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Nicholas C. Wu

Assistant Professor of Biochemistry

Research Interests

Research Topics

Bioinformatics, Host-Pathogen Interactions, Molecular Evolution, Molecular Immunology, Protein Structure, Virology

Disease Research Interests

Cancer, Infectious Diseases

Research Description

Driving forces and functional constraints of influenza evolution

Virus is one of the largest global health concerns. The ability of virus to rapidly evolve underlies the challenge to achieve a virus-free world. The two major problems are 1) immune evasion, which can lead to vaccine escape, and 2) host jump, which can lead to pandemic. Fortunately, not all viral mutations have a deleterious consequence to public health. Most viral mutations disrupt protein functions that are essential in the virus life cycle. Therefore, a significant portion of the viral genome is under strong evolutionary constraints. Our research interest is to characterize virus evolution, including both positive selection pressures (immune evasion and host adaptation) and negative selection pressures (virus-host molecular interactions). While our main focus has been on influenza virus, we occasionally work on other viruses such as HIV, HCV, and SARS-CoV-2. Ongoing research directions include the following:

  • Arms race between antibody response and virus. Antibodies are generated during virus infection or vaccination. While antibodies can offer protection against viral infection, virus can mutate to escape antibody response. As a result, there is a constant arms race between antibody response and virus. Our research aims to understand how affinity and breadth are developed during antibody evolution, as well as how virus escapes antibody response. This research direction provides important insight into vaccine design.
  • Evolutionary constraints of influenza virus. The evolution of influenza virus is functionally constrained since viral proteins possess many functions that are essential to the virus life cycle. Our research aims to investigate the mechanistic basis of these functional constraints, how they vary among different viral strains, and how they change over time. This research direction helps detail the molecular mechanisms of influenza pathogenesis, diversification, and host jump.
  • Egg adaptation of influenza virus. The effectiveness of the seasonal influenza vaccine is quite low, especially for H3N2 subtype. One major problem is the egg-based vaccine production process. Although passaging human influenza virus in embryonated chicken eggs is a highly cost-effective method for vaccine production, it often leads to the emergence of egg-adaptive mutations, which may alter the antigenicity of the virus. Our research aims to characterize the biophysical basis of antigenic alternation due to egg-adaptive mutations, as well as the genetic interactions between different egg-adaptive mutations. This research direction is informative for influenza vaccine strain selection.


Postdoc, The Scripps Research Institute, 2020
Ph.D., University of California, Los Angeles, 2015
B.S., University of Virginia, 2010

Awards and Honors

ASV Ann Palmenberg Junior Investigator Award (2022)
Searle Scholar Award (2022)
Michelson Prize (2021)
ESWI Young Scientist Innovative Award (2021)
NIH Director's New Innovator Award (2021)
NIH Pathway to Independence Award (2019)
Croucher Postdoctoral Fellowship (2015-2017)

Highlighted Publications

Representative Publications

Ouyang WO*, Tan TJC*, Lei R, Song G, Kieffer C, Andrabi R, Matreyek KA, Wu NC. Probing the biophysical constraints of SARS-CoV-2 spike N-terminal domain using deep mutational scanning. Science Advances 8:eadd7221 (2022)

Lei R, Tan TJC, Hernandez Garcia A, Wang Y, Diefenbacher M, Teo C, Gopan G, Tavakoli Dargani Z, Teo QW, Graham CS, Brooke CB, Nair SK, Wu NC. Prevalence and mechanisms of evolutionary contingency in human influenza H3N2 neuraminidase. Nature Communications 13:6443 (2022)

Wang Y*, Yuan M*, Lv H, Peng J, Wilson IA, Wu NC. A large-scale systematic survey reveals recurring molecular features of public antibody responses to SARS-CoV-2. Immunity 55:1105-1117.e4 (2022)

Tan TJC*, Yuan M*, Kuzelka K, Padron GC, Beal JR, Chen X, Wang Y, Rivera-Cardona J, Zhu X, Stadtmueller BM, Brooke CB, Wilson IA#Wu NC#. Sequence signatures of two public antibody clonotypes that bind SARS-CoV-2 receptor binding domain. Nature Communications 12:3815 (2021)

Koenig PA, Das H, Liu H, Kümmerer BM, Gohr FN, Jenster LM, Schiffelers LDJ, Tesfamariam YM, Uchima M, Wuerth JD, Gatterdam K, Ruetalo N, Christensen MH, Fandrey CI, Normann S, Tödtmann JMP, Pritzl S, Hanke L, Boos J, Yuan M, Zhu X, Schmid-Burgk JL, Kato H, Schindler M, Wilson IA, Geyer M, Ludwig KU, Hällberg BM#Wu NC#, Schmidt FI#. Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape. Science 371:eabe6230 (2021)

(*co-first, #co-corresponding)

Recent Publications

Lei, R., Hernandez Garcia, A., Tan, T. J. C., Teo, Q. W., Wang, Y., Zhang, X., Luo, S., Nair, S. K., Peng, J., & Wu, N. C. H. (2023). Mutational fitness landscape of human influenza H3N2 neuraminidase. Cell Reports, 42(1), [111951].

Diefenbacher, M., Tan, T. J. C., Bauer, D. L. V., Stadtmueller, B. M., Wu, N. C., & Brooke, C. B. (2022). Interactions between Influenza A Virus Nucleoprotein and Gene Segment Untranslated Regions Facilitate Selective Modulation of Viral Gene Expression. Journal of virology, 96(10).

Knyazev, S., Chhugani, K., Sarwal, V., Ayyala, R., Singh, H., Karthikeyan, S., Deshpande, D., Baykal, P. I., Comarova, Z., Lu, A., Porozov, Y., Vasylyeva, T. I., Wertheim, J. O., Tierney, B. T., Chiu, C. Y., Sun, R., Wu, A., Abedalthagafi, M. S., Pak, V. M., ... Mangul, S. (2022). Unlocking capacities of genomics for the COVID-19 response and future pandemics. Nature Methods, 19(4), 374-380.

Lei, R., Tan, T. J. C., Hernandez Garcia, A., Wang, Y., Diefenbacher, M., Teo, C., Gopan, G., Tavakoli Dargani, Z., Teo, Q. W., Graham, C. S., Brooke, C. B., Nair, S. K., & Wu, N. C. H. (2022). Prevalence and mechanisms of evolutionary contingency in human influenza H3N2 neuraminidase. Nature communications, 13(1), [6443].

Liu, T., Wang, Y., Tan, T. J. C., Wu, N. C., & Brooke, C. B. (2022). The evolutionary potential of influenza A virus hemagglutinin is highly constrained by epistatic interactions with neuraminidase. Cell Host and Microbe, 30(10), 1363-1369.e4.

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