MICROBIAL GLYCOLIPID DIRECTS HOST BOTH TOLEROGENIC AND ANTI-VIRAL RESPONSES
Hyoung-Soo Cho, Xinyang Song, Alos Diallo, Ji-Sun Yoo, Sungwhan F. Oh, Stefanie Schmieder, Wayne I. Lencer, and Dennis L. Kasper
Commensal microbes in the intestine continuously shape the immune system by producing a wide range of microbial products that have immunomodulatory capabilities. Outer membrane glycolipids of gram-negative bacteria play a pivotal role in host-microbe interaction. However, the compositional complexity and molecular diversity of these lipids preclude a precise investigation of structure-activity relationship. Bacteroidetes phylum occupies up to 60% of normal human gut microbiota and these organisms possess an outer membrane consisting of lipid A-containing glycolipids. Our detailed lipidomic analysis of human gut symbiont B. fragilis outer membrane glycolipids revealed a set of lipid A species that are uniquely variable in the number of acyl chains and the degree of phosphorylation. Of interest, this lipidomic profile of B. fragilis is markedly different from that found in Escherichia coli which is uniformly comprised of hexa-acylated (6A-) and diphosphorylated lipid A (DPLA) species. This variability in the structure of the B. fragilis lipid A led us to examine the immunomodulatory function of these structurally distinct molecules across various human symbiotic microbes.
To better examine immunological implications of variability in structure of lipid A molecules, we took advantage of chemically synthesized lipid A analogs that are structural analogs of lipid A found in various commensal microbes. We observed that variations in molecular structure of lipid A impacts on their binding affinity to the TLR4-MD2 complex. Comprehensive transcriptomic analysis of DCs treated with various synthetic lipid A analogs reveals that the expression of IFN-stimulated genes (ISG) is markedly increased in response to the stimulation with some of these analogs. We found that some analogs have a molecular propensity to be more efficiently endocytosed and preferentially recognized by endosomal compared to DC cell surfaceTLR4. Importantly, we also found that some analogs modulated DCs to express a set of genes and coinhibitory molecules associated with tolerogenic DCs. One analog treatment to a DC-T cell co-culture effectively impaired antigen-induced T cell proliferation and also significantly inhibited TH17 differentiation in vitro. Consistent with these in vitro observations, the oral administration of this analog markedly mitigated colonic inflammation in DSS-induced colitis in mice. Consistent with their elevated ISG signature, DCs treated with the analog are more resistant to influenza A infection. Our study provides critical molecular insights towards directing the immunomodulatory activity of commensal glycolipids to the design of new therapeutics. These gut derived glycolipids have the potential to alleviate inflammatory bowel disease, as well as boost cell-autonomous viral resistance against viral infection.
BTIP Agenda
- In-person convening and light dinner: 5:30 – 5:45pm Eastern Time (US and Canada)
- Zoom presentation: 5:45 – 6:45pm Eastern Time (US and Canada)
- In-person networking: 6:45 – 7:00pm Eastern Time (US and Canada)
Contact
For more information about BTIP or to request an invitation, please contact Ifat Rubin-Bejerano, Senior Director of Translational Research.