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1.
JCI Insight ; 7(15)2022 Aug 08.
Article in English | MEDLINE | ID: covidwho-1902172

ABSTRACT

Long COVID, a type of post-acute sequelae of SARS-CoV-2 (PASC), has been associated with sustained elevated levels of immune activation and inflammation. However, the mechanisms that drive this inflammation remain unknown. Inflammation during acute coronavirus disease 2019 could be exacerbated by microbial translocation (from the gut and/or lung) to blood. Whether microbial translocation contributes to inflammation during PASC is unknown. We did not observe a significant elevation in plasma markers of bacterial translocation during PASC. However, we observed higher levels of fungal translocation - measured as ß-glucan, a fungal cell wall polysaccharide - in the plasma of individuals experiencing PASC compared with those without PASC or SARS-CoV-2-negative controls. The higher ß-glucan correlated with higher inflammation and elevated levels of host metabolites involved in activating N-methyl-d-aspartate receptors (such as metabolites within the tryptophan catabolism pathway) with established neurotoxic properties. Mechanistically, ß-glucan can directly induce inflammation by binding to myeloid cells (via Dectin-1) and activating Syk/NF-κB signaling. Using a Dectin-1/NF-κB reporter model, we found that plasma from individuals experiencing PASC induced higher NF-κB signaling compared with plasma from negative controls. This higher NF-κB signaling was abrogated by piceatannol (Syk inhibitor). These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC.


Subject(s)
COVID-19 , beta-Glucans , COVID-19/complications , Humans , Inflammation , Lectins, C-Type/metabolism , NF-kappa B/metabolism , SARS-CoV-2 , Syk Kinase
2.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-332871

ABSTRACT

Long COVID, a type of Post-Acute Sequelae of SARS CoV-2 infection (PASC), has been associated with sustained elevated levels of immune activation and inflammation. However, the pathophysiological mechanisms that drive this inflammation remain unknown. Inflammation during acute Coronavirus Disease 2019 (COVID-19) could be exacerbated by microbial translocation (from the gut and/or lung) to the blood. Whether microbial translocation contributes to inflammation during PASC is unknown. We found higher levels of fungal translocation - measured as beta-glucan, a fungal cell wall polysaccharide - in the plasma of individuals experiencing PASC compared to those without PASC or SARS-CoV-2 negative controls. The higher beta-glucan correlated with higher levels of markers of inflammation and elevated levels of host metabolites involved in activating N-Methyl-D-aspartate receptors (such as metabolites within the tryptophan catabolism pathway) with established neuro-toxic properties. Mechanistically, beta-glucan can directly induce inflammation by binding to myeloid cells (via the Dectin-1 receptor) and activating Syk/NF-kB signaling. Using an in vitro Dectin-1/NF-kB reporter model, we found that plasma from individuals experiencing PASC induced higher NF-kB signaling compared to plasma from SARS-CoV-2 negative controls. This higher NF-kB signaling was abrogated by the Syk inhibitor Piceatannol. These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC.

3.
Front Cell Dev Biol ; 10: 807149, 2022.
Article in English | MEDLINE | ID: covidwho-1714988

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a highly contagious virus of the coronavirus family that causes coronavirus disease-19 (COVID-19) in humans and a number of animal species. COVID-19 has rapidly propagated in the world in the past 2 years, causing a global pandemic. Here, we performed proteomic analysis of plasma samples from COVID-19 patients compared to healthy control donors in an exploratory study to gain insights into protein-level changes in the patients caused by SARS-CoV-2 infection and to identify potential proteomic and posttranslational signatures of this disease. Our results suggest a global change in protein processing and regulation that occurs in response to SARS-CoV-2, and the existence of a posttranslational COVID-19 signature that includes an elevation in threonine phosphorylation, a change in glycosylation, and a decrease in arginylation, an emerging posttranslational modification not previously implicated in infectious disease. This study provides a resource for COVID-19 researchers and, longer term, and will inform our understanding of this disease and its treatment.

6.
EMBO Mol Med ; 13(8): e13901, 2021 08 09.
Article in English | MEDLINE | ID: covidwho-1346766

ABSTRACT

HIV-1 infects lymphoid and myeloid cells, which can harbor a latent proviral reservoir responsible for maintaining lifelong infection. Glycolytic metabolism has been identified as a determinant of susceptibility to HIV-1 infection, but its role in the development and maintenance of HIV-1 latency has not been elucidated. By combining transcriptomic, proteomic, and metabolomic analyses, we here show that transition to latent HIV-1 infection downregulates glycolysis, while viral reactivation by conventional stimuli reverts this effect. Decreased glycolytic output in latently infected cells is associated with downregulation of NAD+ /NADH. Consequently, infected cells rely on the parallel pentose phosphate pathway and its main product, NADPH, fueling antioxidant pathways maintaining HIV-1 latency. Of note, blocking NADPH downstream effectors, thioredoxin and glutathione, favors HIV-1 reactivation from latency in lymphoid and myeloid cellular models. This provides a "shock and kill effect" decreasing proviral DNA in cells from people living with HIV/AIDS. Overall, our data show that downmodulation of glycolysis is a metabolic signature of HIV-1 latency that can be exploited to target latently infected cells with eradication strategies.


Subject(s)
HIV Infections , HIV-1 , CD4-Positive T-Lymphocytes , Down-Regulation , Glycolysis , Humans , Oxidative Stress , Proteomics , Virus Activation , Virus Latency
7.
Front Immunol ; 12: 686240, 2021.
Article in English | MEDLINE | ID: covidwho-1285294

ABSTRACT

A disruption of the crosstalk between the gut and the lung has been implicated as a driver of severity during respiratory-related diseases. Lung injury causes systemic inflammation, which disrupts gut barrier integrity, increasing the permeability to gut microbes and their products. This exacerbates inflammation, resulting in positive feedback. We aimed to test whether severe Coronavirus disease 2019 (COVID-19) is associated with markers of disrupted gut permeability. We applied a multi-omic systems biology approach to analyze plasma samples from COVID-19 patients with varying disease severity and SARS-CoV-2 negative controls. We investigated the potential links between plasma markers of gut barrier integrity, microbial translocation, systemic inflammation, metabolome, lipidome, and glycome, and COVID-19 severity. We found that severe COVID-19 is associated with high levels of markers of tight junction permeability and translocation of bacterial and fungal products into the blood. These markers of disrupted intestinal barrier integrity and microbial translocation correlate strongly with higher levels of markers of systemic inflammation and immune activation, lower levels of markers of intestinal function, disrupted plasma metabolome and glycome, and higher mortality rate. Our study highlights an underappreciated factor with significant clinical implications, disruption in gut functions, as a potential force that may contribute to COVID-19 severity.


Subject(s)
COVID-19/immunology , Gastrointestinal Microbiome/immunology , Inflammation/immunology , Intestines/physiology , SARS-CoV-2/physiology , Female , Glycomics , Haptoglobins/metabolism , Humans , Lipidomics , Male , Metabolomics , Middle Aged , Permeability , Protein Precursors/metabolism , Tight Junctions/metabolism
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