Sialylation and fucosylation modulate inflammasome-activating eIF2 Signaling and microbial translocation during HIV infection

• DOI: 10.1038/s41385-020-0279-5
• Publication Date: 2020-03-09T18:03:41Z
• Authors: Leila B. Giron; Ceylan E. Tanes; Mariane H. Schlei...; Phillip A. Engen; Lisa M. Mattei; Alitzel Anzurez; Mohammad Damra; Huanjia Zhang; Kyle Bittinger; Frederic Bushman; Andrew Kossenkov; Paul W. Denton; Hiroaki Tateno; Ali Keshavarzian; Alan L. Landay; Mohamed Abdel-Mohsen
• Keywords: 0301 basic medicine; Glycosylation; Inflammasomes; Eukaryotic Initiation Factor-2; Epitopes, T-Lymphocyte; HIV Infections; Article; Immunocompromised Host; 03 medical and health sciences; INTESTINAL MICROBIOTA; Colon, Sigmoid; Antiretroviral Therapy, Highly Active; COMMENSAL BACTERIA; Humans; Intestinal Mucosa; NON-SECRETOR STATUS; BACTEROIDES-VULGATUS; GUT MICROBIOTA; PERSISTENCE; Biodiversity; NEURAMINIDASE; Viral Load; Gastrointestinal Microbiome; 3. Good health; ULCERATIVE-COLITIS; CELL-ACTIVATION; SYSTEMIC IMMUNE ACTIVATION; Dysbiosis; Metagenome; Metagenomics; Protein Processing, Post-Translational; Signal Transduction

An emerging paradigm suggests that gut glycosylation is a key force in maintaining the homeostatic relationship between the gut and its microbiota. Nevertheless, it is unclear how gut glycosylation contributes to the HIV-associated microbial translocation and inflammation that persist despite viral suppression and contribute to the development of several comorbidities. We examined terminal ileum, right colon, and sigmoid colon biopsies from HIV-infected virally-suppressed individuals and found that gut glycomic patterns are associated with distinct microbial compositions and differential levels of chronic inflammation and HIV persistence. In particular, high levels of the pro-inflammatory hypo-sialylated T-antigen glycans and low levels of the anti-inflammatory fucosylated glycans were associated with higher abundance of glycan-degrading microbial species (in particular, Bacteroides vulgatus), a less diverse microbiome, higher levels of inflammation, and higher levels of ileum-associated HIV DNA. These findings are linked to the activation of the inflammasome-mediating eIF2 signaling pathway. Our study thus provides the first proof-of-concept evidence that a previously unappreciated factor, gut glycosylation, is a force that may impact the vicious cycle between HIV infection, microbial translocation, and chronic inflammation.