Biology subjects

Tankelevich, M.

Publications and source records attributed to Tankelevich, M..

5 recordsLinked to original sources

bioRxiv2026

Persistent SARS-CoV-2 Spike is Associated with Localized Immune Dysregulation in Long COVID Gut Biopsies

SARS-CoV-2 persistence is a proposed driver of Long COVID (LC), but the in-situ relationship between residual viral antigen and immune dysregulation remains poorly defined. To address this critical gap, we employed a high-resolution, multi-modal approach--combining RNAscope, GeoMx Digital Spatial Profiling (DSP), spatial transcriptomics, and multiplex immunofluorescence--on 25 terminal ileum and left colon biopsies from a clinical cohort of 8 LC participants and 5 healthy controls. We confirmed the persistence of SARS-CoV-2 Spike transcript and protein in the gut tissue of all LC cases and controls tested. Yet, comparison of Spike-positive (Spike+) regions in LC versus healthy control colon tissues revealed a differential, symptomatic state-associated signature, with 57 differentially expressed genes (DEGs) (26 upregulated, 31 downregulated), revealing genes that disrupt the immune response in LC subjects. LC colon Spike+ regions demonstrated increased expression of AQP8 and other absorptive-related genes (SLC26A3, SLC26A2, and CLCA4) which are involved with Chrons disease along with transcripts involved in tumorigenesis (GUCA2A, S100P, TSPAN1). Simultaneous downregulation of key homeostatic chemokines (CXCL13, CCL19, CCL21), and other transcripts reported to exhibit low expression in colorectal cancers (TMEM88B, NIBAN3, DMBT1), suggesting a paradox of epithelial tissue stress yet dysfunctional immune trafficking. Further analysis comparing Spike+ versus Spike-regions within LC colon tissue demonstrated an active, localized, antigen-driven immune microenvironment, identifying 122 DEGs (82 upregulated, 40 downregulated), including tumorigenesis genes. Cellular deconvolution of Spike+ regions revealed a statistically significant focal enrichment of myeloid-derived cells (macrophages, non-classical/intermediate monocytes), plasma cells, and regulatory T cells, coupled with significant enrichment in T-cell-related pathways, including "Antigen processing and presentation," and "Th1/Th2/Th17 cell differentiation." The ileum displayed a similar, though less pronounced, signature, demonstrating these statistically significant findings are specific to the colon of LC subjects. In contrast, corresponding Spike+ vs. Spike-analysis in healthy control colon tissues showed a more modest transcriptional response with 38 DEGs. Our data provide robust evidence that persistent SARS-CoV-2 Spike protein detection in the gut is not immunologically inert. Instead, it is actively associated with distinct, immune cell composition shifts and a dysfunctional pro-inflammatory transcriptional profile, supporting the hypothesis that retained viral antigen drives chronic immune dysregulation in tissue of Long COVID subjects.

genomics↗

bioRxiv2024

HIV-1 infection is associated with depletion of germinal center B cells and a decrease in IgA+ plasma cells in the GI tract

Gastrointestinal (GI) B cells and plasma cells (PCs) are critical to mucosal homeostasis and the host response to HIV-1 infection. Here, high resolution mapping of human B cells and PCs sampled from the colon and ileum during both viremic and suppressed HIV-1 infection identified a reduction in germinal center (GC) B cells and follicular dendritic cells (FDCs) during HIV-1 viremia. IgA+ PCs are the major cellular output of intestinal GCs and were significantly reduced during viremic HIV-1 infection. PC-associated transcriptional perturbations, including type I interferon signaling, persisted in antiretroviral therapy (ART)-treated individuals, suggesting ongoing disruption of the intestinal immune milieu during ART. GI humoral immune perturbations were associated with changes in the intestinal microbiome composition and systemic inflammation. These findings highlight a key immune defect in the GI mucosa due to HIV-1 viremia. One Sentence SummaryIntestinal germinal center B cell reduction in HIV-1 infection linked to reduced IgA+ plasma cells and systemic inflammation.

immunology↗

bioRxiv2023

Myeloid cell influx into the colonic epithelium is associated with disease severity and non-response to anti-Tumor Necrosis Factor Therapy in patients with Ulcerative Colitis.

Ulcerative colitis (UC) is an idiopathic chronic inflammatory disease of the colon with sharply rising global prevalence. Dysfunctional epithelial compartment (EC) dynamics are implicated in UC pathogenesis although EC-specific studies are sparse. Applying orthogonal high-dimensional EC profiling to a Primary Cohort (PC; n=222), we detail major epithelial and immune cell perturbations in active UC. Prominently, reduced frequencies of mature BEST4+OTOP2+ absorptive and BEST2+WFDC2+ secretory epithelial enterocytes were associated with the replacement of homeostatic, resident TRDC+KLRD1+HOPX+ {gamma}{delta}+ T cells with RORA+CCL20+S100A4+ TH17 cells and the influx of inflammatory myeloid cells. The EC transcriptome (exemplified by S100A8, HIF1A, TREM1, CXCR1) correlated with clinical, endoscopic, and histological severity of UC in an independent validation cohort (n=649). Furthermore, therapeutic relevance of the observed cellular and transcriptomic changes was investigated in 3 additional published UC cohorts (n=23, 48 and 204 respectively) to reveal that non-response to anti-Tumor Necrosis Factor (anti-TNF) therapy was associated with EC related myeloid cell perturbations. Altogether, these data provide high resolution mapping of the EC to facilitate therapeutic decision-making and personalization of therapy in patients with UC.

immunology↗

bioRxiv2023

Gut-associated lymphoid tissue attrition associates with response to anti-α4β7 therapy in ulcerative colitis

Targeting the 4{beta}7-MAdCAM-1 axis with vedolizumab (VDZ) is a front-line therapeutic paradigm in ulcerative colitis (UC). However, mechanism(s) of action (MOA) of VDZ remain relatively undefined. Here, we examined three distinct cohorts of patients with UC (n=83, n=60, and n=21), to determine the effect of VDZ on the mucosal and peripheral immune system. Transcriptomic studies with protein level validation were used to study drug MOA using conventional and transgenic murine models. We found a significant decrease in colonic and ileal naive B and T cells and circulating gut-homing plasmablasts ({beta}7+) in VDZ-treated patients, pointing to gut-associated lymphoid tissue (GALT) targeting by VDZ. Murine Peyers patches (PP) demonstrated a significant loss cellularity associated with reduction in follicular B cells, including a unique population of epithelium-associated B cells, following anti-4{beta}7 antibody (mAb) administration. Photoconvertible (KikGR) mice unequivocally demonstrated impaired cellular entry into PPs in anti-4{beta}7 mAb treated mice. In VDZ-treated, but not anti-tumor necrosis factor-treated UC patients, lymphoid aggregate size was significantly reduced in treatment responders compared to non-responders, with an independent validation cohort further confirming these data. GALT targeting represents a novel MOA of 4{beta}7-targeted therapies, with major implications for this therapeutic paradigm in UC, and for the development of new therapeutic strategies.

immunology↗

bioRxiv2020

Evolution of Antibody Immunity to SARS-CoV-2

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with development of variable levels of antibodies with neutralizing activity that can protect against infection in animal models. Antibody levels decrease with time, but the nature and quality of the memory B cells that would be called upon to produce antibodies upon re-infection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection. We find that IgM, and IgG anti-SARS-CoV-2 spike protein receptor binding domain (RBD) antibody titers decrease significantly with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by five-fold in pseudotype virus assays. In contrast, the number of RBD-specific memory B cells is unchanged. Memory B cells display clonal turnover after 6.2 months, and the antibodies they express have greater somatic hypermutation, increased potency and resistance to RBD mutations, indicative of continued evolution of the humoral response. Analysis of intestinal biopsies obtained from asymptomatic individuals 4 months after coronavirus disease-2019 (COVID-19) onset, using immunofluorescence, or polymerase chain reaction, revealed persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small bowel of 7 out of 14 volunteers. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence.

immunology↗