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 glycosylation in viral and exosome biogenesis,  b) Glycosylation as a marker and critical component of vaginal innate immunity and c) the role of glycans in host response to pathogens.

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 in the process of identifying the mechanism underlying this motif and ascertaining whether the same mechanism may impact host protein incorporation into  enveloped viruses, potentially providing an opportunity to control these events and thus pathogenesis and viral tropism.

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). Our most recent  work extends 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. These unique studies are uncovering new potential roles for glycosylation in antiviral immunity with implications for product development.

Currently our laboratory is using systems-biology approaches to explore the role of glycosylation in host response to influenza as part of the FluDyNeMo team headed by Dr. Elodie Ghedin (NYU) and Dr. Bin Zhang (MSSM). Although it is well known that sialic acid is the host receptor for influenza, very little is known about how or whether glycosylation changes in the host upon infection with influenza and how that might impact severity of disease within the host. 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.

In collaboration with Dr. Photini Sinnis (Johns Hopkins) we are also examining the role of glycosylation in host interactions of malaria.  In recent work, her laboratory identified glycosylation of proteins in the malarial parasite on key proteins. Using our lectin microarray technology, we are currently examining glycosylation at varying points of the malarial lifecycle.

References

  1. 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.
  2. 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.
  3. 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
  4. 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.