About

Nicholas Ching Hai Wu is an Associate Professor of Biochemistry and Biomedical and Translational Sciences at the University of Illinois. He is also an affiliate of the Carl R. Woese Institute for Genomic Biology. Professor Wu's research focuses on understanding the constraints of virus evolution, predicting antibody specificity, and improving the quality and speed of vaccine design. His lab primarily studies influenza virus and SARS-CoV-2, employing a multidisciplinary approach that includes molecular virology, protein biochemistry, next-generation sequencing, high-throughput assays, x-ray crystallography, cryo-electron microscopy, and machine learning. Professor Wu completed his postdoctoral training at The Scripps Research Institute in 2020, earned his Ph.D. from the University of California, Los Angeles in 2015, and obtained his B.S. from the University of Virginia in 2010. His work has been recognized with numerous awards, including the NIH Director's New Innovator Award, the Searle Scholar Award, the Vallee Scholar Award, and several honors from the University of Illinois, reflecting his contributions to the fields of immunology, virology, molecular evolution, protein structure, and bioinformatics. His research addresses critical questions in infectious diseases, particularly focusing on the molecular mechanisms underlying virus-host interactions and immune responses.

Research topics

• Biology
• Medicine
• Computational biology
• Genetics
• Virology
• Internal medicine
• Computer Science
• Immunology
• Mathematics
• Evolutionary biology
• Cell biology

Selected publications

• SARS-CoV-2 wastewater genomic surveillance: approaches, challenges, and opportunities

  Genome biology · 2026-01-12 · 4 citations

  articleOpen access

  Wastewater-based genomic surveillance (WWGS) has proven effective for monitoring SARS-CoV-2 and other viruses within communities. It enables rapid detection of known and emerging mutations and provides insights into circulating lineages. Despite its advantages, WWGS faces challenges in sample processing and computational analysis, particularly in distinguishing similar lineages and identifying novel ones. Recent methods for wastewater sequencing (WWS) analysis remain largely untested amid declining clinical surveillance and ongoing viral evolution. This review examines opportunities and limitations of WWGS, focusing on sample preparation, sequencing technologies, and bioinformatics approaches, and highlights its potential to strengthen public health monitoring systems.

  PublisherOA PDFDOI

• Somatic evolution of a cross-reactive germline antibody that expands its breadth to neutralize new SARS-CoV-2 variants

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-25

  articleOpen access

  ABSTRACT Rapid antigenic drift of the SARS-CoV-2 receptor-binding domain (RBD) underlies immune escape and continues to challenge the durability of antibody-mediated protection. Among the major classes of RBD-directed antibodies, germline-encoded IGHV3-53 responses are highly potent against early SARS-CoV-2 variants but are generally compromised by Omicron-associated mutations. Here, we identify an intrinsically cross-reactive IGHV3-53 germline antibody that recognizes multiple pre-Omicron variants, including SARS-CoV-2 wild-type, Alpha, and Delta. Notably, we demonstrate that targeted somatic evolution can further expand this breadth to overcome the immune escape of different Omicron variants. Guided by integrated structural and sequence analyses, we introduce four somatic mutations (G26E, T28I, S53P, and Y58F) into the germline antibody, resulting in markedly enhanced binding and neutralization of Omicron BA.1, BA.2, and BA.4/5. High-resolution crystal structures reveal that these mutations re-establish critical interactions disrupted by substitutions on Omicron RBD and optimize affinity at a remodeled epitope interface. Collectively, our findings delineate a structural and mechanistic pathway through which an inherently cross-reactive germline antibody lineage can be adaptively refined to counter highly divergent SARS-CoV-2 variants. This work highlights the underappreciated breadth encoded within the naïve B-cell repertoire and provides a conceptual framework for engineering and eliciting antibody responses resilient to future antigenic drift.

  PublisherOA PDFDOI

• Systematic investigation of double emulsion dewetting dynamics for the robust production of giant unilamellar vesicles

  Lab on a Chip · 2026-01-01

  articleOpen access

  saturation successfully overcomes salt-induced inhibition. Our results improve the reliability and accessibility of droplet-microfluidics GUV platforms to catalyze advances in biophysics, synthetic biology, and drug discovery.

  PublisherOA PDFDOI

• Experimental immunologists in the era of artificial intelligence

  Trends in Immunology · 2026-03-01

  articleOpen accessSenior author

  While artificial intelligence (AI) is transforming biological science, its full potential in immunology has yet to be realized due to limited data and the need for extensive experimental validation. This review provides a practical guide for experimental immunologists to actively contribute to AI development, with a focus on applications for B- and T-cell receptors. It not only gives an overview of common AI techniques in immunology but also highlights the important role of high-throughput experimental methodologies. Overall, we believe that the synergy between AI and experimental innovation will be a crucial catalyst for advancing the field of immunology.

  PublisherDOI

• Structural insights into antibody responses against influenza A virus in its natural reservoir

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-12

  articleOpen accessSenior authorCorresponding

  While influenza A virus undergoes rapid antigenic drift in humans, at least some subtypes, such as H3, have relatively stable antigenicity in natural waterfowl reservoirs, despite the presence of immune pressure. However, the underlying mechanisms remain poorly understood. This study identified and characterized 187 antibodies to H3 hemagglutinin from experimentally infected mallard ducks, 18 of which were further analyzed by cryo-EM. Compared with human H3 antibodies, duck H3 antibodies exhibited higher glycan-binding propensity, more balanced immunodominance hierarchy, and targeted distinct epitopes. Other unique features of duck H3 antibodies included a convergent CDR H3-independent heavy chain-only binding mode and an N-glycosylated CDR H3 as decoy receptor. By annotating duck immunoglobulin germline genes, we also demonstrated the importance of gene conversion in duck H3 antibodies. Overall, our findings provide insights into how millennia of coevolution have shaped the interplay between influenza A virus antigenic drift and antibody responses in the natural reservoir.

  PublisherDOI

• Correction: Winter torpor and body mass patterns of a cave-roosting bat in cool and warm climates

  Oecologia · 2026-01-22

  articleOpen access
  PublisherOA PDFDOI

• B cell imprinting in children impairs antibodies to the haemagglutinin stalk

  Nature · 2026-03-11

  articleOpen access

  is a phenomenon whereby the immune system preferentially recalls its initial response to a related, often evolving pathogen after subsequent exposure. Despite its important implications for vaccine development, the causes of imprinting remain unclear. Here, to understand the basis and impact of imprinting by influenza A viruses, we characterized the B cell responses of young children after consecutive first infections with divergent H1N1 and H3N2 strains of influenza. Children had a primary but otherwise similar B cell response to that of adults. Adult B cells commonly cross-reacted with past strains using more stereotyped and mutated immunoglobulin genes, indicating substantial homosubtypic imprinting. In children, after consecutive heterosubtypic primary infections, up to 6% of memory B cells are H1/H3 cross-reactive and bind to the highly conserved central stalk epitope-a lead target for broadly protective vaccine candidates. Over 90% of these B cells had a higher affinity for the imprinting H3N2 strain, resulting in reduced breadth and neutralization potency against H1N1 strains. Mechanistically, the imprinting H3 strains and affected H1 strains shared a residue change in the stalk epitope (D46N) that was central to the nearly universal shift in reactivity, despite differing by only a single atomic group. In conclusion, imprinting by influenza viruses can cause a deleterious shift of nearly the entire memory recall response against key, conserved epitopes.

  PublisherDOI

• Compartmentalized cytokine networks and systemic immune remodeling in bovine mammary H5N1 infection

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-06

  articleOpen access

  Highly pathogenic avian influenza A H5N1 has recently expanded its mammalian host range; in 2024, genotype B3.13 emerged in U.S. dairy cattle with pronounced mammary tropism. In the past, Influenza A virus immunology has been characterized primarily in respiratory infection models, whereas this study delineates immune responses after intramammary infection. An intramammary H5N1 challenge in Jersey cows in the early dry-off period enabled integration of dose- and compartment-resolved (alveoli versus teat cistern) cytokine and chemokine profiles with peripheral leukocyte dynamics and H5/N1-specific antibody responses. Infection-induced quarter-restricted, monophasic inflammatory networks peaking at 3-7 days post-infection, coordinated peripheral myeloid expansion and IFN-γ-competent lymphocyte activation, and rising antibody titers across quarters.

  PublisherDOI

• TRIM21 is a molecular rheostat for influenza A virus replication

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-17

  articleOpen accessSenior authorCorresponding

  TRIM21 is a multifunctional E3 ubiquitin ligase and intracellular antibody receptor, yet its role during viral infection remains unclear, with reports describing both antiviral and proviral activities. Here, we show that TRIM21 regulates influenza infection in an expression-dependent manner by functioning as a molecular rheostat rather than a binary restriction factor. This graded activity of TRIM21, which leads to both suppression and promotion of influenza replication, couples linkage-specific ubiquitination of viral nucleoprotein with modulation of innate immune signaling. Additionally, loss of TRIM21 unmasks a compensatory antiviral program centered on PRKDC, which is a ubiquitination target of TRIM21. This positions PRKDC as a latent restriction factor selectively engaged when primary TRIM21 control is lost. Together, these findings reveal a hierarchical and plastic antiviral network in which TRIM21 sets an adjustable threshold for host defense while restraining secondary restriction pathways. This framework highlights the sophisticated layers of regulation of the host ubiquitin-mediated antiviral immunity.

  PublisherOA PDFDOI

• Reimagining the serocatalytic model for infectious diseases: A case study of common coronaviruses

  Epidemics · 2025-10-09 · 1 citations

  articleOpen access

  Despite the increased availability of serological data, understanding serodynamics remains challenging. Serocatalytic models, which describe the rate of seroconversion (gain of antibodies) and seroreversion (loss of antibodies) within a population, have traditionally been fit to cross-sectional serological data to capture long-term transmission dynamics. However, a key limitation is their binary assumption on serological status, ignoring heterogeneity in optical density levels, antibody titers, and/or exposure history. Here, we implemented Gaussian mixture models - an established statistical tool - to cross-sectional data in order to characterize serological diversity of seasonal human coronaviruses (sHCoVs) across a wide range of age groups. These methods consistently identified multiple distinct seropositive levels, suggesting that among seropositive individuals, the number of prior exposures or response to infection may vary. We fit adapted, multi-compartment serocatalytic models with different assumptions on exposure history and waning of antibodies. The best fit model for each sHCoV was always one that accounted for host variation in the scale of serological response to infection. These models allowed us to estimate the strength and frequency of serological responses, finding that the time for a seronegative individual to become seropositive ranges from 2.40 to 7.03 years across sHCoVs, and most individuals mount a strong antibody response reflected in high optical density values, skipping lower levels of seropositivity. We find that despite frequent infection and strong serological responses, for all sHCoVs except 229E, individuals are likely to become seronegative again at some point after their first infection. Nonetheless, our results also indicate that by age 22, for each sHCoV the probability of having seroconverted at least once is over 95%. Crucially, our reimagined serocatalytic methods can be flexibly adapted across pathogens, having the potential to be broadly applied beyond this work.

  PublisherDOI

Recent grants

• Sequence-function relationship of influenza broadly neutralizing antibodies

  NIH · $2.5M · 2022–2026

• Biophysical constraints of influenza neuraminidase evolution

  NIH · $2.0M · 2022–2027

• High-throughput identification of antibody features for sequence-based epitope prediction

  NIH · $2.4M · 2021–2026

• MECHANISTIC UNDERSTANDING OF INFLUENZA-HOST INTERACTIONS FROM A ZOONOTIC PERSPECTIVE

  NIH · $492k · 2019–2022

• Mechanistic understanding of influenza-host interactions from a zoonotic perspective

  NIH · $132k · 2019–2021

Frequent coauthors

• Ian A. Wilson

  Scripps Research Institute

  112 shared

• Huibin Lv

  103 shared

• Chris Ka Pun Mok

  Chinese University of Hong Kong

  62 shared

• Meng Yuan

  Northeast Forestry University

  61 shared

• Timothy J.C. Tan

  University of Illinois Urbana-Champaign

  59 shared

• Yiquan Wang

  University of Illinois Urbana-Champaign

  56 shared

• Qi Wen Teo

  University of Illinois Urbana-Champaign

  55 shared

• Ren Sun

  51 shared

Labs

• Wu lab @ UIUCPI

  People

Education

• Ph.D. Molecular Biology, Molecular Biology Interdepartmental Doctoral Program

  University of California Los Angeles

  2015

• B.S. Biochemistry, Department of Chemistry

  University of Virginia

  2010

Awards & honors

• UIUC I.C. Gunsalus Scholar Award (2025)
• UIUC Distinguished Promotion Award (2025)
• UIUC MCB Outstanding Graduate Student Mentor Award (2024)
• Vallee Scholar Award (2024)
• Viruses Early Career Investigator Award (2022)