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IScience Dec 2023Infection with West Nile virus (WNV) drives a wide range of responses, from asymptomatic to flu-like symptoms/fever or severe cases of encephalitis and death. To...
Infection with West Nile virus (WNV) drives a wide range of responses, from asymptomatic to flu-like symptoms/fever or severe cases of encephalitis and death. To identify cellular and molecular signatures distinguishing WNV severity, we employed systems profiling of peripheral blood from asymptomatic and severely ill individuals infected with WNV. We interrogated immune responses longitudinally from acute infection through convalescence employing single-cell protein and transcriptional profiling complemented with matched serum proteomics and metabolomics as well as multi-omics analysis. At the acute time point, we detected both elevation of pro-inflammatory markers in innate immune cell types and reduction of regulatory T cell activity in participants with severe infection, whereas asymptomatic donors had higher expression of genes associated with anti-inflammatory CD16 monocytes. Therefore, we demonstrated the potential of systems immunology using multiple cell-type and cell-state-specific analyses to identify correlates of infection severity and host cellular activity contributing to an effective anti-viral response.
PubMed: 38047068
DOI: 10.1016/j.isci.2023.108387 -
Neurology(R) Neuroimmunology &... Mar 2021To discuss the pathogenic and diagnostic relevance of cellular and humoral immune responses against severe acute respiratory syndrome novel coronavirus (SARS-COV-2) and... (Review)
Review
OBJECTIVE
To discuss the pathogenic and diagnostic relevance of cellular and humoral immune responses against severe acute respiratory syndrome novel coronavirus (SARS-COV-2) and pertinent observations made in progressive multifocal leukoencephalopathy (PML).
METHODS
Review of pertinent literature RESULTS: There is at least 1 precedent for an antibody response against a viral pathogen that fails to provide host protection in the absence of immune-competent CD4 T cells. PML is an infection of the CNS caused by JC virus (JCV), which commonly occurs during treatment with the therapeutic monoclonal antibody natalizumab. In this context, the humoral immune response fails to prevent JCV reactivation, and elevated anti-JCV serum indices are associated with a higher PML incidence. The more relevant immune-competent cells in host defense against JCV appear to be T cells. T cell-mediated responses are also detectable in convalescing patients with SARS-COV-2 irrespective of the humoral immune response.
CONCLUSION
Based on pathogenic lessons learned from PML under natalizumab therapy, we suggest the incorporation of functional assays that determine neutralizing properties of SARS-CoV-2-specific antibodies. In addition, we outline the potential role of T-cell detection assays in determining herd immunity in a given population or in studying therapeutic responses to vaccines.
Topics: Adaptive Immunity; Antibodies, Viral; Antibody Formation; Humans; Immunity, Humoral; Leukoencephalopathy, Progressive Multifocal; SARS-CoV-2; T-Lymphocytes
PubMed: 33361386
DOI: 10.1212/NXI.0000000000000935 -
Journal of Virology Mar 2023Polyomavirus small T antigen (tAg) plays important roles in regulating viral replication, the innate immune response, apoptosis, and transformation for SV40, Merkel cell...
Polyomavirus small T antigen (tAg) plays important roles in regulating viral replication, the innate immune response, apoptosis, and transformation for SV40, Merkel cell polyomavirus (MCPyV), murine polyomavirus (MuPyV), and JC polyomavirus (JCPyV). However, the function of BK polyomavirus (BKPyV) tAg has been much less studied. Here, we constructed mutant viruses that do not express tAg, and we showed that, in contrast with other polyomaviruses, BKPyV tAg inhibits large T antigen (TAg) gene expression and viral DNA replication. However, this occurs only in an archetype viral background. We also observed that the transduction of cells with a lentivirus-expressing BKPyV tAg kills the cells. We further discovered that BKPyV tAg interacts not only with PP2A A and C subunits, as has been demonstrated for other polyomavirus tAg proteins, but also with PP2A B''' subunit members. Knocking down either of two B''' subunits, namely STRN or STRN3, mimics the phenotype of the tAg mutant virus. However, a virus containing a point mutation in the PP2A binding domain of tAg only partially affected virus TAg expression and DNA replication. These results indicate that BKPyV tAg downregulates viral gene expression and DNA replication and that this occurs in part through interactions with PP2A. BK polyomavirus is a virus that establishes a lifelong infection of the majority of people. The infection usually does not cause any clinical symptoms, but, in transplant recipients whose immune systems have been suppressed, unchecked virus replication can cause severe disease. In this study, we show that a viral protein called small T antigen is one of the ways that the virus can persist without high levels of replication. Understanding which factors control viral replication enhances our knowledge of the virus life cycle and could lead to potential interventions for these patients.
Topics: Animals; Mice; Antigens, Viral, Tumor; BK Virus; DNA Replication; DNA, Viral; Polyomavirus Infections; Virus Replication
PubMed: 36916919
DOI: 10.1128/jvi.00077-23 -
Viruses Oct 2020Polyomaviruses are small, non-enveloped DNA tumor viruses that cause serious disease in immunosuppressed people, including progressive multifocal leukoencephalopathy...
Polyomaviruses are small, non-enveloped DNA tumor viruses that cause serious disease in immunosuppressed people, including progressive multifocal leukoencephalopathy (PML) in patients infected with JC polyomavirus, but the molecular events mediating polyomavirus entry are poorly understood. Through genetic knockdown approaches, we identified phosphoinositide 3'-kinase γ (PI3Kγ) and its regulatory subunit PIK3R5 as cellular proteins that facilitate infection of human SVG-A glial cells by JCPyV. PI3Kα appears less important for polyomavirus infection than PI3Kγ. CRISPR/Cas9-mediated knockout of PIK3R5 or PI3Kγ inhibited infection by authentic JCPyV and by JC pseudovirus. PI3Kγ knockout also inhibited infection by BK and Merkel Cell pseudoviruses, other pathogenic human polyomaviruses, and SV40, an important model polyomavirus. Reintroduction of the wild-type gene into the PI3Kγ knock-out SVG-A cells rescued the JCPyV infection defect. Disruption of the PI3Kγ pathway did not block binding of JCPyV to cells or virus internalization, implying that PI3Kγ facilitates some intracellular step(s) of infection. These results imply that agents that inhibit PI3Kγ signaling may have a role in managing polyomavirus infections.
Topics: Cell Line; Humans; JC Virus; Leukoencephalopathy, Progressive Multifocal; Neuroglia; Phosphatidylinositol 3-Kinases; Phosphatidylinositols; Polyomavirus; Polyomavirus Infections; Virus Internalization
PubMed: 33092168
DOI: 10.3390/v12101190 -
Brain Communications Feb 2022Although most of the progressive multifocal leukoencephalopathy cases in sarcoidosis patients are explained by the treatment with immunosuppressive drugs, it is also...
Although most of the progressive multifocal leukoencephalopathy cases in sarcoidosis patients are explained by the treatment with immunosuppressive drugs, it is also reported in treatment-naive sarcoidosis patients, which implies a general predisposition of sarcoidosis patients for progressive multifocal leukoencephalopathy. Indeed, it was shown that active sarcoidosis patients have increased regulatory T cell frequencies which could lead to a subsequent systemic immunosuppression. However, if sarcoidosis with systemic changes of T cell subsets frequencies constitute a risk factor for the development of progressive multifocal leukoencephalopathy, which could then be counteracted by sarcoidosis treatment, is not known. In this cohort study, we included, characterized and followed-up six patients with bioptically confirmed definite progressive multifocal leukoencephalopathy and definite or probable sarcoidosis presenting between April 2013 and January 2019, four of them had no immunosuppressive therapy at the time of developing first progressive multifocal leukoencephalopathy symptoms. Analysis of immune cell subsets in these patients revealed significant imbalances of CD4 T cell and regulatory T cell frequencies. Due to the progression of progressive multifocal leukoencephalopathy in four patients, we decided to treat sarcoidosis anticipating normalization of immune cell subset frequencies and thereby improving progressive multifocal leukoencephalopathy. Notably, by treatment with infliximab, an antibody directed against tumour necrosis factor-α, three patients continuously improved clinically, JC virus was no longer detectable in the cerebrospinal fluid and regulatory T cell frequencies decreased. One patient was initially misdiagnosed as neurosarcoidosis and died 9 weeks after treatment initiation due to aspiration pneumonia. Our study provides insight that sarcoidosis can lead to changes in T cell subset frequencies, which predisposes to progressive multifocal leukoencephalopathy. Although immunosuppressive drugs should be avoided in progressive multifocal leukoencephalopathy, paradoxically in patients with sarcoidosis treatment with the immunosuppressive infliximab might restore normal T cell distribution and thereby halt progressive multifocal leukoencephalopathy progression.
PubMed: 34993476
DOI: 10.1093/braincomms/fcab292 -
Annals of Clinical and Translational... Mar 2021Based on publicly available data, we reevaluated current algorithms for stratifying the risk of progressive multifocal leukoencephalopathy (PML) in natalizumab-treated...
Based on publicly available data, we reevaluated current algorithms for stratifying the risk of progressive multifocal leukoencephalopathy (PML) in natalizumab-treated patients with multiple sclerosis, and found that there are a number of issues. First and foremost, our analysis highlights the necessity of separate PML incidence assessments for the U.S. versus Europe, and indicates that the risk in John Cunningham virus (JCV) antibody-negative patients may be higher than previously communicated. Additionally, we advocate introducing a low-risk JCV index threshold of 0.45 for individuals with prior exposure to an immunosuppressant, and setting the low-risk threshold at 0.6 instead of 0.9 for those without such pretherapies. On the other hand, the risk of PML on natalizumab, in general, appears to not only plateau but to actually decrease after about 5 years of continuous dosing.
Topics: Algorithms; Antibodies, Viral; Canada; Europe; Humans; Immunologic Factors; JC Virus; Leukoencephalopathy, Progressive Multifocal; Multiple Sclerosis; Natalizumab; Risk Assessment; United States
PubMed: 33539683
DOI: 10.1002/acn3.51130 -
Frontiers in Cellular Neuroscience 2022
PubMed: 35450209
DOI: 10.3389/fncel.2022.883221 -
Viruses Sep 2020In the fifty years since the discovery of JC polyomavirus (JCPyV), the body of research representing our collective knowledge on this virus has grown substantially. As... (Review)
Review
In the fifty years since the discovery of JC polyomavirus (JCPyV), the body of research representing our collective knowledge on this virus has grown substantially. As the causative agent of progressive multifocal leukoencephalopathy (PML), an often fatal central nervous system disease, JCPyV remains enigmatic in its ability to live a dual lifestyle. In most individuals, JCPyV reproduces benignly in renal tissues, but in a subset of immunocompromised individuals, JCPyV undergoes rearrangement and begins lytic infection of the central nervous system, subsequently becoming highly debilitating-and in many cases, deadly. Understanding the mechanisms allowing this process to occur is vital to the development of new and more effective diagnosis and treatment options for those at risk of developing PML. Here, we discuss the current state of affairs with regards to JCPyV and PML; first summarizing the history of PML as a disease and then discussing current treatment options and the viral biology of JCPyV as we understand it. We highlight the foundational research published in recent years on PML and JCPyV and attempt to outline which next steps are most necessary to reduce the disease burden of PML in populations at risk.
Topics: Animals; History, 20th Century; History, 21st Century; Humans; JC Virus; Polyomavirus Infections; Tumor Virus Infections
PubMed: 32882975
DOI: 10.3390/v12090969 -
Neurotherapeutics : the Journal of the... Jul 2020Progressive multifocal leukoencephalopathy (PML) is a viral disease of the brain associated with immunodeficiency, immune suppressing medications, and malignancy. In the... (Review)
Review
Progressive multifocal leukoencephalopathy (PML) is a viral disease of the brain associated with immunodeficiency, immune suppressing medications, and malignancy. In the absence of effective anti-viral therapy for the causative JC virus, immune restoration has emerged as the critical therapeutic alternative. The evolving treatment of PML (and other rare JC virus-associated neurologic syndromes) requires consideration of baseline immune functioning and comorbid diseases while selecting from a number of therapeutic options to restore an effective immune response. This review focuses on the current options for management of PML in typical situations where this disease presents, including several where immune restoration is a standard therapeutic approach such as in PML associated with HIV/AIDS and in multiple sclerosis associated with natalizumab. Other circumstances in which PML occurs including associated with primary immunodeficiencies, malignancies, and transplants present greater challenges to immune reconstitution, but emerging concepts may enhance therapeutic options for these situations. Particular attention is focused on recent experience with checkpoint inhibitors, guidance for MS drug discontinuation, and strategies to monitor and facilitate immune restoration.
Topics: Animals; Antibodies, Monoclonal, Humanized; Humans; Immune Reconstitution; Immunosuppressive Agents; Leukoencephalopathy, Progressive Multifocal; Natalizumab; Treatment Outcome
PubMed: 32166631
DOI: 10.1007/s13311-020-00848-z -
Frontiers in Cellular and Infection... 2023Banna virus (BAV), a potential pathogen that may cause human encephalitis, is the prototype species of genus within the family , and has been isolated from a variety of...
INTRODUCTION
Banna virus (BAV), a potential pathogen that may cause human encephalitis, is the prototype species of genus within the family , and has been isolated from a variety of blood-sucking insects and mammals in Asia.
METHODS
, , and were collected overnight in Yunnan, China, during 2016-2023 using light traps. Virus was isolated from these collected blood-sucking insects and grown using (C6/36) cells. Preliminary identification of the virus was performed by agarose gel electrophoresis (AGE). The full genome sequences of the BAVs were determined by full-length amplification of cDNAs (FLAC) and sequenced using next-generation sequencing.
RESULTS
In this study, 13 strains BAV were isolated from , and . Their viral genome consisted of 12 segments of double-stranded RNA (dsRNA), and with three distinct distribution patterns. Sequence analysis showed that Seg-5 of four strains (SJ_M46, SJ_M49, JC_M19-13 and JC_C24-13) has 435 bases nucleotide sequence insertions in their ORF compared to other BAVs, resulting in the length of Seg-5 up to 2128 nt. There are 34 bases sequence deletion in Seg-9 of 3 strains (WS_T06, MS_M166 and MS_M140). Comparison of the coding sequences of VP1, VP2, VP5, VP9 and VP12 of the 13 BAV strains, the results show that VP1, VP2 and VP12 are characterised by high levels of sequence conservation, while VP9 is highly variable, under great pressure to adapt and may be correlated with serotype. While also variable, VP5 appears to be under less adaptive pressure than VP9. Additionally, phylogenetic analysis indicates that the 13 BAV strains locate in the same evolutionary cluster as BAVs isolated from various blood-sucking insects, and are clustered according to geographical distribution.
CONCLUSION
The data obtained herein would be beneficial for the surveillance of evolutionary characteristics of BAV in China and neighboring countries as well as extend the knowledge about its genomic diversity and geographic distribution.
Topics: Animals; Aedes; Ceratopogonidae; China; Coltivirus; Genome, Viral; Mammals; Phylogeny; Ticks
PubMed: 38035340
DOI: 10.3389/fcimb.2023.1283580