1. Sialylation and fucosylation modulate inflammasome-activating eIF2 Signaling and microbial translocation during HIV infection.
- Author
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Giron LB, Tanes CE, Schleimann MH, Engen PA, Mattei LM, Anzurez A, Damra M, Zhang H, Bittinger K, Bushman F, Kossenkov A, Denton PW, Tateno H, Keshavarzian A, Landay AL, and Abdel-Mohsen M
- Subjects
- Antiretroviral Therapy, Highly Active, Biodiversity, Colon, Sigmoid immunology, Colon, Sigmoid metabolism, Colon, Sigmoid microbiology, Dysbiosis, Epitopes, T-Lymphocyte immunology, Glycosylation, HIV Infections drug therapy, HIV Infections immunology, HIV Infections virology, Humans, Immunocompromised Host, Intestinal Mucosa immunology, Intestinal Mucosa metabolism, Intestinal Mucosa microbiology, Intestinal Mucosa pathology, Metagenome, Metagenomics methods, Protein Processing, Post-Translational, Viral Load, Eukaryotic Initiation Factor-2 metabolism, Gastrointestinal Microbiome immunology, HIV Infections metabolism, Inflammasomes metabolism, Signal Transduction
- Abstract
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.
- Published
- 2020
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