-
Immunity Dec 2023In triple-negative breast cancer (TNBC), stromal restriction of CD8 T cells associates with poor clinical outcomes and lack of responsiveness to immune-checkpoint...
In triple-negative breast cancer (TNBC), stromal restriction of CD8 T cells associates with poor clinical outcomes and lack of responsiveness to immune-checkpoint blockade (ICB). To identify mediators of T cell stromal restriction, we profiled murine breast tumors lacking the transcription factor Stat3, which is commonly hyperactive in breast cancers and promotes an immunosuppressive tumor microenvironment. Expression of the cytokine Chi3l1 was decreased in Stat3 tumors. CHI3L1 expression was elevated in human TNBCs and other solid tumors exhibiting T cell stromal restriction. Chi3l1 ablation in the polyoma virus middle T (PyMT) breast cancer model generated an anti-tumor immune response and delayed mammary tumor onset. These effects were associated with increased T cell tumor infiltration and improved response to ICB. Mechanistically, Chi3l1 promoted neutrophil recruitment and neutrophil extracellular trap formation, which blocked T cell infiltration. Our findings provide insight into the mechanism underlying stromal restriction of CD8 T cells and suggest that targeting Chi3l1 may promote anti-tumor immunity in various tumor types.
Topics: Animals; Humans; Mice; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cytokines; Extracellular Traps; Triple Negative Breast Neoplasms; Tumor Microenvironment
PubMed: 38039967
DOI: 10.1016/j.immuni.2023.11.002 -
Neurology Oct 2023JC polyomavirus (JCV) establishes an asymptomatic latent and/or persistent infection in most of the adult population. However, in immunocompromised individuals, JCV can... (Review)
Review
JC polyomavirus (JCV) establishes an asymptomatic latent and/or persistent infection in most of the adult population. However, in immunocompromised individuals, JCV can cause a symptomatic infection of the brain, foremost progressive multifocal leukoencephalopathy (PML). In the past 2 decades, there has been increasing concern among patients and the medical community because PML was observed as an adverse event in individuals treated with modern (selective) immune suppressive treatments for various immune-mediated diseases, especially multiple sclerosis. It became evident that this devastating complication also needs to be considered beyond the patient populations historically at risk, including those with hematologic malignancies or HIV-infected individuals. We review the clinical presentation of PML, its variants, pathogenesis, and current diagnostic approaches. We further discuss the need to validate JCV-directed interventions and highlight current management strategies based on early diagnosis and restoring JCV-specific cellular immunity, which is crucial for viral clearance and survival. Finally, we discuss the importance of biomarkers for diagnosis and response to therapy, instrumental in defining sensitive study end points for successful clinical trials of curative or preventive therapeutics. Advances in understanding PML pathophysiology, host and viral genetics, and diagnostics in conjunction with novel immunotherapeutic approaches indicate that the time is right to design and perform definitive trials to develop preventive options and curative therapy for JCV-associated diseases.
Topics: Adult; Humans; Leukoencephalopathy, Progressive Multifocal; JC Virus; Brain; Multiple Sclerosis; Biomarkers
PubMed: 37487750
DOI: 10.1212/WNL.0000000000207622 -
Journal of Neurovirology Oct 2023Since its definition 65 years ago, progressive multifocal leukoencephalopathy (PML) has continued to devastate a growing population of immunosuppressed patients despite... (Review)
Review
Since its definition 65 years ago, progressive multifocal leukoencephalopathy (PML) has continued to devastate a growing population of immunosuppressed patients despite major advances in our understanding of the causative JC virus (JCV). Unless contained by the immune system, JCV lyses host oligodendrocytes collateral to its life cycle, leading to demyelination, neurodegeneration, and death. Novel treatments have stagnated in the absence of an animal model while current antiviral agents fail to address the now ubiquitous polyomavirus. In this review, we highlight the established pathogenesis by which JCV infection progresses to PML, highlighting major challenges that must be overcome to eliminate the underlying virus and, therefore, the debilitating disease.
Topics: Animals; Humans; Leukoencephalopathy, Progressive Multifocal; JC Virus; Polyomavirus Infections; Immunocompromised Host
PubMed: 37659983
DOI: 10.1007/s13365-023-01164-w -
Viruses Oct 2023JC polyomavirus (JCPyV) is a human-specific polyomavirus that establishes a silent lifelong infection in multiple peripheral organs, predominantly those of the urinary... (Review)
Review
JC polyomavirus (JCPyV) is a human-specific polyomavirus that establishes a silent lifelong infection in multiple peripheral organs, predominantly those of the urinary tract, of immunocompetent individuals. In immunocompromised settings, however, JCPyV can infiltrate the central nervous system (CNS), where it causes several encephalopathies of high morbidity and mortality. JCPyV-induced progressive multifocal leukoencephalopathy (PML), a devastating demyelinating brain disease, was an AIDS-defining illness before antiretroviral therapy that has "reemerged" as a complication of immunomodulating and chemotherapeutic agents. No effective anti-polyomavirus therapeutics are currently available. How depressed immune status sets the stage for JCPyV resurgence in the urinary tract, how the virus evades pre-existing antiviral antibodies to become viremic, and where/how it enters the CNS are incompletely understood. Addressing these questions requires a tractable animal model of JCPyV CNS infection. Although no animal model can replicate all aspects of any human disease, mouse polyomavirus (MuPyV) in mice and JCPyV in humans share key features of peripheral and CNS infection and antiviral immunity. In this review, we discuss the evidence suggesting how JCPyV migrates from the periphery to the CNS, innate and adaptive immune responses to polyomavirus infection, and how the MuPyV-mouse model provides insights into the pathogenesis of JCPyV CNS disease.
Topics: Humans; Animals; Mice; Polyomavirus; Leukoencephalopathy, Progressive Multifocal; JC Virus; Polyomavirus Infections; Brain Diseases
PubMed: 37896889
DOI: 10.3390/v15102112 -
Microbial Pathogenesis Oct 2023Cancer is a serious public health problem globally. Many human cancers are induced by viruses. Understanding of the mechanisms by which oncogenic (tumorigenic) viruses... (Review)
Review
Cancer is a serious public health problem globally. Many human cancers are induced by viruses. Understanding of the mechanisms by which oncogenic (tumorigenic) viruses induce cancer is essential in the prevention and control of cancer. This review covers comprehensive characteristics and molecular mechanisms of the main virus-attributed cancers caused by human papillomavirus, hepatitis B virus, hepatitis C virus, Epstein-Barr virus, human herpesvirus type 8, human T-cell lymphotropic virus, human polyomaviruses, Merkel cell polyomavirus, and HIV. Oncogenic viruses employ biological processes to replicate and avoid detection by host cell immune systems. Tumorigenic infectious agents activate oncogenes in a variety of ways, allowing the pathogen to block host tumour suppressor proteins, inhibit apoptosis, enhance cell proliferation, and promote invasion of host cells. Furthermore, this review assesses many pathways of viruses linked to cancer, including host cellular communication perturbation, DNA damage mechanisms, immunity, and microRNA targets that promote the beginning and progression of cancer. The current cancer prevention is primarily focused on non-communicable diseases, but infection-attributable cancer also needs attention to significantly reduce the rising cancer burden and related deaths.
Topics: Humans; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Neoplasms; Oncogenic Viruses; Hepacivirus
PubMed: 37557930
DOI: 10.1016/j.micpath.2023.106292 -
Journal of Medical Virology Sep 2023Bladder cancer (BC) is a complex disease affecting the urinary system and is regulated by several carcinogenic factors. Viral infection is one such factor that has... (Review)
Review
Bladder cancer (BC) is a complex disease affecting the urinary system and is regulated by several carcinogenic factors. Viral infection is one such factor that has attracted extensive attention in BC. Human papillomavirus (HPV) is the most common sexually transmitted infection, and although multiple researchers have explored the role of HPV in BC, a consensus has not yet been reached. In addition, HPV-associated viruses (e.g., human immunodeficiency virus, herpes simplex virus, BK virus, and JC virus) appear to be responsible for the occurrence and progression of BC. This study systematically reviews the relationship between HPV-associated viruses and BC to elucidate the role of these viruses in the onset and progression of BC. In addition, the study aims to provide a greater insight into the biology of HPV-associated viruses, and assess potential strategies for treating virus-induced BC. The study additionally focuses on the rapid development of oncolytic viruses that provide a potentially novel option for the treatment of BC.
Topics: Humans; Human Papillomavirus Viruses; Satellite Viruses; Papillomavirus Infections; Urinary Bladder Neoplasms; BK Virus
PubMed: 37706751
DOI: 10.1002/jmv.29088 -
Journal of Dental Research Mar 2024The oral cavity is an epidemiologically relevant route of viral transmission due to the shedding of viruses in saliva. With advancements in salivary diagnostics, an... (Review)
Review
The oral cavity is an epidemiologically relevant route of viral transmission due to the shedding of viruses in saliva. With advancements in salivary diagnostics, an increasing number of viruses have been detected. However, the anatomic source of virus in saliva is still largely unknown. Some viruses have a well-established tropism for the salivary glands (SGs), and recent studies have emphasized the importance of the glands as potential reservoirs for infectious viruses. Viral infections of the SGs have been linked to acute and chronic SG pathology and may be associated with SG dysfunction, with phenotypes similar to those seen in SjÖgren's disease (SjD), an autoimmune condition that affects the salivary and lacrimal glands. Understanding the breadth of viruses that infect the SG and the conserved or distinct host responses to these infections may provide insights into the pathogenesis of virus-mediated SG diseases. There is a need for further research to fully understand the molecular mechanisms by which viruses enter and replicate in the glands, their physiologic impact on SG function, and whether the SGs can serve as a long-term reservoir for infectious viral particles. The purpose of this review is to highlight a group of viruses that infect the salivary gland: hepatitis C virus, hepatitis D virus, severe acute respiratory syndrome coronavirus 2, enteric viruses, human T-cell leukemia virus type I, human immunodeficiency virus, human cytomegalovirus, and BK polyomavirus. We focus on the effects of viral infection on salivary gland (SG) inflammation, function, and its association with SjD.
Topics: Humans; Salivary Glands; Sjogren's Syndrome; Saliva; Inflammation
PubMed: 38344753
DOI: 10.1177/00220345231222871 -
JAAPA : Official Journal of the... Nov 2023Merkel cell carcinoma (MCC) is a rare and aggressive type of metastatic, nonmelanoma skin cancer derived from Merkel cells in the epidermis. MCC can be induced by sun... (Review)
Review
Merkel cell carcinoma (MCC) is a rare and aggressive type of metastatic, nonmelanoma skin cancer derived from Merkel cells in the epidermis. MCC can be induced by sun exposure or via Merkel cell polyomavirus (MCV) gene expression. MCV is found in most patients with MCC and is associated with a lower recurrence rate of MCC. MCC has a wide range of clinical presentations that make diagnosis challenging. Histologic examination is performed using unique markers to differentiate it from other diagnoses. This article reviews the pathogenesis, clinical presentation, histopathology, differential diagnosis, and treatment of MCC.
Topics: Humans; Carcinoma, Merkel Cell; Polyomavirus Infections; Tumor Virus Infections; Skin Neoplasms; Merkel cell polyomavirus
PubMed: 37820270
DOI: 10.1097/01.JAA.0000979460.69305.b7