Host-Pathogen Glycomics

Glycosylation plays a crucial role in establishing healthy symbiotic bacterial colonization patterns, maintaining mucosal barriers to infection, regulating both adaptive and innate immunity, and in host-pathogen interactions. For example, we recently found that glycomic shifts in blood sera are conserved in experimental mouse sepsis models (1). Furthermore, we found that proteins associated with human sepsis undergo dramatic shifts in glycosylation upon induction (1). This data suggests both a common mechanism for bacterially induced sepsis, and an important role for glycans in this response. Our lab continues to use systems-based approaches to study the mechanisms underlying critical immune functions.

Our Areas of Focus

Host Glycomics Response to Pathogens

Influenza

Working with a team headed by Dr. Elodie Ghedin (NIAID), Dr. Bin Zhang (MSSM) and Dr. Ted Ross (UGA), we identified a potential mechanism underlying influenza severity. Activation of the UPR pathway upon influenza infection turns on expression of high mannose, which is then recognized by the innate immune lectin MBL2, activating the complement cascade and subsequent inflammation. An overabundance of high mannose or high MBL2 may dysregulate the immune system, leading to severe damage and death (2). We are currently examining this hypothesis in more detail. Our most recent work in influenza focuses on vaccine efficacy. The inability to establish effective protection post-vaccination could be attributed to high baseline levels of the blood group epitope Lewis A antigen (Lea). Glycoproteomic analysis showed that Lea-bearing proteins are enriched in complement activation pathways – thus, complement proteins may mediate antibody induction upon vaccination and may predict immune response to vaccines (3). Our work has broad implications for potential antiviral agents and vaccination strategies, so we've partnered with the Center for Influenza Vaccine Research for High-Risk Populations (CIVR-HRP), part of the Collaborative Influenza Vaccine Innovation Centers (CIVICs). Click to watch a video discussing our work below.

SARS-CoV-2

We partnered with Dr. Tom Hobman (UAlberta) to study SARS-CoV-2 (4). Work by our collaborators Dr. John Klassen and Dr. Matthew Macauley identified mammalian glycans binding the SARS-CoV-2 receptor binding domain (RBD), as well as sialylated glycans as co-factors (5). This finding suggests that viral entry is facilitated by the SARS-CoV-2 RBD. In ongoing work, our lab is using our lectin microarray technology to identify glycomic host-responses to this pathogen (coming soon).

Glycosylation as a Marker of Innate Immunity

The glycome is both a modulator and potential marker of innate immunity. Changes in glycosylation state have powerful effects on antibody function and protein stabilization, and can alter microbicidal effects of immune molecules. In collaboration with Dr. Sharon Hillier at Magee Women’s Research Institute and the FAME research group, we demonstrated 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 (6). We extended these studies to examine the impact of microbicide formulations, i.e., the form a drug is delivered in, on the glycome and its correlations to innate anti-HIV-1 and herpes simplex virus (HSV) immunity (7). We are now expanding our work to look further into the glycome-microbiome connection in other systems.

The Role of Glycans in Exosome and Viral Biogenesis

In earlier work, we found that the glycan coats of both HIV-1 and exosomes are enriched in high mannose and poly/multi-N-acetyllactosamine (mLacNAc) through the use of lectin microarray technology, which suggests that HIV-1 co-opts the exocytic pathway of exosomes. We also found evidence that HIV-1 alters its infectivity by passaging through different cells, as these particles showed greater similarity to exosomes derived from the same cell line (8, HIV-1, Nature Chem. Biol., 2009, highlighted in June 2015 as one of their “Greatest Hits”). We followed up this work by comparing the glycosylation patterns of exosomes derived from a variety of biological sources, and identified enrichment and depletion of specific glycan epitopes in these particles (9). Subsequent data suggests that this glycan signature acts as a trafficking motif for select glycoproteins into exosomes (10). We are currently looking into the role these glycans may play in exosomes and immunity.

References

Heindel, D.W.; Chen, S.; Aziz, P.V.; Chung, J.Y.; Marth, J.D.; Mahal, L.K. Glycomic analysis reveals a conserved response to bacterial sepsis induced by different bacterial pathogens. ACS Infectious Diseases, 2022. doi: 10.1021/acsinfecdis.2c00082. Formerly bioRxiv doi: 10.1101/2020.12.11.421610
Heindel, D.W.; Koppolu, S.; Zhang, Y.; Kasper, B.; Meche, L.; Vaiana, C.A.; Bissel, S.J.; Carter, C.E.; Kelvin, A.A.; Zhang, B.; Zhou, B.; TChou, T.-W.; Lashua, L.; Ross, T.M.; Ghedin, E.; Mahal, L.K. Glycomic analysis of host-response reveals high mannose as a key mediator of influenza severity. Proc. Nat. Acad. Sci. U.S.A., 2020, 117, 26926-26935. doi: 10.1073/pnas.2008203117. Formerly bioRxiv doi: 10.1101/2020.04.21.054098
Qin, R.; Meng, G.; Pushalkar, S.; Carlock, M.A.; Ross, T.; Vogel, C.; Mahal, L.K. Glycomic analysis identifies pre-vaccination markers of response to influenza vaccine, implicating the complement pathway. medRixv, 2022, doi: 10.1101/2022.02.09.22270754. In submission.
Kumar, A.; Ishida, R.; Strilets, T.; Cole, J.; Lopez-Orozco, J.; Fayad, N.; Felix-Lopez, A.; Elaish, M.; Evseev, D.; Magor, K.; Mahal, L.K.; Nagata, L.; Evans, D.; Hobman, T. SARS-CoV-2 non-structural protein 1 inhibits the interferon response by causing depletion of key host signaling factors. Journal of Virology, 2021, 95, 13, e0026621. doi: 10.1128/jvi.00266-21
Nguyen, L.; McCord, K.A.; Bui, D.T.; Bouwman, K.M.; Kitova, E.N.; Elaish, M.; Kumawat, D.; Daskhan, G.C.; Tomris, I.; Han, L.; Chopra, P.; Yang, T.-J.; Willows, S.D.; Mason, A.L.; Mahal, L.K.; Lowary, T.L.; West, L.J.; Hsu, S.-T.D.; Hobman, T., Tompkins, S.M.; Boons, G.-J.; de Vries, R.P.; Macauley, M.S.; Klassen, J.S. Sialic acid-dependent binding and viral entry of SARS-CoV-2. Nature Chemical Biology, 2022, 18, 81-90. doi: 10.1038/s41589-021-00924-1
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
Koppolu, S.; Wang, L.; Mathur, A.; Nigam, J.A.; Dezzutti, C.S.; Isaacs, C.; Meyn, L.; Bunge, K.E.; Moncla, B.J.; Hillier, S.L.; Rohan, L.C.; Mahal, L.K. Vaginal product formulation alters the innate anti-viral activity and glycome of cervicovaginal fluids with implications for viral susceptibility. ACS Infectious Disease, 2018, 4, 1613-1622. doi: 10.1021/acsinfecdis.8b00157
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. doi: 10.1038/nchembio.151
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. doi: 10.1021/pr200434y
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

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F.A.Q.

What is the Canada Excellence Research Chair?

The Canada Excellence Research Chairs (CERC) Program awards universities up to $10 million over seven years to support world‑renowned researchers and their teams to establish ambitious research programs at Canadian universities.

Where is the University of Alberta?

Located in beautiful Edmonton, Alberta, Canada, the Chemistry Department at the UofA is renown for its active research. It is one of the best equipped and well funded departments in Canada.

What is lectin microarray technology?

It is a glycomic technology developed in the Mahal Lab, provide a rapid analysis of the glycome (1-3). These microarrays utilize immobilized carbohydrate-binding proteins at high spatial density to give specific information on the repertoire of glycans present.

Why study microRNA regulation of glycosylation?

miRNA can be used to identify glycosylation enzymes and their corresponding glycans that drive disease states.

How do I apply for grad school?

At the UofA, you do not have to find a supervisor in order to apply. The department has a process in place for students to find a supervisor and join a research group once they arrive to start their program. However, it is recommended for applicants to contact chemistry faculty members whose areas of research are of interest to you. Information about requirements and how to apply can be found here.