The skin is a complex tissue that provides a strong physical barrier against invading pathogens. Despite this, many viruses can access the skin and successfully replicate in either the epidermal keratinocytes or dermal immune cells. In this review, we provide an overview of the antiviral T cell biology responding to cutaneous viral infections and how these responses differ depending on the cellular targets of infection.
View Article and Find Full Text PDFMacrophages orchestrate tissue immunity from the initiation and resolution of antimicrobial immune responses to the repair of damaged tissue. Murine studies demonstrate that tissue-resident macrophages are a heterogenous mixture of yolk sac-derived cells that populate the tissue before birth, and bone marrow-derived replacements recruited in adult tissues at steady-state and in increased numbers in response to tissue damage or infection. How this translates to species that are constantly under immunologic challenge, such as humans, is unknown.
View Article and Find Full Text PDFHuman poxvirus infections have caused significant public health burdens both historically and recently during the unprecedented global Mpox virus outbreak. Although vaccinia virus (VACV) infection of mice is a commonly used model to explore the anti-poxvirus immune response, little is known about the metabolic changes that occur during infection. We hypothesized that the metabolome of VACV-infected skin would reflect the increased energetic requirements of both virus-infected cells and immune cells recruited to sites of infection.
View Article and Find Full Text PDFAfter recognition of cognate antigen (Ag), effector CD8 T cells secrete serine proteases called granzymes in conjunction with perforin, allowing granzymes to enter and kill target cells. While the roles for some granzymes during antiviral immune responses are well characterized, the function of others, such as granzyme C and its human ortholog granzyme H, is still unclear. Granzyme C is constitutively expressed by mature, cytolytic innate lymphoid 1 cells (ILC1s).
View Article and Find Full Text PDFThe success of poxviruses as pathogens depends on their antagonism of host responses by multiple immunomodulatory proteins. The largest of these expressed by ectromelia virus (the agent of mousepox) is C15, one member of a well-conserved poxviral family previously shown to inhibit T cell activation. Here, we demonstrate by quantitative immunofluorescence imaging that C15 also limits contact between natural killer (NK) cells and infected cells .
View Article and Find Full Text PDFLow nadir CD4 T-cell counts in HIV patients are associated with high morbidity and mortality and lasting immune dysfunction, even after antiretroviral therapy (ART). The early events of immune recovery of T cells and B cells in severely lymphopenic HIV patients have not been fully characterized. In a cohort of lymphopenic (CD4 T-cell count < 100/µL) HIV patients, we studied mononuclear cells isolated from peripheral blood (PB) and lymph nodes (LN) pre-ART (n = 40) and 6-8 weeks post-ART (n = 30) with evaluation of cellular immunophenotypes; histology on LN sections; functionality of circulating T follicular helper (cTfh) cells; transcriptional and B-cell receptor profile on unfractionated LN and PB samples; and plasma biomarker measurements.
View Article and Find Full Text PDFImmune reconstitution inflammatory syndrome (IRIS) is an inflammatory complication associated with an underlying opportunistic infection that can be observed in HIV-infected individuals shortly after the initiation of antiretroviral therapy, despite successful suppression of HIV viral load and CD4 T cell recovery. Better understanding of IRIS pathogenesis would allow for targeted prevention and therapeutic approaches. In this study, we sought to evaluate the metabolic perturbations in IRIS across longitudinal time points using an unbiased plasma metabolomics approach as well as integrated analyses to include plasma inflammatory biomarker profile and whole blood transcriptome.
View Article and Find Full Text PDFMicrobial translocation contributes to persistent inflammation in both treated and untreated HIV infection. Although translocation is due in part to a disintegration of the intestinal epithelial barrier, there is a bias towards the translocation of Proteobacteria. We hypothesized that intestinal epithelial microvesicle cargo differs after HIV infection and contributes to biased translocation.
View Article and Find Full Text PDFMycobacterium genavense is a challenging opportunistic pathogen to diagnose and manage in patients with human immunodeficiency virus (HIV). Persistent immunosuppression or protracted immune reconstitution inflammatory syndrome can lead to complicated clinical courses. We describe 3 cases of M.
View Article and Find Full Text PDFCD4 expression identifies a subset of mature T cells primarily assisting the germinal center reaction and contributing to CD8+ T-cell and B-cell activation, functions, and longevity. Herein, we present a family in which a novel variant disrupting the translation-initiation codon of the CD4 gene resulted in complete loss of membrane and plasma soluble CD4 in peripheral blood, lymph node, bone marrow, skin, and ileum of a homozygous proband. This inherited CD4 knockout disease illustrates the clinical and immunological features of a complete deficiency of any functional component of CD4 and its similarities and differences with other clinical models of primary or acquired loss of CD4+ T cells.
View Article and Find Full Text PDFDistinguishing disseminated Mycobacterium marinum from multifocal cutaneous disease in persons with human immunodeficiency virus/AIDS can present a diagnostic challenge, especially in the context of immune reconstitution inflammatory syndrome (IRIS). In this work, we demonstrate the utility of flow cytometry and whole genome sequencing (WGS) to diagnose disseminated M. marinum unmasked by IRIS following initiation of antiretroviral therapy.
View Article and Find Full Text PDFParadoxical inflammatory reactions associated with treatment of neurotuberculosis can lead to severe morbidity and mortality and may not be controlled by steroids alone. We report the use of the Janus kinase inhibitor ruxolitinib to treat a steroid-refractory neurotuberculosis paradoxical reaction.
View Article and Find Full Text PDFPatients with primary immunodeficiencies undergoing allogeneic hematopoietic cell transplantation (HCT) for difficult-to-control infections can experience immune reconstitution inflammatory syndrome (IRIS) following engraftment. In 3 patients with post-HCT IRIS related to mycobacterial infection, in vitro data demonstrate the emergence of pathogen-specific immune responses and a concomitant rise in plasma inflammatory markers.
View Article and Find Full Text PDFBackground: Immune reconstitution inflammatory syndrome (IRIS) is an aberrant inflammatory response in individuals with advanced human immunodeficiency virus (HIV) infection, after antiretroviral therapy (ART) initiation. The pathogenesis of Mycobacterium avium complex (MAC)-associated IRIS has not been fully elucidated.
Methods: We investigated monocyte and CD4+ T-cell responses in vitro, tumor necrosis factor (TNF) expression in tissues, and plasma cytokines and inflammatory markers, in 13 HIV-infected patients with MAC-IRIS and 14 HIV-uninfected patients with pulmonary MAC infection.
The management of corticosteroid refractory immune reconstitution inflammatory syndrome (IRIS) is currently unclear. Infliximab administration was associated with clinical improvement without significant adverse events in 3 patients with mycobacterial IRIS. Immunologic and virologic responses to antiretroviral therapy were unaffected.
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