destruction until highly active replication is restricted by host responses. Conversely, pathological conditions could result in unbridled MCPyV replication that licenses MCC tumorigenesis.
Asunto(s)
Citocinas/inmunología , Fibroblastos/inmunología , Inmunidad Innata/inmunología , Poliomavirus de Células de Merkel/inmunología , Piel/inmunología , Sistemas CRISPR-Cas/genética , Carcinoma de Células de Merkel/patología , Células Cultivadas , Citocinas/biosíntesis , Fibroblastos/virología , Células HEK293 , Humanos , Inmunidad Innata/genética , Interferones/biosíntesis , Interferones/inmunología , Proteínas de la Membrana/genética , Poliomavirus de Células de Merkel/crecimiento & desarrollo , FN-kappa B/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Nucleotidiltransferasas/genética , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Infecciones por Polyomavirus/inmunología , Piel/citología , Infecciones Tumorales por Virus/inmunologíaRESUMEN
Merkel cell carcinoma (MCC) is a rare skin malignancy that is a paradigm cancer for solid tumor immunotherapy. MCCs associated with Merkel cell polyomavirus (virus-positive MCC [VP-MCC]) or chronic UV exposure (virus-negative MCC [VN-MCC]) are anti-PD(L)1 responsive, despite VP-MCC's low mutational burden. This suggests that antigen quality, not merely mutation quantity, dictates immunotherapy responsiveness, and cell-based therapies targeting optimal antigens may be effective. Despite VP-MCC's antigenic homogeneity, diverse T-cell infiltration patterns are observed, implying microenvironment plasticity and multifactorial contributions to immune recognition. Moreover, VP-MCC exemplifies how antitumor adaptive immunity can provide tumor burden biomarkers for early detection and disease monitoring.
Asunto(s)
Carcinoma de Células de Merkel/inmunología , Poliomavirus de Células de Merkel/inmunología , Infecciones por Polyomavirus/inmunología , Neoplasias Cutáneas/inmunología , Infecciones Tumorales por Virus/inmunología , Inmunidad Adaptativa , Antígenos de Neoplasias/análisis , Antígenos de Neoplasias/inmunología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/inmunología , Carcinoma de Células de Merkel/diagnóstico , Carcinoma de Células de Merkel/terapia , Carcinoma de Células de Merkel/virología , Resistencia a Antineoplásicos , Epítopos de Linfocito T/inmunología , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/métodos , Linfocitos Infiltrantes de Tumor/inmunología , Infecciones por Polyomavirus/diagnóstico , Infecciones por Polyomavirus/terapia , Infecciones por Polyomavirus/virología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/terapia , Neoplasias Cutáneas/virología , Linfocitos T/inmunología , Microambiente Tumoral/inmunología , Infecciones Tumorales por Virus/diagnóstico , Infecciones Tumorales por Virus/terapia , Infecciones Tumorales por Virus/virologíaRESUMEN
BK polyomavirus nephropathy (BKVN) and allograft rejection are two closely-associated diseases on opposite ends of the immune scale in kidney transplant recipients. The principle of balancing the immune system remains the mainstay of therapeutic strategy. While patient outcomes can be improved through screening, risk factors identification, and rapid reduction of immunosuppressants, a lack of standard curative therapy is the primary concern during clinical practice. Additionally, difficulty in pathological differential diagnosis and clinicopathology's dissociation pose problems for a definite diagnosis. This article discusses the delicate evaluation needed to optimize immunosuppression and reviews recent advances in molecular diagnosis and immunological therapy for BKVN patients. New biomarkers for BKVN diagnosis are under development. For example, measurement of virus-specific T cell level may play a role in steering immunosuppressants. The development of cellular therapy may provide prevention, even a cure, for BKVN, a complex post-transplant complication.
Asunto(s)
Rechazo de Injerto/inmunología , Enfermedades Renales/inmunología , Trasplante de Riñón/efectos adversos , Infecciones por Polyomavirus/inmunología , Infecciones Tumorales por Virus/inmunología , Virus BK/inmunología , Humanos , Terapia de Inmunosupresión , Receptores de TrasplantesRESUMEN
The BK polyomavirus (BKPyV) is a ubiquitous human virus that persists in the renourinary epithelium. Immunosuppression can lead to BKPyV reactivation in the first year post-transplantation in kidney transplant recipients (KTRs) and hematopoietic stem cell transplant recipients. In KTRs, persistent DNAemia has been correlated to the occurrence of polyomavirus-associated nephropathy (PVAN) that can lead to graft loss if not properly controlled. Based on recent observations that conventional dendritic cells (cDCs) specifically infiltrate PVAN lesions, we hypothesized that those cells could play a role in BKPyV infection. We first demonstrated that monocyte-derived dendritic cells (MDDCs), an in vitro model for mDCs, captured BKPyV particles through an unconventional GRAF-1 endocytic pathway. Neither BKPyV particles nor BKPyV-infected cells were shown to activate MDDCs. Endocytosed virions were efficiently transmitted to permissive cells and protected from the antibody-mediated neutralization. Finally, we demonstrated that freshly isolated CD1c+ mDCs from the blood and kidney parenchyma behaved similarly to MDDCs thus extending our results to cells of clinical relevance. This study sheds light on a potential unprecedented CD1c+ mDC involvement in the BKPyV infection as a promoter of viral spreading.
Asunto(s)
Antígenos CD1/metabolismo , Virus BK/inmunología , Células Dendríticas/inmunología , Células Epiteliales/inmunología , Glicoproteínas/metabolismo , Riñón/inmunología , Infecciones por Polyomavirus/inmunología , Infecciones Tumorales por Virus/inmunología , Anticuerpos Neutralizantes/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/virología , Células Epiteliales/metabolismo , Células Epiteliales/virología , Humanos , Riñón/metabolismo , Riñón/virología , Monocitos/inmunología , Monocitos/metabolismo , Monocitos/virología , Infecciones por Polyomavirus/metabolismo , Infecciones por Polyomavirus/virología , Infecciones Tumorales por Virus/metabolismo , Infecciones Tumorales por Virus/virología , Replicación ViralRESUMEN
BK virus (BKV)-hemorrhagic cystitis (HC) is a well-known and rarely fatal complication of hematopoietic stem cell transplantation (HSCT). Treatment for BKV-HC is limited, but virus-specific T-cells (VST) represent a promising therapeutic option feasible for use posttransplant. We report on the case of a 16-year-old male with dedicator of cytokinesis 8 (DOCK8) deficiency who underwent haploidentical HSCT complicated by severe BKV-HC, catastrophic renal hemorrhage, and VST-associated cytokine release syndrome (CRS). Gross hematuria refractory to multiple interventions began with initiation of posttransplant cyclophosphamide (PT/Cy). Complete left renal arterial embolization (day +43) was ultimately indicated to control intractable renal hemorrhage. Subsequent infusion of anti-BK VSTs was complicated by CRS and progressive multiorgan failure, with postmortem analysis confirming diagnosis of hepatic sinusoidal obstruction syndrome (SOS). This case illustrates opportunities for improvement in the management of severe BKV-HC posttransplant while highlighting rare and potentially life-threatening complications of BKV-HC and VST therapy.