Matthew McCallum
PhD
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Dr. Matthew McCallum is a structural virologist who studies how viruses enter human cells and how this process can be blocked to prevent infection.
He completed his undergraduate training at Western University, where he investigated the bacterial capsule to identify new antimicrobial targets. He later studied HIV drug resistance at McGill University before earning his PhD in Biochemistry at the University of Toronto. During his doctoral work, he used X-ray crystallography and cryo-electron microscopy (cryoEM) to reveal how bacterial grappling hook-like pili function at the atomic level.
Dr. McCallum then joined the University of Washington and the Howard Hughes Medical Institute as a postdoctoral researcher in the laboratory of Dr. David Veesler. There, he combined computational protein engineering with high-resolution structural imaging to stabilize viral glycoproteins and define how viral fusion proteins mediate membrane fusion and evade immune recognition. His work contributed to key discoveries on SARS-CoV-2 and other emerging viruses, informing vaccine development and the characterization of neutralizing antibodies during the COVID-19 pandemic.
At the University of Toronto, he leads a research program that integrates cryoEM and computational protein design to understand and engineer stabilized viral fusion proteins, with a focus on herpesviruses and other medically important pathogens.
Research Synopsis
Herpesviruses infect most people worldwide, establish lifelong infections, and are linked to cancer, autoimmune disease, and neurodegeneration. Epstein-Barr virus (EBV) alone infects more than 90% of the global population, accounts for nearly 2% of all human cancers, and is strongly associated with the development of multiple sclerosis. Herpes simplex viruses (HSV-1/2) and related alpha-herpesviruses have been implicated in dementia and Alzheimer’s disease. Despite this impact, effective vaccines are still lacking for most herpesviruses.
Herpesvirus entry is driven by viral glycoproteins that undergo dramatic structural rearrangements during membrane fusion. These viral fusion proteins change shape rapidly during infection, making them difficult to study and target. The McCallum Laboratory iterates between computational protein design and cryoEM to capture and stabilize these transient states and enable structure-guided vaccine design and next-generation antiviral strategies.
Research aims
1. Mechanisms of Viral Entry
We define the structural changes viral proteins undergo during infection to understand how viruses select cell types, evade immunity, and cause disease.
2. Engineering Stable Viral Proteins
We redesign unstable viral proteins to lock them into key conformations. These engineered molecules serve as research tools and as candidates for next-generation vaccine antigens.
3. Neutralizing Antibody Development
We integrate structural biology and immunology to develop potent antibodies and nanobodies that prevent infection and reduce the long-term burden of chronic disease.
Through collaborations spanning structural biology, immunology, and virology, the lab translates molecular insight into clinical innovation.
Training and Mentorship
Dr. McCallum mentors trainees in an interdisciplinary environment spanning structural biology, computational protein design, and virology. The laboratory welcomes graduate students, postdoctoral fellows, and research staff interested in viral mechanisms and next-generation antiviral strategies.
Selected Publications
McCallum, M.*† and Veesler, D.† 2024. Computational design of prefusion stabilized Herpesvirus gB trimers. bioRxiv.
Liu, P.*, Huang, M.-L.*, Guo, H.*, McCallum, M.*, Si, J.-Y., Chen, Y.-M., Wang, C.-L., Yu, X., Shi, L.-L., Xiong, Q., Ma, C.-B., Bowen, J.E., Tong, F., Liu, C., Sun, Y.-H., Yang, X., Chen, J., Guo, M., Li, J., Corti, D., Veesler, D.†, Shi, Z.-L.†, and Yan, H.† 2024. Design of customized coronavirus receptors. Nature 635: 978–986.
McCallum, M.*, Park, Y.J.*, Stewart, C., Sprouse, K.R., Brown, J., Tortorici, M.A., Gibson, C., Wong, E., Ieven, M., Telenti, A., Veesler, D.† 2024. Human coronavirus HKU1 recognition of the TMPRSS2 host receptor. Cell 187(16):4231–4245.e13.
Wang, Z.*, McCallum, M.*, Yan, L.*, Gibson, C.A., Sharkey, W., Park, Y., Dang, H.V., Amaya, M., Person, A., Broder, C.C., and Veesler, D.† 2023. Structure and design of Langya virus glycoprotein antigens. Proceedings of the National Academy of Sciences 121(16):e2314990121.
McCallum, M.*, Czudnochowski, N.*, Rosen, L.E., Zepeda, S.K., Bowen, J.E., Walls, A.C., Hauser, K., Joshi, A., Stewart, C., Dillen, J.R., Powell, A.E., Croll, T.I., Nix, J., Virgin, H.W., Corti, D., Snell, G.†, and Veesler, D.† 2022. Structural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement. Science 375(6583):864–868.
McCallum, M.*, Walls, A.C., Sprouse, K.R., Bowen, J.E., Rosen, L., Dang, H.V., de Marco, A., Franko, N., Tilles, S.W., Logue, J., Miranda, M.C., Ahlrichs, M., Carter, L., Snell, G., Pizzuto, M.S., Chu, H.Y., Van Voorhis, W.C., Corti, D.†, and Veesler, D.† 2021. Molecular basis of immune evasion by the delta and kappa SARS-CoV-2 variants. Science 374(6575):1621–1626.
McCallum, M.*, Bassi, J.*, de Marco, A.*, Chen, A.*, Walls, A.C.*, di Iulio, J., Tortorici, M.A., Navarro, M., Silacci-Fregni, C., Saliba, C., Sprouce, K.R., Agostini, M., Pinto, D., Culap, K., Bianchi, S., Jaconi, S., Cameroni, E., Bowen, J.E., Tilles, S.W., Pizzuto, M.S., Guastalla, S.B., Bona, G., Pellanda, A.F., Garzoni, C., Van Voorhis, W.C., Rosen, L.E., Snell, G., Telenti, A., Virgin, H.W., Piccoli, L., Corti, D.†, and Veesler, D.† 2021. SARS-CoV-2 immune evasion by variant B.1.427/B.1.429. Science 373(6555):648–654.
McCallum, M.*, de Marco, A.*, Lempp, F.A., Tortorici, M.A., Pinto, D., Walls, A.C., Beltramello, M., Chen, A., Liu, A., Zatta, F., Zepeda, S., di Iulio, J., Bowen, J.E., Montiel-Ruiz, M., Zhou, J., Rosen, L.E., Bianchi, S., Guarino, B., Fregni, C.S., Abdelnabi, R., Foo, S.C., Rothlauf, P.W., Bloyet, L.M., Benigni, F., Cameroni, E., Neyts, J., Riva, A., Snell, G., Telenti, A., Whelan, S.P.J., Virgin, H.W., Corti, D.†, Pizzuto, M.S.†, and Veesler, D.† 2021. N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2. Cell 184(9):2332–2347.
McCallum, M.*, Walls, A.C., Bowen, J.E., Corti, D.†, and Veesler, D.† 2020. Structure-guided covalent stabilization of coronavirus spike glycoprotein trimers in the closed conformation. Nature Structural & Molecular Biology 27(10):942–949.
McCallum, M.*, Tammam, S., Khan, A., Burrows, L.L.†, and Howell, P.L.† 2017. The molecular mechanism of the type IVa pilus motor. Nature Communications 8:15091.
Appointments
Assistant Professor, University of Toronto
Honours and Awards (selected)
2024 APECx Grant – Co-Investigator (ARPA-H)
2020 Postdoctoral Fellowship, Natural Sciences & Engineering Research Council of Canada
2017 Ontario Graduate Scholarships (OGS), Province of Ontario
2018 Connell Award for Top Publication, University of Toronto Biochemistry Dept.
2018 Pauling Poster Prize, American Crystallographic Association (ACA) Conference
2014 Doctoral Award, Canadian Institutes of Health Research (CIHR)
2012 Master’s Training Award, Fonds de recherche Québec - Santé (FRQS)