Nicholas C Wu
Computational Biology, Genetics, Host-Pathogen Interactions, Molecular Evolution, Molecular Immunology, Protein Dynamics, Protein Structure, Receptor Biochemistry, Virology
Disease Research Interests
Postdoc, The Scripps Research Institute, 2020
Ph.D., University of California, Los Angeles, 2015
B.S., University of Virginia, 2010
Driving forces and functional constraints of influenza evolution
Research overviewVirus 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 followings:
Arm race between antibody response and virusAntibodies 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 arm 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 virusThe 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 virusThe 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.
K99/R00 Pathway to Independence Award, NIH/NIAID (2019-present)
Croucher Postdoctoral Fellowship, Croucher Foundation (2015-2017)
Dissertation Year Fellowship, UCLA (2014-2015)
Audree Fowler Fellowship in Protein Science, UCLA (2014)
Philip Whitcome Pre-Doctoral Fellowship, UCLA (2011-2014)
Yuan M*, Wu NC*, Zhu X, Lee CCD, So RTY, Lv H, Mok CKP, Wilson IA. A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV. Science 368:630-633 (2020). *Equal Contributors
Wu NC, Otwinowski J, Thompson AJ, Nycholat CM, Nourmohammad A, Wilson IA. Major antigenic site B of human influenza H3N2 viruses has an evolving local fitness landscape. Nature Communications 11:1233 (2020).
Wu NC, Lv H, Thompson AJ, Wu DC, Ng WWS, Kadam RU, Lin CW, Nycholat CM, McBride R, Liang W, Paulson JC, Mok CKP, Wilson IA. Preventing an antigenically disruptive mutation in egg-based H3N2 seasonal influenza vaccines by mutational incompatibility. Cell Host & Microbe 25:836-844.e5 (2019).
Wu NC, Thompson AJ, Xie J, Lin CW, Nycholat CM, Zhu X, Lerner RA, Paulson JC, Wilson IA. A complex epistatic network limits the mutational reversibility in the influenza hemagglutinin receptor-binding site. Nature Communications 9:1264 (2018).
Wu NC, Zost SJ, Thompson AJ, Oyen D, Nycholat CM, McBride R, Paulson JC, Hensley SE, Wilson IA. A structural explanation for the low effectiveness of the seasonal influenza H3N2 vaccine. PLoS Pathogens 13:e1006682 (2017).
Wu NC*, Dai L*, Olson CA, Lloyd-Smith JO, Sun R. Adaptation in protein fitness landscapes is facilitated by indirect paths. eLife 5:e16965 (2016). *Equal Contributors
Olson CA, Wu NC, Sun R. A comprehensive biophysical description of pairwise epistasis throughout an entire protein domain.Current Biology 24:2643-2651 (2014).