Role of Glycosylation
Glycosylation plays a crucial role in the establishment of healthy symbiotic bacterial colonization patterns, the maintenance of mucosal barriers to infection, pathogenic interactions of viruses with the host and regulation of both adaptive and innate immunity.
Our research in this area centers on three main areas:
a) The role of glycans in host-response to pathogens such as influenza and SARS-Cov-2
b) Glycosylation as a marker and critical component of vaginal innate immunity and
c) The role of glycans in exosome and viral biogenesis.
Our laboratory is using systems-biology approaches to explore the role of glycosylation in host response to influenza and SARS-Cov-2. Working with a team headed by Dr. Elodie Ghedin (NIAID) and Dr. Bin Zhang (MSSM), we found that influenza severity is associated with high mannose, a glycan recognized by innate immune lectins. Infection causes this epitope to appear on the cell surface where it may be a critical marker of damage and disease. Our current work in this area is leading to exciting discoveries on the role of glycans in host response with broad implications for antiviral agents. To see a video discussing our latest work click here.
Changes in glycosylation state have powerful effects on antibody function and protein stabilization and can alter microbicidal effects of immune molecules. Thus, the glycome is both a modulator and potential marker of innate immunity. Our laboratory studies the impact of the glycome on innate antiviral immunity in the human reproductive tract. In collaboration with the laboratory of Dr. Sharon Hillier at Magee Women’s Research Institute and the FAME research group we have demostrated that the glycome of cervico-vaginal lavage (CVL) fluids from patients map onto shifts in the microbiome underlying bacterial vaginosis (BV) in ways that may impact innate immunity (4). We extended these studies to examine the impact of microbicide formulations (i.e. in what form a drug is delivered (gel, film, different matrices)) on the glycome and its correlations to innate anti-HIV-1 and herpes simplex virus (HSV) immunity. We are now expanding our work to look further into the glycome-microbiome connection in other systems.
In earlier work, we identified a glycomic signature (via lectin microarray) enriched in high mannose and poly/multi-N-acetyllactosamine (mLacNAc) enriched in both exosomes (small viral-like natural vesicles) and human immunodeficiency virus-1 (HIV-1, Nature Chem. Biol., 2009, highlighted in June 2015 as one of their “Greatest Hits”) (1). We followed up this work by identifying this glycan signature in exosomes from a variety of cell types (2), and have shown that glycans can act as a trafficking motif for select glycoproteins into exosomes (and potentially viruses) (3). We are currently looking at the role that these glycans may play in exosomes and immunity.
- Krishnamoorthy, L.; Bess, J.W.; Preston, A.B.; Nagashima, K.; Mahal, L.K. HIV-1 and microvesicles from T cells share a common glycome, arguing for a common origin, Nature Chem. Biol. 2009 5, 244-250.
- Batista, B.S.; Eng, W.S.; Pilobello, K.T.; Hendricks-Muñoz, K.; Mahal, L.K. Identification of a Conserved Glycan Signature for Microvesicles. J. Proteome Res. 2011, 10, 4624-33.
- Liang, Y.; Eng, W.S.; Colquhoun, D.R.; Dinglasan, R.R.; Graham, D.R.; Mahal, L.K. Complex N-linked Glycans Serve as a Determinant for Exosome/Microvesicle Cargo Recruitment. J. Biol. Chem., 2014, 289, 32526-37. doi: 10.1074/jbc.M114.606269
- Wang, L.; Koppolu, S.; Chappell, C.; Moncla, B.J.; Hillier, S.L.; Mahal, L.K. Studying the effects of reproductive hormones and bacterial vaginosis on the glycome of lavage samples from the cervicovaginal cavity. PLoS One, 2015, 10, e0127021. doi: 10.1371/journal.pone.0127021.