ABSTRACT
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.
Subject(s)
BK Virus , COVID-19 , Cytomegalovirus Infections , Graft Rejection , Kidney Transplantation , Polyomavirus Infections , Tumor Virus Infections , Humans , Female , COVID-19/complications , COVID-19/immunology , COVID-19/diagnosis , Aged , Kidney Transplantation/adverse effects , Polyomavirus Infections/immunology , Polyomavirus Infections/virology , Polyomavirus Infections/diagnosis , Cytomegalovirus Infections/immunology , Cytomegalovirus Infections/diagnosis , Cytomegalovirus Infections/virology , Cytomegalovirus Infections/drug therapy , Graft Rejection/immunology , Graft Rejection/virology , BK Virus/pathogenicity , BK Virus/immunology , Tumor Virus Infections/immunology , Tumor Virus Infections/virology , Tumor Virus Infections/diagnosis , Disease Progression , Treatment Outcome , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/therapeutic use , CoinfectionABSTRACT
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.
Subject(s)
Merkel cell polyomavirus , Polyomavirus Infections , Protein Serine-Threonine Kinases , Tumor Virus Infections , Protein Serine-Threonine Kinases/metabolism , Polyomavirus Infections/metabolism , Polyomavirus Infections/immunology , Polyomavirus Infections/virology , Humans , Tumor Virus Infections/metabolism , Tumor Virus Infections/immunology , Tumor Virus Infections/virology , Carcinoma, Merkel Cell/virology , Carcinoma, Merkel Cell/metabolism , Membrane Proteins/metabolism , Signal Transduction , Viral Proteins/metabolism , Virus Replication , Skin Neoplasms/virology , Skin Neoplasms/metabolism , Skin Neoplasms/immunology , AnimalsABSTRACT
BACKGROUND: BK polyomavirus (BKV) DNAemia is a challenging infectious complication after kidney transplant (KT). Reduction of immunosuppression is the mainstay of management, and tacrolimus is often the first immunosuppressive medication adjusted upon the diagnosis of BKV DNAemia. This study aimed to evaluate the impact of a new institutional protocol with lower target tacrolimus levels on BKV DNAemia, allograft rejection, and de novo donor-specific antibodies (dnDSA) among pediatric KT recipients. METHODS: We conducted a retrospective chart review of all KT episodes between January 2013 and December 2018. The new protocol with lower target tacrolimus levels was implemented in March 2015. One hundred twenty-seven patients were included in primary analysis. All patients received induction with basiliximab and methylprednisolone and were maintained on a steroid-based immunosuppressive regimen. RESULTS: In the post-intervention cohort, cumulative incidence of BKV DNAemia at 100 days (13.4% vs. 17.8%, p = .605) and 18 months post-KT (34.1% vs. 26.7%, p = .504) was not significantly different from the pre-intervention cohort. Biopsy-proven rejection rate did not change. However, we observed a trend toward earlier development of dnDSA in the post-intervention cohort using the Kaplan-Meier survival analysis (log-rank p = .06). Younger recipient age at the time of transplant was found to slightly increase the risk of BKV DNAemia (OR: 1.09, 95% CI [1.01, 1.16], p = .024). There was an association between BKV DNAemia and biopsy-proven rejection of any type (adjustedOR: 2.77, 95% CI [1.26, 6.23], p = .012), especially acute T-cell-mediated rejection grade 1A and above (adjustedOR: 2.95, 95% CI [1.06, 8.30], p = .037), after adjusted for recipient age at the time of transplant. CONCLUSIONS: Targeting lower tacrolimus levels did not decrease the incidence of BKV DNAemia within 100 days or 18 months post-KT, nor did it increase the risk of biopsy-proven rejection among pediatric KT recipients in our center. However, there was a trend toward earlier development of dnDSA, which may portend worse long-term graft outcome post-KT. Our findings highlight the need for individualized immunosuppressive regimens based on immunologic and infectious risk factors and the importance of implementing innovative biomarkers to guide therapy and improve outcomes.
Subject(s)
BK Virus , Graft Rejection , Immunosuppressive Agents , Kidney Transplantation , Polyomavirus Infections , Tacrolimus , Tumor Virus Infections , Humans , Retrospective Studies , Male , Female , Graft Rejection/prevention & control , Graft Rejection/blood , Graft Rejection/immunology , Child , Tacrolimus/therapeutic use , Immunosuppressive Agents/therapeutic use , Polyomavirus Infections/blood , Adolescent , Tumor Virus Infections/blood , Tumor Virus Infections/immunology , Child, Preschool , DNA, Viral/blood , Infant , Postoperative Complications/blood , Postoperative Complications/etiology , Postoperative Complications/prevention & control , Postoperative Complications/virologyABSTRACT
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.
Subject(s)
BK Virus , Kidney Transplantation , Polyomavirus Infections , Prosthesis Design , Stents , Tumor Virus Infections , Viremia , Humans , Kidney Transplantation/adverse effects , BK Virus/pathogenicity , BK Virus/immunology , Male , Viremia/diagnosis , Viremia/virology , Female , Middle Aged , Polyomavirus Infections/virology , Polyomavirus Infections/diagnosis , Polyomavirus Infections/immunology , Polyomavirus Infections/urine , Risk Factors , Treatment Outcome , Adult , Tumor Virus Infections/virology , Tumor Virus Infections/diagnosis , Tumor Virus Infections/immunology , Tumor Virus Infections/urine , Time Factors , Preliminary Data , Retrospective StudiesABSTRACT
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.
Subject(s)
BK Virus , Graft Rejection , Graft Survival , Kidney Function Tests , Kidney Transplantation , Polyomavirus Infections , Tumor Virus Infections , Viremia , Humans , Kidney Transplantation/adverse effects , BK Virus/immunology , BK Virus/isolation & purification , Female , Male , Polyomavirus Infections/immunology , Polyomavirus Infections/virology , Polyomavirus Infections/complications , Middle Aged , Graft Rejection/etiology , Graft Rejection/immunology , Follow-Up Studies , Tumor Virus Infections/immunology , Tumor Virus Infections/virology , Viremia/immunology , Viremia/virology , Prognosis , Risk Factors , Glomerular Filtration Rate , Adult , Postoperative Complications , Immunosuppressive Agents/therapeutic use , Immunosuppressive Agents/adverse effects , Retrospective Studies , Kidney Failure, Chronic/surgery , Kidney Failure, Chronic/immunology , Kidney Diseases/virology , Kidney Diseases/immunology , Kidney Diseases/surgery , Transplant RecipientsSubject(s)
Antibodies, Neutralizing , BK Virus , Polyomavirus Infections , Virus Replication , Humans , BK Virus/immunology , Polyomavirus Infections/immunology , Polyomavirus Infections/virology , Polyomavirus Infections/prevention & control , Antibodies, Neutralizing/immunology , Tumor Virus Infections/immunology , Tumor Virus Infections/prevention & control , Tumor Virus Infections/virology , Animals , Antibodies, Viral/immunologyABSTRACT
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.
Subject(s)
Carcinoma, Merkel Cell , Interferons , Polyomavirus Infections , Signal Transduction , Tumor Virus Infections , Merkel cell polyomavirus/immunology , Interferons/physiology , Signal Transduction/immunology , Polyomavirus Infections/immunology , Tumor Virus Infections/immunology , Carcinoma, Merkel Cell/immunology , Immunity, Innate/immunology , Host Microbial Interactions/immunology , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Gene Expression/immunology , Virus Replication/geneticsABSTRACT
The germinal center (GC) plays a central role in the generation of antigen-specific B cells and antibodies. Tight regulation of the GC is essential due to the inherent risks of tumorigenesis and autoimmunity posed by inappropriate GC B cell processes. Gammaherpesviruses such as Epstein-Barr virus (EBV) and murine gammaherpesvirus 68 (MHV68) utilize numerous armaments to drive infected naïve B cells, independent of antigen, through GC reactions to expand the latently infected B cell population and establish a stable latency reservoir. We previously demonstrated that the MHV68 microRNA (miRNA) mghv-miR-M1-7-5p represses host EWSR1 (Ewing sarcoma breakpoint region 1) to promote B cell infection. EWSR1 is a transcription and splicing regulator that is recognized for its involvement as a fusion protein in Ewing sarcoma. A function for EWSR1 in B cell responses has not been previously reported. Here, we demonstrate that 1) B cell-specific deletion of EWSR1 had no effect on generation of mature B cell subsets or basal immunoglobulin levels in naïve mice, 2) repression or ablation of EWSR1 in B cells promoted expansion of MHV68 latently infected GC B cells, and 3) B cell-specific deletion of EWSR1 during a normal immune response to nonviral antigen resulted in significantly elevated numbers of antigen-specific GC B cells, plasma cells, and circulating antibodies. Notably, EWSR1 deficiency did not affect the proliferation or survival of GC B cells but instead resulted in the generation of increased numbers of precursor GC B cells. Cumulatively, these findings demonstrate that EWSR1 is a negative regulator of B cell responses.
Subject(s)
B-Lymphocytes , Gammaherpesvirinae , Germinal Center , Herpesviridae Infections , MicroRNAs , RNA-Binding Protein EWS , Tumor Virus Infections , Animals , B-Lymphocytes/immunology , B-Lymphocytes/virology , Gammaherpesvirinae/genetics , Gammaherpesvirinae/physiology , Gene Deletion , Germinal Center/immunology , Germinal Center/virology , Herpesviridae Infections/genetics , Herpesviridae Infections/immunology , Herpesviridae Infections/virology , Mice , MicroRNAs/genetics , MicroRNAs/metabolism , RNA-Binding Protein EWS/genetics , RNA-Binding Protein EWS/metabolism , Tumor Virus Infections/genetics , Tumor Virus Infections/immunology , Tumor Virus Infections/virology , Virus LatencyABSTRACT
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.
Subject(s)
BK Virus/physiology , Cytokines/physiology , Kidney Diseases/virology , Kidney Transplantation , Polyomavirus Infections/immunology , Postoperative Complications/immunology , Postoperative Complications/virology , Tumor Virus Infections/immunology , Virus Activation , Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Young AdultABSTRACT
BACKGROUND: Viral infections are prevalent in human cancers and they have great diagnostic and theranostic values in clinical practice. Recently, their potential of shaping the tumor immune microenvironment (TIME) has been related to the immunotherapy of human cancers. However, the landscape of viral expressions and immune status in human cancers remains incompletely understood. METHODS: We developed a next-generation sequencing (NGS)-based pipeline to detect viral sequences from the whole transcriptome and used machine learning algorithms to classify different TIME subtypes. RESULTS: We revealed a pan-cancer landscape of viral expressions in human cancers where 9 types of viruses were detected in 744 tumors of 25 cancer types. Viral infections showed different tissue tendencies and expression levels. Multi-omics analyses further revealed their distinct impacts on genomic, transcriptomic and immune responses. Epstein-Barr virus (EBV)-infected stomach adenocarcinoma (STAD) and Human Papillomavirus (HPV)-infected head and neck squamous cell carcinoma (HNSC) showed decreased genomic variations, significantly altered gene expressions, and effectively triggered anti-viral immune responses. We identified three TIME subtypes, in which the "Immune-Stimulation" subtype might be the promising candidate for immunotherapy. EBV-infected STAD and HPV-infected HNSC showed a higher frequency of the "Immune-Stimulation" subtype. Finally, we constructed the eVIIS pipeline to simultaneously evaluate viral infection and immune status in external datasets. CONCLUSIONS: Viral infections are prevalent in human cancers and have distinct influences on hosts. EBV and HPV infections combined with the TIME subtype could be promising biomarkers of immunotherapy in STAD and HNSC, respectively. The eVIIS pipeline could be a practical tool to facilitate clinical practice and relevant studies.
Subject(s)
Immunotherapy , Machine Learning , Neoplasms , Oncogenic Viruses , Tumor Microenvironment , Tumor Virus Infections , Biomarkers, Tumor/genetics , Biomarkers, Tumor/immunology , DNA, Viral/genetics , Epstein-Barr Virus Infections , Genetic Variation , Genome, Viral , Head and Neck Neoplasms/immunology , Head and Neck Neoplasms/therapy , Head and Neck Neoplasms/virology , Herpesvirus 4, Human/genetics , High-Throughput Nucleotide Sequencing/methods , Humans , Kaplan-Meier Estimate , Leukocytes/classification , Leukocytes/cytology , Mutation , Neoplasms/immunology , Neoplasms/therapy , Neoplasms/virology , Oncogenic Viruses/genetics , Oncogenic Viruses/immunology , Papillomaviridae/genetics , Papillomavirus Infections , RNA-Seq , Squamous Cell Carcinoma of Head and Neck/immunology , Squamous Cell Carcinoma of Head and Neck/virology , Stomach Neoplasms/immunology , Stomach Neoplasms/therapy , Stomach Neoplasms/virology , Support Vector Machine , Transcriptome , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology , Tumor Virus Infections/genetics , Tumor Virus Infections/immunologyABSTRACT
The human γ-herpesviruses Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) encode oncogenes for B cell transformation but are carried by most infected individuals without symptoms. For this purpose, they manipulate the anti-apoptotic pathway macroautophagy, cellular proliferation and apoptosis, as well as immune recognition. The mechanisms and functional relevance of these manipulations are discussed in this review. They allow both viruses to strike the balance between efficient persistence and dissemination in their human hosts without ever being cleared after infection and avoiding pathologies in most of their carriers.
Subject(s)
Cell Differentiation/immunology , Epstein-Barr Virus Infections/immunology , Epstein-Barr Virus Infections/virology , Herpesvirus 4, Human/immunology , Host-Pathogen Interactions/immunology , Macroautophagy/immunology , Tumor Virus Infections/immunology , Tumor Virus Infections/virology , Animals , B-Lymphocytes/cytology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Herpesvirus 8, Human/immunology , Humans , Lymphopoiesis , Viral Proteins/immunology , Viral Proteins/metabolismABSTRACT
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.
Subject(s)
DNA, Viral/immunology , Immunity, Innate/immunology , Membrane Proteins/metabolism , Nuclear Proteins/metabolism , Nucleotidyltransferases/metabolism , Phosphoproteins/metabolism , Polyomavirus Infections/immunology , Polyomavirus/immunology , Tumor Virus Infections/immunology , Animals , DNA, Viral/genetics , Host-Pathogen Interactions , Interferon-beta/metabolism , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/genetics , Mice , Nuclear Proteins/antagonists & inhibitors , Nuclear Proteins/genetics , Nucleotidyltransferases/antagonists & inhibitors , Nucleotidyltransferases/genetics , Phosphoproteins/antagonists & inhibitors , Phosphoproteins/genetics , Phosphorylation , Polyomavirus/genetics , Polyomavirus Infections/virology , Tumor Virus Infections/virologyABSTRACT
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.
Subject(s)
Cytokines/immunology , Fibroblasts/immunology , Immunity, Innate/immunology , Merkel cell polyomavirus/immunology , Skin/immunology , CRISPR-Cas Systems/genetics , Carcinoma, Merkel Cell/pathology , Cells, Cultured , Cytokines/biosynthesis , Fibroblasts/virology , HEK293 Cells , Humans , Immunity, Innate/genetics , Interferons/biosynthesis , Interferons/immunology , Membrane Proteins/genetics , Merkel cell polyomavirus/growth & development , NF-kappa B/genetics , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Nucleotidyltransferases/genetics , Phosphoproteins/genetics , Phosphoproteins/metabolism , Polyomavirus Infections/immunology , Skin/cytology , Tumor Virus Infections/immunologyABSTRACT
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.
Subject(s)
Carcinoma, Merkel Cell/immunology , Merkel cell polyomavirus/immunology , Polyomavirus Infections/immunology , Skin Neoplasms/immunology , Tumor Virus Infections/immunology , Adaptive Immunity , Antigens, Neoplasm/analysis , Antigens, Neoplasm/immunology , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/metabolism , Biomarkers, Tumor/analysis , Biomarkers, Tumor/immunology , Carcinoma, Merkel Cell/diagnosis , Carcinoma, Merkel Cell/therapy , Carcinoma, Merkel Cell/virology , Drug Resistance, Neoplasm , Epitopes, T-Lymphocyte/immunology , Humans , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Immunotherapy/methods , Lymphocytes, Tumor-Infiltrating/immunology , Polyomavirus Infections/diagnosis , Polyomavirus Infections/therapy , Polyomavirus Infections/virology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/metabolism , Skin Neoplasms/diagnosis , Skin Neoplasms/therapy , Skin Neoplasms/virology , T-Lymphocytes/immunology , Tumor Microenvironment/immunology , Tumor Virus Infections/diagnosis , Tumor Virus Infections/therapy , Tumor Virus Infections/virologyABSTRACT
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.
Subject(s)
Graft Rejection/immunology , Kidney Diseases/immunology , Kidney Transplantation/adverse effects , Polyomavirus Infections/immunology , Tumor Virus Infections/immunology , BK Virus/immunology , Humans , Immunosuppression Therapy , Transplant RecipientsABSTRACT
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.
Subject(s)
Antigens, CD1/metabolism , BK Virus/immunology , Dendritic Cells/immunology , Epithelial Cells/immunology , Glycoproteins/metabolism , Kidney/immunology , Polyomavirus Infections/immunology , Tumor Virus Infections/immunology , Antibodies, Neutralizing/immunology , Dendritic Cells/metabolism , Dendritic Cells/virology , Epithelial Cells/metabolism , Epithelial Cells/virology , Humans , Kidney/metabolism , Kidney/virology , Monocytes/immunology , Monocytes/metabolism , Monocytes/virology , Polyomavirus Infections/metabolism , Polyomavirus Infections/virology , Tumor Virus Infections/metabolism , Tumor Virus Infections/virology , Virus ReplicationABSTRACT
The present review provides an overview of recent advances regarding the function of Th17 cells and their produced cytokines in the progression of viral diseases. Viral infections alone do not lead to virus-induced malignancies, as both genetic and host safety factors are also involved in the occurrence of malignancies. Acquired immune responses, through the differentiation of Th17 cells, form the novel components of the Th17 cell pathway when reacting with viral infections all the way from the beginning to its final stages. As a result, instead of inducing the right immune responses, these events lead to the suppression of the immune system. In fact, the responses from Th17 cells during persistent viral infections causes chronic inflammation through the production of IL-17 and other cytokines which provide a favorable environment for tumor growth and its development. Additionally, during the past decade, these cells have been understood to be involved in tumor progression and metastasis. However, further research is required to understand Th17 cells' immune mechanisms in the vast variety of viral diseases. This review aims to determine the roles and effects of the immune system, especially Th17 cells, in the progression of viral diseases; which can be highly beneficial for the diagnosis and treatment of these infections.
Subject(s)
Cell Transformation, Viral , Neoplasms/virology , Th17 Cells/virology , Tumor Virus Infections/virology , Viruses/pathogenicity , Animals , Host-Pathogen Interactions , Humans , Neoplasms/immunology , Neoplasms/metabolism , Th17 Cells/immunology , Th17 Cells/metabolism , Tumor Microenvironment , Tumor Virus Infections/immunology , Tumor Virus Infections/metabolism , Viruses/immunologyABSTRACT
Oncogenic viruses are associated with approximately 15% of human cancers. In viral infections, microRNAs play an important role in host-pathogen interactions. miR-21 is a highly conserved non-coding RNA that not only regulates the development of oncogenic viral diseases, but also responds to the regulation of intracellular signal pathways. Oncogenic viruses, including HBV, HCV, HPV, and EBV, co-evolve with their hosts and cause persistent infections. The upregulation of host miR-21 manipulates key cellular pathways to evade host immune responses and then promote viral replication. Thus, a better understanding of the role of miR-21 in viral infections may help us to develop effective genetically-engineered oncolytic virus-based therapies against cancer.
Subject(s)
Host-Pathogen Interactions/genetics , MicroRNAs/physiology , Oncogenic Viruses/pathogenicity , Tumor Virus Infections/genetics , Animals , Humans , Neoplasms/genetics , Neoplasms/pathology , Neoplasms/virology , Oncogenic Viruses/genetics , Oncogenic Viruses/immunology , Tumor Virus Infections/immunology , Tumor Virus Infections/pathology , Tumor Virus Infections/virology , Virus Replication/geneticsABSTRACT
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.
Subject(s)
Adoptive Transfer/adverse effects , BK Virus/pathogenicity , Cystitis/therapy , Cytokine Release Syndrome/immunology , Hematopoietic Stem Cell Transplantation/adverse effects , Hemorrhage/therapy , Polyomavirus Infections/therapy , T-Lymphocytes/transplantation , Tumor Virus Infections/therapy , Adolescent , BK Virus/immunology , Cystitis/diagnosis , Cystitis/immunology , Cystitis/virology , Cytokine Release Syndrome/diagnosis , Fatal Outcome , Hemorrhage/diagnosis , Hemorrhage/immunology , Hemorrhage/virology , Humans , Male , Multiple Organ Failure/etiology , Polyomavirus Infections/diagnosis , Polyomavirus Infections/immunology , Polyomavirus Infections/virology , Severity of Illness Index , T-Lymphocytes/immunology , T-Lymphocytes/virology , Treatment Outcome , Tumor Virus Infections/diagnosis , Tumor Virus Infections/immunology , Tumor Virus Infections/virologyABSTRACT
BACKGROUND: Metastatic carcinoma of a renal allograft is a rare but life threatening event with a difficult clinical management. Recent reports suggested a potential role of BK polyomavirus (BKPyV) in the development of urologic tract malignancies in kidney transplant recipients. METHODS: We investigated a kidney-pancreas female recipient with an history of BKPyV nephritis who developed a rapidly progressive and widely metastatic donor-derived renal carcinoma 9 years after transplantation. RESULTS: Histology and fluorescence in situ hybridization analysis revealed a donor-derived (XY tumor cells) collecting (Bellini) duct carcinoma. The presence of BKPyV oncogenic large tumor antigen was identified in large amount within the kidney tumor and the bowel metastases. Whole genome sequencing of the tumor confirmed multiple genome BKPyV integrations. The transplanted kidney was removed, immunosuppression was withdrawn, and recombinant interleukin-2 (IL-2) was administered for 3 months, inducing a complete tumor clearance, with no evidence of disease at 6-year follow-up. The immunological profiling during IL-2 therapy revealed the presence of donor-specific T cells and expanded cytokine-producing bright natural killer cells but no donor-specific antibodies. Finally, we found persistently elevated anti-BK virus IgG titers and a specific anti-BKPyV T cell response. CONCLUSIONS: This investigation showed evidence for the potential oncogenic role of BKPyV in collecting duct carcinoma in renal allografts and demonstrated that immunosuppression withdrawal and IL-2 therapy can lead to an efficient antitumor cellular mediated rejection possibly via 3 distinct mechanisms including (1) host-versus-graft, (2) host-versus-tumor, and (3) anti-BKPyV responses.