Highlights People living with HIV do not achieve an optional immune reconstitution despite the sustained virologic suppression. Circulating CD4 T cells fail to replenish their lymphoid tissue counterparts in people living with HIV. Irrespective of ART, coffin hyperactivation and impaired T cell mobility persist in people living with HIV. Cofilin may represent a novel therapeutic target to restore T cell mobility in people living with HIV.
Systemic vascular injury occurs in COVID-19 patients, yet the underlying mechanisms remain unknown. To clarify the role of inflammatory factors in COVID-19 vascular injury, we used a multiplex immunoassay to profile 65 inflammatory cytokines/chemokines/growth factors in plasma samples from 24 hospitalized (severe/critical) COVID-19 patients, 14 mild/moderate cases, and 13 healthy controls (HCs). COVID-19 patients had significantly higher plasma levels of 20 analytes than HCs. Surprisingly, only one cytokine (MIF) was among these altered analytes, while the rest were chemokines/growth factors. Additionally, only MMP-1 and VEGF-A were significantly elevated in hospitalized COVID-19 patients when compared to mild/moderate cases. We further studied MMP-1 enzymatic activity and multiple endothelial cell (EC) activation markers (soluble forms of CD146, ICAM-1, and VCAM-1) and found that they were highly dysregulated in COVID-19 patients. Thus, COVID-19 patients have a unique inflammatory profile, and excessive MMP-1 and hyperactivation of ECs are associated with the severity of COVID-19.
This study aimed to comprehensively analyze inflammatory and autoimmune characteristics of patients with sickle cell disease (SCD) at a steady-state condition (StSt) compared to healthy controls (HCs) to explore the pathogenesis of StSt and its impact on patients’ well-being. The study cohort consisted of 40 StSt participants and 23 HCs enrolled between July 2021 and April 2023. StSt participants showed elevated white blood cell (WBC) counts and altered hematological measurements when compared to HCs. A multiplex immunoassay was used to profile 80 inflammatory cytokines/chemokines/growth factors in plasma samples from these SCD participants and HCs. Significantly higher plasma levels of 35 analytes were observed in SCD participants, with HGF, IL-18, IP-10, and MCP-2 being among the most significantly affected analytes. Additionally, autoantibody profiles were also altered, with elevated levels of anti-SSA/Ro60, anti-Ribosomal P, anti-Myeloperoxidase (MPO), and anti-PM/Scl-100 observed in SCD participants. Flow cytometric analysis revealed higher rates of red blood cell (RBC)/reticulocyte-leukocyte aggregation in SCD participants, predominantly involving monocytes. Notably, correlation analysis identified associations between inflammatory mediator levels, autoantibodies, RBC/reticulocyte-leukocyte aggregation, clinical lab test results, and pain crisis/sensitivity, shedding light on the intricate interactions between these factors. The findings underscore the potential significance of specific biomarkers and therapeutic targets that may hold promise for future investigations and clinical interventions tailored to the unique challenges posed by SCD. In addition, the correlations between vaso-occlusive crisis (VOC)/pain/sensory sensitivity and inflammation/immune dysregulation offer valuable insights into the pathogenesis of SCD and may lead to more targeted and effective therapeutic strategies. Clinical Trial Registration ClinicalTrials.gov , Identifier: NCT05045820.
Abstract CD4 T cells are the primary targets for HIV-1 infection and their loss is a hallmark of HIV-1 disease. However, T follicular helper (Tfh) cells, a distinct subset of CD4 T cells that are specialized in helping B cells form germinal centers (GCs) for the generation of high-affinity class-switched antibodies, undergo expansion in people living with HIV-1 (PLHIV). Indeed, Tfh cells with latent HIV-1 are enriched in PLHIV, whether the PLHIV are on antiretroviral therapy (ART) or not. This shows that Tfh cells are preferentially infected by HIV-1 and are able to survive infection. Through total RNAseq of tonsillar subsets of T cells, including Tfh cells, our lab was able to find a sharp upregulation of an inhibitor of apoptosis family member gene (BIRC5) and a distinct metabolic gene profile in Tfhs compared to the other subsets. We further were able to find and confirm that (1) BIRC5 was highly expressed in human tonsil Tfh cells and the expression was upregulated upon HIV-1 infection, (2) human tonsil Tfh cells had high levels of Fatty Acid Oxidation related genes, but low levels of glycolytic genes, when compared with non-Tfh CD4 T cells, and (3) inhibition of FaO and BIRC5 led to changes in the survival of Tfh cells following HIV-1 infection. Our results show that Tfh survival of HIV-1 is associated with both the metabolic profile and expression of BIRC5 due to their ability to inhibit virus-induced direct and bystander apoptosis. Supported by grants from the NIH T32: Immunology and Infectious Disease Training Program
Abstract Enteroviruses initiate infection in the gastrointestinal tract, and sex is often a biological variable that impacts pathogenesis. Previous data suggest that sex hormones can influence intestinal replication of Coxsackievirus B3 (CVB3), an enterovirus in the Picornaviridae family. However, the specific sex hormone(s) that regulate intestinal CVB3 replication is poorly understood. To determine if testosterone promotes intestinal CVB3 replication, we orally inoculated male and female Ifnar -/- mice that were treated with either placebo or testosterone-filled capsules. Following oral inoculation, we found that testosterone-treated male and female mice shed significantly more CVB3 in the feces than placebo-treated mice indicating that testosterone enhances intestinal replication. Similarly, testosterone enhanced viral dissemination in both sexes as we observed higher viral loads in peripheral tissues following infection. Further, male mice treated with testosterone also had a higher mortality rate than testosterone-depleted male mice. Finally, we observed that testosterone significantly affected the immune response to CVB3. We found that testosterone broadly increased pro-inflammatory cytokines and chemokines while decreasing the number of splenic B cells and dendritic cells following CVB3 infection. Moreover, while testosterone did not affect the early CD4 T cell response to CVB3, testosterone reduced the activation of CD8 T cells. These data indicate that testosterone can promote intestinal CVB3 replication and dissemination while impacting the subsequent viral immune response. Importance Biological sex plays a significant role in the outcome of various infections and diseases. The impact of sex hormones on intestinal replication and dissemination of Coxsackievirus B3 remains poorly understood. Using an oral inoculation model, we found that testosterone enhances CVB3 shedding and dissemination in male and female mice. Further, testosterone can alter the immune response to CVB3. This work highlights the role of testosterone in CVB3 pathogenesis and suggests that sex hormones can impact the replication and dissemination of enteric viruses.
Background and objectives: Depression is a low mood-based disorder that affects approximately one in six people in the UK. Analyses of the gut in depressed individuals have demonstrated dysbiosis in the normal gut microbial composition. These imbalances have been associated with gut symptoms such as abdominal pain and nausea. This study aims to investigate the relationships between self-reported depression, gastro-intestinal (GI) symptoms and dietary intake. Methods: Participants with self-reported depression and healthy controls were recruited via Prolific. Participants were asked to complete a web-based online survey tool (Qualtrics), which included questions on diet, gut health and mental health. Estimated micronutrient intakes from reported fruit and vegetable intakes (FAVI) were calculated using dietary analysis software (myFood24). Results: In total, 496 adults consented to participate (n = 249 with self-reported life-time diagnosis of depression, n = 247 healthy controls). There was a significant positive correlation between the GI symptom score and the depression score (r = 0.506, p < 0.001) which included reported measures of nausea (r = 0.359) and pain (r = 0.419). FAVI and omega-3 intakes were inversely related to GI symptoms (p = 0.010, p < 0.001, respectively) and depression scores (p < 0.05) and significant mediators of the association between GI symptoms and depression (effect size −0.006, −0.025 respectively). Those with depression were found to have significantly lower intakes of vitamin C, folate, vitamin E and magnesium (p < 0.05), though analysis did not identify any significant mediation effects of micronutrient intake on the relationship between GI symptoms and depression scores. Discussion: Dietary intake has a significant mediation effect on the relationship between GI symptoms and depression. Participants in the depression group consumed significantly lower intakes of some important micronutrients found in FAVI, which suggests that depression and gut symptoms could influence food choices. Further research will be required to identify whether these observations correspond to the changes in the microbiome that have been associated with depression.
Abstract Immune checkpoints (ICPs) consist of paired receptor-ligand molecules that exert inhibitory or stimulatory effects on immune defense, surveillance, regulation, and self-tolerance. ICPs exist in both membrane and soluble forms in vivo and in vitro . Imbalances between inhibitory and stimulatory membrane-bound ICPs (mICPs) in malignant cells and immune cells in the tumor immune microenvironment (TIME) have been well documented. Blockades of inhibitory mICPs have emerged as an immense breakthrough in cancer therapeutics. However, the origin, structure, production regulation, and biological significance of soluble ICPs (sICPs) in health and disease largely remains elusive. Soluble ICPs can be generated through either alternative mRNA splicing and secretion or protease-mediated shedding from mICPs. Since sICPs are found in the bloodstream, they likely form a circulating immune regulatory system. In fact, there is increasing evidence that sICPs exhibit biological functions including (1) regulation of antibacterial immunity, (2) interaction with their mICP compartments to positively or negatively regulate immune responses, and (3) competition with their mICP compartments for binding to the ICP blocking antibodies, thereby reducing the efficacy of ICP blockade therapies. Here, we summarize current data of sICPs in cancer and infectious diseases. We particularly focus on sICPs in COVID-19 and HIV infection as they are the two ongoing global pandemics and have created the world’s most serious public health challenges. A “storm” of sICPs occurs in the peripheral circulation of COVID-19 patients and is associated with the severity of COVID-19. Similarly, sICPs are highly dysregulated in people living with HIV (PLHIV) and some sICPs remain dysregulated in PLHIV on antiretroviral therapy (ART), indicating these sICPs may serve as biomarkers of incomplete immune reconstitution in PLHIV on ART. We reveal that HIV infection in the setting of alcohol abuse exacerbates sICP dysregulation as PLHIV with heavy alcohol consumption have significantly elevated plasma levels of many sICPs. Thus, both stimulatory and inhibitory sICPs are present in the bloodstream of healthy people and their balance can be disrupted under pathophysiological conditions such as cancer, COVID-19, HIV infection, and alcohol abuse. There is an urgent need to study the role of sICPs in immune regulation in health and disease.
Systemic vascular injury occurs in coronavirus disease 2019 (COVID-19) patients; however, the underlying mechanisms remain unknown. To clarify the role of inflammatory factors in COVID-19 vascular injury, we used a multiplex immunoassay to profile 65 inflammatory cytokines/chemokines/growth factors in plasma samples from 24 hospitalized (severe/critical) COVID-19 patients, 14 mild/moderate cases, and 13 healthy controls (HCs). COVID-19 patients had significantly higher plasma levels of 20 analytes than HCs. Surprisingly, only 1 cytokine, macrophage migration inhibitory factor (MIF), was among these altered analytes, while the rest were chemokines/growth factors. Additionally, only matrix metalloproteinase-1 (MMP-1) and vascular endothelial growth factor A (VEGF-A) were significantly elevated in hospitalized COVID-19 patients when compared to mild/moderate cases. We further studied MMP-1 enzymatic activity and multiple endothelial cell (EC) activation markers (soluble forms of CD146, intercellular adhesion molecule 1 [ICAM-1], and vascular cell adhesion molecule 1 [VCAM-1]) and found that they were highly dysregulated in COVID-19 patients. COVID-19 patients have a unique inflammatory profile, and excessive MMP-1 and hyperactivation of ECs are associated with the severity of COVID-19.
Abstract HIV-1 predominantly infects and depletes CD4 T cell populations. Multiple subsets of CD4 T cells exist, one of which is the follicular helper T (Tfh) subset. This subset is primarily present in lymphoid tissues, such as tonsil tissue, where it is specialized in helping B cells form germinal centers (GCs) for generation of high-affinity class-switched antibodies. Tfh cells in HIV-1 patients are expanded and become a major active and latent HIV-1 reservoir. To explore whether Tfh cells have a unique metabolic program that is responsible for Tfh cell expansion and survival under HIV-1 infection, we used flow cytometric analysis to sort GC Tfh (CD3+CD4+PD-1highCXCR5high) versus non-Tfh (CD3+CD4+PD-1−CXCR5−) cells from tonsil mononuclear cells for RNA sequencing (RNAseq). We found that Tfh cells express significantly lower levels of glycolytic genes, but higher levels of gluconeogenic and fatty acid oxidation genes. Inhibition of glycolysis via a lack of glucose in culture medium aided in the differentiation of Tfh cells from naive CD4 T cells and promoted Tfh cell survival against HIV-1 infection. Furthermore, use of chemical inhibition of alternative metabolic pathways effected the response of T cell subsets to HIV-1 infection. Our studies into metabolism in Tfh cells suggest a relationship between their unique metabolic phenotype and HIV-1 infection, replication and latency.
Heavy alcohol consumption disrupts gut epithelial integrity, leading to increased permeability of the gastrointestinal tract and subsequent translocation of microbes. Regenerating islet-derived protein 3α (REG3α) and Trefoil factor 3 (TFF3) are mainly secreted to the gut lumen by Paneth and Goblet cells, respectively, and are functionally linked to gut barrier integrity. Circulating levels of REG3α and TFF3 have been identified as biomarkers for gut damage in several human diseases. We examined whether plasma levels of REG3α and TFF3 were dysregulated and correlated with conventional markers of microbial translocation (MT) and pro-inflammatory mediators in heavy drinkers with and without alcoholic hepatitis (AH).Cross-sectional and longitudinal studies were performed to monitor plasma levels of REG3α and TFF3 in 79 AH patients, 66 heavy drinkers without liver disease (HDC), and 46 healthy controls (HC) at enrollment and at 6- and 12-month follow-ups. Spearman correlation was used to measure the relationships of REG3α and TFF3 levels with MT, disease severity, inflammation, and effects of abstinence from alcohol.At enrollment, AH patients had significantly higher levels of REG3α and TFF3 than HDC and HC. The elevated REG3α levels were positively correlated with the 30-day fatality rate. Plasma levels of REG3α and TFF3 in AH patients differentially correlated with conventional MT markers (sCD14, sCD163, and LBP) and several highly up-regulated inflammatory cytokines/chemokines/growth factors. At follow-ups, although REG3α and TFF3 levels were decreased in AH patients with alcohol abstinence, they did not fully return to baseline levels.Circulating levels of REG3α and TFF3 were highly elevated in AH patients and differentially correlated with AH disease severity, MT, and inflammation, thereby serving as potential biomarkers of MT and gut epithelial damage in AH patients.
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