Lab In The News
Wistar Scientists Discover Sugar Molecule on HIV-infected Cell Plays Role in Evading Immune System — They Exploit as Weakness to Make More Effective “Natural Killers” Against HIVA new study by researchers at The Wistar Institute, an international biomedical research leader in cancer, immunology, infectious disease, and vaccine development, shows how key features on the surface of HIV-infected cells help the disease evade detection by the immune system. It also shows how...
The Wistar Institute Is Pleased to Announce the Promotion of Dr. Rahul Shinde to Assistant Professor, and the Promotions of Drs. Mohamed Abdel-Mohsen and Alessandro Gardini to Associate Professor
Wistar is honored these talented and accomplished scientists commit each day in their lab to bringing new and creative insights to cancer, immunology, and infectious disease research.
Looking Inside the Gut for Answers to Long-COVID
This Q&A offers a behind the science peek into some of the long-term effects of COVID on the body influenced by the gut microbiome. In a paper published in JCI Insight, Mohamed Abdel-Mohsen, Ph.D., associate professor in The Wistar Institute Vaccine & Immunotherapy Center, and collaborators from...
The Abdel-Mohsen Laboratory
Recent advances in the emerging field of glycoimmunology show that the human glycome is not just a biomarker of biological functions but also plays critical roles in driving or modulating immune responses, and in cell-cell and cell-pathogen interactions. The new knowledge from glycoscience may allow us to leverage advances in the human genome and proteome to realize the goals of personalized medicine.
Our recent discoveries and publications have shown that host glycosylation—a previously unappreciated factor—impacts chronic inflammation and viral persistence during HIV infection. These studies set the stage for broader-scale studies to understand the upstream mechanisms and downstream consequences of our observations and to design novel strategies to manipulate glycosylation to reduce viral persistence and/or prevent or delay the development of viral-associated co-morbidities.
This research has the potential to expand the boundaries of current knowledge about the link between infections, chronic inflammation, and the development of chronic diseases, and will be important not just for HIV, but for other diseases involving inflammation, autoimmune disorders, cancer, and pathogen infections.
Leila Giron, Ph.D.
Samson Adeniji, Ph.D.
Pratima Saini, Ph.D.
Shalini Singh, Ph.D.
Kai Ying Hong (Ferlina)
Glycoimmunology is an emerging field focused on understanding how immune responses are mediated by glycans (carbohydrates) and their interaction with glycan-binding proteins called lectins. How glycans influence immunological functions is increasingly well understood. In parallel, research in the HIV field is unveiling how the host immune system controls HIV persistence and immunopathogenesis. However, the role played by the host glycosylation machinery in modulating the persistence and immunopathogenesis of HIV has mostly been overlooked despite its potential for therapeutic applications.
Our laboratory is using several advanced glycomic technologies to investigate the role of the host glycosylation machinery in regulating molecular mechanisms central to HIV infection. We aim to create a new paradigm for discovering novel biomarkers of viral/host interactions and/or glycan-based interactions that can be therapeutically targeted to cure HIV and/or enhance the quality of life for people living with it. We believe that our research has the potential to expand the boundaries of current knowledge about the link between infections, chronic inflammation and the development of chronic diseases. This information will be important not just for HIV, but for other diseases involving inflammation, autoimmune disorders, cancer, and pathogen infections.
Below, we illustrate four areas in which the links between glycan-lectin interactions and immunology, and between immunology and HIV are described. Our laboratory is investigating the links between glycoimmunology and HIV persistence/immunopathogenesis within these areas.
Chronic inflammation has been associated with aberrant IgG glycosylation patterns and is prevalent in HIV+ individuals despite antiretroviral therapy (ART). Sialylated and galactosylated glycans have been associated with anti-inflammatory responses while bisected N-acetylglucosamine (GlcNAc) has been associated with pro-inflammatory responses. HIV infection causes pro-inflammatory changes, e.g., ART-irreversible loss of sialic acid and ART-reversible loss of galactose. Whether the HIV-induced changes in the circulating glycome are linked to chronic inflammation and HIV-associated co-morbidities (such as cardiovascular diseases and neurological impairments) is not clear. Asn = Asparagine.
Antibody-mediated effector functions are significantly affected by changes in IgG glycosylation and are important for preventing and controlling HIV infection. The presence of core fucose reduces antibody-dependent cellular cytotoxicity (ADCC), and the presence of galactose induces ADCC, antibody-dependent cellular phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC). The size of the HIV reservoir, measured using nucleic acid-based methods (CD4+ T cell-associated HIV DNA and RNA), negatively associates with levels of non-fucosylated galactosylated glycans during suppressive ART. However, it is not clear if the documented roles of non-fucosylated galactosylated glycans in promoting ADCC and ADCP impact viral control during ART. C1q = Complement component 1q.
The potential role of the gut glycome in regulating the homeostatic relationship between the host and its gut microbiota during HIV infection. The potential role of the gut glycome in regulating the homeostatic relationship between the host and its gut microbiota, during HIV infection. The degree of glycosylation in the gut directly impacts the ability to maintain functional and healthy intestines. Here we give one example, by illustrating the role of gut fucosylation in the host-microbe interplay. Fucosylated glycans in the gut (left) enhance the beneficial activity of symbionts and improve resistance against colonization by pathogens and pathobionts. In the absence of gut fucosylation (right), beneficial symbionts are weakened and decreased in abundance, and pathogenic bacteria increase, which leads to microbial translocation, inflammation, and breakdown of the epithelial barrier. Fucosylated glycans are only one group out of many glycan structures composing the gut glycome. A change in the gut glycome may alter the distribution of microbial species. Therefore, it is possible that alterations in glycan metabolism may contribute to HIV-mediated intestinal damage, microbial translocation, and chronic inflammation.
Cell-surface glycan-lectin interactions mediate signals that define cellular processes and immunological functions, many of which are central to HIV infection. The specific structure of a glycan allows it to bind to specific glycan-binding proteins called lectins, leading to activation of downstream signaling pathways. These pathways are critical for a variety of cellular processes and immunological functions:
- T cells. Galectin-1 induces T cell apoptosis. Galectin-9 induces T-cell receptor (TCR) signaling, while galectin-3 reduces it. Galectin-3 alters T-cell function through interaction with LAG3 and other immune negative checkpoints. Last, the fucosylation of PD-1 impacts its function.
- NK cells. Siglecs-7 and -9 inhibit NK activity. Galectin-9 impairs NK function/cytotoxicity and cytokine production. Galectin-3 antagonizes NK cell-mediated antitumor immunity
- B cells. Siglec-6 induces B-cell exhaustion. Galectin-1 is a pre-B cell receptor ligand that induces receptor clustering, leading to efficient B cell differentiation. Galectin-9 suppresses B-cell receptor (BCR) signaling.
- T-regs. Galectins-1 and -9 can expand T-regs.
- Myeloid-derived suppressive cells (MDSC). The galectin-9/Tim3 interaction drives the expansion of CD11b+ly6G+ MDSC. Granulocytic MDSCs induce γδ-T cells to produce galectin-1, thus transforming them into immunosuppressive cells. These glycan-lectin interactions represent potential novel targets to enhance immune functionality during HIV infection to either cure HIV or prevent HIV-associated immune dysfunction and the subsequent development of immune dysfunction-associated diseases.
Adeniji, O.S., Kuri-Cervantes, L., Yu, C., Xu, Z., Ho, M., Chew, G.M., Shikuma, C., Tomescu, C., George, A.F., Roan, N.R., et al. “Siglec-9 Defines and Restrains a Natural Killer Subpopulation Highly Cytotoxic to HIV-infected Cells.” PLoS Pathog. 2021 Nov 11;17(11):e1010034. doi: 10.1371/journal.ppat.1010034. eCollection 2021 Nov.
Giron, L.B., Palmer, C.S., Liu, Q., Yin, X., Papasavvas, E., Sharaf, R., Etemad, B., Damra, M., Goldman, A.R., Tang, H., et al. “Non-invasive Plasma Glycomic and Metabolic Biomarkers of Post-treatment Control of HIV.” Nat Commun. 2021 Jun 29;12(1):3922. doi: 10.1038/s41467-021-24077-w.
Abdel-Mohsen, M., Richman, D., Siliciano, R.F., Nussenzweig, M.C., Howell, B.J., Martinez-Picado, J., Chomont, N., Bar, K.J., Yu, X.G., Lichterfeld, M., et al. “Recommendations for Measuring HIV Reservoir Size in Cure-directed Clinical Trials.” Nat Med. 2020 Sep;26(9):1339-1350. doi: 10.1038/s41591-020-1022-1.
Colomb, F., Giron, L.B., Kuri-Cervantes, L., Adeniji, O.S., Ma, T., Dweep, H., Battivelli, E., Verdin, E., Palmer, C.S., Tateno, H., Kossenkov, A.V., Roan, N.R., Betts, M.R., Abdel-Mohsen, M. “Sialyl-Lewis X Glycoantigen Is Enriched on Cells with Persistent HIV Transcription during Therapy.” Cell Rep. 2020 Aug 4;32(5):107991. doi: 10.1016/j.celrep.2020.107991.
Giron, L.B., Tanes, C.E., Schleimann, M.H., Engen, P.A., Mattei, L.M., Anzurez, A., Damra, M., Zhang, H., Bittinger, K., Bushman, F., et al. “Sialylation and fucosylation modulate inflammasome-activating eIF2 Signaling and microbial translocation during HIV infection.” Mucosal Immunol. 2020 Mar 9. doi: 10.1038/s41385-020-0279-5.