Role of Intestinal Barrier Integrity in Modulating the Host Glycome During COVID-19

PROJECT SUMMARY. Hyper-inflammation and complement activation have been implicated in Coronavirusdisease 2019 (COVID-19) pathogenesis and outcomes; however, the pathophysiological mechanismsunderlying these phenomena remain unknown. SARS-CoV2 infects gut cells, and viral infections in the gutcauses changes in gut structure and breakdown of the epithelial barrier, which can increase permeability to gutmicrobes and microbial products. This microbial translocation has a direct impact on systemic inflammation, butit may also indirectly impact it by modulating circulating glycomes. Recently, it has been shown that viral-infections-mediated alterations to glycans, in particular loss of sialic acid and loss of galactose, on circulatingglycoproteins and antibodies (IgG and IgA) mediate and drive inflammation and complement activation. Gutmicrobial translocation is a potential source of glycomic alterations during viral infections. Translocation ofglycan-degrading enzymes (such as sialidase and galactosidases) released by several members of the gutmicrobiome can efficiently alter circulating glycomes, leading to the exacerbation of inflammation. In ourpreliminary data, we found that levels of several gut bacteria genera correlate with plasma IgG glycosylationduring viral infection. We also found that these pro-inflammatory glycans on IgG correlate with both markers ofmicrobial translocation, as well as with markers of systemic inflammation. These data suggest a link betweenmicrobial dysbiosis, microbial translocation, circulating glycomes, and systemic inflammation during viralinfections. However, the role of circulating glycomes in regulating inflammation during COVID-19 has never beeninvestigated. To fill this knowledge gap, we propose to test the hypothesis that SARS-CoV2 impairs intestinalbarrier integrity leading to translocation of microbial products that alter circulating glycomes, whichimpact COVID-19 pathogenesis and outcomes. In Aim 1, we will test the hypothesis that severe COVID-19 isassociated with disrupted intestinal barrier integrity and dysregulated circulating glycomes. 1.a) We will compareplasma markers of mucosal structural integrity, bacterial translocation, and microbial metabolites of 120 COVID-19 patients (with varying disease outcomes); and 120 controls (matched for age, gender, and ethnicity). 1.b) Wewill compare the glycomic profiles of total plasma, plasma IgG, and plasma IgA of the 120 COVID-19 patientsand controls. 1.c) We will test if levels of plasma markers of mucosal structural integrity and bacterialtranslocation associate with the glycosylation of plasma, plasma IgG, and plasma IgA. In Aim 2, we will test thehypothesis that circulating hyposialylated and agalactosylated glycomic signatures are linked to higherinflammation, higher immune activation, and worse clinical outcomes during COVID-19. This supplement canadvance our knowledge of the microbial and glycomic underpinnings of COVID-19, which can serve as 1) novelbiomarkers for disease risk stratification, disease course, and therapeutic response (to be used immediatelyupon validation); and 2) a foundation to develop innovative therapeutics in the future.