Scholars@Duke
Nicholas Scott Heaton

Nicholas Scott Heaton

Associate Professor of Molecular Genetics and Microbiology
Molecular Genetics and Microbiology
nicholas.heaton@duke.edu
3136 MSRB III, Box 3054, Durham, NC 27710
3136 MSRB III, Box 3054, Durham, NC 27710

Selected Publications

Fluorescent and bioluminescent bovine H5N1 influenza viruses for evaluation of antiviral interventions.

Journal Article J Virol · November 19, 2024 In early 2024, a clade 2.3.4.4b high pathogenic H5N1 avian influenza virus was detected in dairy cows and humans in the United States. Since then, it has spread to herds in at least 13 states and caused symptomatic disease in at least fifteen people. To fa ... Full text Link to item Cite

Headless hemagglutinin-containing influenza viral particles direct immune responses toward more conserved epitopes.

Journal Article J Virol · October 22, 2024 Seasonal influenza vaccines provide mostly strain-specific protection due to the elicitation of antibody responses focused on evolutionarily plastic antigenic sites in the hemagglutinin head domain. To direct the humoral response toward more conserved epit ... Full text Link to item Cite

Improved influenza vaccine responses after expression of multiple viral glycoproteins from a single mRNA.

Journal Article Nat Commun · October 8, 2024 Influenza viruses cause substantial morbidity and mortality every year despite seasonal vaccination. mRNA-based vaccines have the potential to elicit more protective immune responses, but for maximal breadth and durability, it is desirable to deliver both ... Full text Link to item Cite

mRNA-encoded Cas13 treatment of Influenza via site-specific degradation of genomic RNA.

Journal Article PLoS Pathog · July 2024 The CRISPR-Cas13 system has been proposed as an alternative treatment of viral infections. However, for this approach to be adopted as an antiviral, it must be optimized until levels of efficacy rival or exceed the performance of conventional approaches. T ... Full text Link to item Cite

Vaccination with antigenically complex hemagglutinin mixtures confers broad protection from influenza disease.

Journal Article Sci Transl Med · May 2024 Current seasonal influenza virus vaccines induce responses primarily against immunodominant but highly plastic epitopes in the globular head of the hemagglutinin (HA) glycoprotein. Because of viral antigenic drift at these sites, vaccines need to be update ... Full text Link to item Cite

Genome-wide CRISPR activation screen identifies JADE3 as an antiviral activator of NF-kB-dependent IFITM3 expression.

Journal Article J Biol Chem · April 2024 The innate immune system features a web of interacting pathways that require exquisite regulation. To identify novel nodes in this immune landscape, we conducted a gain-of-function, genome-wide CRISPR activation screen with influenza A virus. We identified ... Full text Link to item Cite

Segmented, Negative-Sense RNA Viruses of Humans: Genetic Systems and Experimental Uses of Reporter Strains.

Journal Article Annu Rev Virol · September 29, 2023 Negative-stranded RNA viruses are a large group of viruses that encode their genomes in RNA across multiple segments in an orientation antisense to messenger RNA. Their members infect broad ranges of hosts, and there are a number of notable human pathogens ... Full text Link to item Cite

Approaches for timeline reductions in pathogenesis studies using genetically modified mice.

Journal Article Microbiol Spectr · September 11, 2023 Although genetically modified mouse models have long been a powerful tool for microbiology research, the manipulation of the mouse genome is expensive, time consuming, and has historically remained the domain of dedicated animal facilities. The recent use ... Full text Link to item Cite

Influenza virus transcription and progeny production are poorly correlated in single cells.

Journal Article Elife · September 7, 2023 The ultimate success of a viral infection at the cellular level is determined by the number of progeny virions produced. However, most single-cell studies of infection quantify the expression of viral transcripts and proteins, rather than the amount of pro ... Full text Link to item Cite

A low-background, fluorescent assay to evaluate inhibitors of diverse viral proteases.

Journal Article J Virol · August 31, 2023 Multiple coronaviruses (CoVs) can cause respiratory diseases in humans. While prophylactic vaccines designed to prevent infection are available for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), incomplete vaccine efficacy, vaccine hesitancy ... Full text Link to item Cite

Virology under the Microscope-a Call for Rational Discourse.

Journal Article mSphere · April 20, 2023 Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. D ... Full text Link to item Cite

Virology under the Microscope-a Call for Rational Discourse.

Journal Article mBio · February 28, 2023 Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. D ... Full text Link to item Cite

Virology under the Microscope-a Call for Rational Discourse.

Journal Article J Virol · February 28, 2023 Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. D ... Full text Link to item Cite

Single-cell genome-wide association reveals that a nonsynonymous variant in ERAP1 confers increased susceptibility to influenza virus.

Journal Article Cell Genom · November 9, 2022 During pandemics, individuals exhibit differences in risk and clinical outcomes. Here, we developed single-cell high-throughput human in vitro susceptibility testing (scHi-HOST), a method for rapidly identifying genetic variants that confer resistance and ... Full text Link to item Cite

Cellular glycan modification by B3GAT1 broadly restricts influenza virus infection.

Journal Article Nat Commun · October 29, 2022 Communicable respiratory viral infections pose both epidemic and pandemic threats and broad-spectrum antiviral strategies could improve preparedness for these events. To discover host antiviral restriction factors that may act as suitable targets for the d ... Full text Link to item Cite

ZBTB7A promotes virus-host homeostasis during human coronavirus 229E infection.

Journal Article Cell Rep · October 25, 2022 The cellular fate after infection with human coronaviruses (HCoVs) is typically death. Previous data suggest, however, that the transcriptional state of an individual cell may sometimes allow additional outcomes of infection. Here, to probe the range of in ... Full text Link to item Cite

Host protein kinases required for SARS-CoV-2 nucleocapsid phosphorylation and viral replication.

Journal Article Sci Signal · October 25, 2022 Multiple coronaviruses have emerged independently in the past 20 years that cause lethal human diseases. Although vaccine development targeting these viruses has been accelerated substantially, there remain patients requiring treatment who cannot be vaccin ... Full text Open Access Link to item Cite

Rapid tissue prototyping with micro-organospheres.

Journal Article Stem Cell Reports · September 13, 2022 In vitro tissue models hold great promise for modeling diseases and drug responses. Here, we used emulsion microfluidics to form micro-organospheres (MOSs), which are droplet-encapsulated miniature three-dimensional (3D) tissue models that can be establish ... Full text Open Access Link to item Cite

A Virion-Based Combination Vaccine Protects against Influenza and SARS-CoV-2 Disease in Mice.

Journal Article J Virol · August 10, 2022 Vaccines targeting SARS-CoV-2 have been shown to be highly effective; however, the breadth against emerging variants and the longevity of protection remains unclear. Postimmunization boosting has been shown to be beneficial for disease protection, and as n ... Full text Link to item Cite

In Vivo Profiling of Individual Multiciliated Cells during Acute Influenza A Virus Infection.

Journal Article J Virol · July 27, 2022 Influenza virus infections are thought to be initiated in a small number of cells; however, the heterogeneity across the cellular responses of the epithelial cells during establishment of disease is incompletely understood. Here, we used an H1N1 influenza ... Full text Link to item Cite

Nonrespiratory sites of influenza-associated disease: mechanisms and experimental systems for continued study.

Journal Article FEBS J · July 2022 The productive replication of human influenza viruses is almost exclusively restricted to cells in the respiratory tract. However, a key aspect of the host response to viral infection is the production of inflammatory cytokines and chemokines that are not ... Full text Link to item Cite

From high-throughput to therapeutic: host-directed interventions against influenza viruses.

Journal Article Curr Opin Virol · April 2022 Influenza viruses are simultaneously supported and antagonized by factors within the host cell. This close relationship is the theoretical basis for future antivirals that target the host rather than the virus itself, a concept termed host-directed therape ... Full text Link to item Cite

The Impact of Estrogens and Their Receptors on Immunity and Inflammation during Infection.

Journal Article Cancers (Basel) · February 12, 2022 Sex hormones, such as estrogen and testosterone, are steroid compounds with well-characterized effects on the coordination and development of vertebrate reproductive systems. Since their discovery, however, it has become clear that these "sex hormones" als ... Full text Link to item Cite

Influenza A virus segments five and six can harbor artificial introns allowing expanded coding capacity.

Journal Article PLoS Pathog · September 2021 Influenza A viruses encode their genomes across eight, negative sense RNA segments. The six largest segments produce mRNA transcripts that do not generally splice; however, the two smallest segments are actively spliced to produce the essential viral prote ... Full text Link to item Cite

Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2.

Journal Article Science · August 20, 2021 There is an urgent need for antiviral agents that treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We screened a library of 1900 clinically safe drugs against OC43, a human beta coronavirus that causes the common cold, and eval ... Full text Link to item Cite

ETV7 limits antiviral gene expression and control of influenza viruses.

Journal Article Sci Signal · July 13, 2021 The type I interferon (IFN) response is an important component of the innate immune response to viral infection. Precise control of IFN responses is critical because insufficient expression of IFN-stimulated genes (ISGs) can lead to a failure to restrict v ... Full text Link to item Cite

TMEM41B is a host factor required for the replication of diverse coronaviruses including SARS-CoV-2.

Journal Article PLoS pathogens · May 2021 Antiviral therapeutics are a front-line defense against virally induced diseases. Because viruses frequently mutate to escape direct inhibition of viral proteins, there is interest in targeting the host proteins that the virus must co-opt to complete its r ... Full text Cite

Engineered influenza virions reveal the contributions of non-hemagglutinin structural proteins to vaccine mediated protection.

Journal Article J Virol · April 26, 2021 The development of improved and universal anti-influenza vaccines would represent a major advance in the protection of human health. In order to facilitate the development of such vaccines, understanding how viral proteins can contribute to protection from ... Full text Link to item Cite

GPER1 is required to protect fetal health from maternal inflammation.

Journal Article Science · January 15, 2021 Type I interferon (IFN) signaling in fetal tissues causes developmental abnormalities and fetal demise. Although pathogens that infect fetal tissues can induce birth defects through the local production of type I IFN, it remains unknown why systemic IFN ge ... Full text Link to item Cite

Human Lung Stem Cell-Based Alveolospheres Provide Insights into SARS-CoV-2-Mediated Interferon Responses and Pneumocyte Dysfunction.

Journal Article Cell Stem Cell · December 3, 2020 Coronavirus infection causes diffuse alveolar damage leading to acute respiratory distress syndrome. The absence of ex vivo models of human alveolar epithelium is hindering an understanding of coronavirus disease 2019 (COVID-19) pathogenesis. Here, we repo ... Full text Open Access Link to item Cite

Development of a Fluorescence-Based, High-Throughput SARS-CoV-2 3CLpro Reporter Assay.

Journal Article J Virol · October 27, 2020 In late 2019, a human coronavirus, now known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged, likely from a zoonotic reservoir. This virus causes COVID-19, has infected millions of people, and has led to hundreds of thousands of de ... Full text Link to item Cite

Heterogeneity of Antiviral Responses in the Upper Respiratory Tract Mediates Differential Non-lytic Clearance of Influenza Viruses.

Journal Article Cell Rep · September 1, 2020 Influenza viruses initiate infection in the upper respiratory tract (URT), but early viral tropism and the importance of cell-type-specific antiviral responses in this tissue remain incompletely understood. By infecting transgenic lox-stop-lox reporter mic ... Full text Link to item Cite

Development of CRISPR as an Antiviral Strategy to Combat SARS-CoV-2 and Influenza.

Journal Article Cell · May 14, 2020 The coronavirus disease 2019 (COVID-19) pandemic, caused by the SARS-CoV-2 virus, has highlighted the need for antiviral approaches that can target emerging viruses with no effective vaccines or pharmaceuticals. Here, we demonstrate a CRISPR-Cas13-based st ... Full text Link to item Cite

DNA mismatch repair is required for the host innate response and controls cellular fate after influenza virus infection.

Journal Article Nat Microbiol · November 2019 Despite the cytopathic nature of influenza A virus (IAV) replication, we recently reported that a subset of lung epithelial club cells is able to intrinsically clear the virus and survive infection. However, the mechanisms that drive cell survival during a ... Full text Link to item Cite

Influenza viruses that require 10 genomic segments as antiviral therapeutics.

Journal Article PLoS Pathog · November 2019 Influenza A viruses (IAVs) encode their genome across eight, negative sense RNA segments. During viral assembly, the failure to package all eight segments, or packaging a mutated segment, renders the resulting virion incompletely infectious. It is known th ... Full text Link to item Cite

Long-term surviving influenza infected cells evade CD8+ T cell mediated clearance.

Journal Article PLoS Pathog · September 2019 Influenza A virus (IAV) is a seasonal pathogen with the potential to cause devastating pandemics. IAV infects multiple epithelial cell subsets in the respiratory tract, eliciting damage to the lungs. Clearance of IAV is primarily dependent on CD8+ T cells, ... Full text Link to item Cite

The Development and Use of Reporter Influenza B Viruses.

Journal Article Viruses · August 9, 2019 Influenza B viruses (IBVs) are major contributors to total human influenza disease, responsible for ~1/3 of all infections. These viruses, however, are relatively less studied than the related influenza A viruses (IAVs). While it has historically been assu ... Full text Link to item Cite

Control of antiviral innate immune response by protein geranylgeranylation.

Journal Article Sci Adv · May 2019 The mitochondrial antiviral signaling protein (MAVS) orchestrates host antiviral innate immune response to RNA virus infection. However, how MAVS signaling is controlled to eradicate virus while preventing self-destructive inflammation remains obscure. Her ... Full text Open Access Link to item Cite

Non-lytic clearance of influenza B virus from infected cells preserves epithelial barrier function.

Journal Article Nat Commun · February 15, 2019 Influenza B virus (IBV) is an acute, respiratory RNA virus that has been assumed to induce the eventual death of all infected cells. We and others have shown however, that infection with apparently cytopathic viruses does not necessarily lead to cell death ... Full text Link to item Cite

The Influenza B Virus Hemagglutinin Head Domain Is Less Tolerant to Transposon Mutagenesis than That of the Influenza A Virus.

Journal Article J Virol · August 15, 2018 Influenza A and B viruses can continuously evade humoral immune responses by developing mutations in the globular head of the hemagglutinin (HA) that prevent antibody binding. However, the influenza B virus HA over time displays less antigenic variation de ... Full text Link to item Cite

Efforts to Improve the Seasonal Influenza Vaccine.

Journal Article Vaccines (Basel) · March 30, 2018 Influenza viruses infect approximately 20% of the global population annually, resulting in hundreds of thousands of deaths. While there are Food and Drug Administration (FDA) approved antiviral drugs for combating the disease, vaccination remains the best ... Full text Link to item Cite

Viruses hijack a long non-coding RNA.

Journal Article Nature · December 14, 2017 Full text Link to item Cite

Epitranscriptomic Enhancement of Influenza A Virus Gene Expression and Replication.

Journal Article Cell Host Microbe · September 13, 2017 Many viral RNAs are modified by methylation of the N6 position of adenosine (m6A). m6A is thought to regulate RNA splicing, stability, translation, and secondary structure. Influenza A virus (IAV) expresses m6A-modified RNAs, but the effects of m6A on this ... Full text Link to item Cite

A CRISPR Activation Screen Identifies a Pan-avian Influenza Virus Inhibitory Host Factor.

Journal Article Cell Rep · August 15, 2017 Influenza A virus (IAV) is a pathogen that poses significant risks to human health. It is therefore critical to develop strategies to prevent influenza disease. Many loss-of-function screens have been performed to identify the host proteins required for vi ... Full text Link to item Cite

Rationally Designed Influenza Virus Vaccines That Are Antigenically Stable during Growth in Eggs.

Journal Article mBio · June 6, 2017 Influenza virus vaccine production is currently limited by the ability to grow circulating human strains in chicken eggs or in cell culture. To facilitate cost-effective growth, vaccine strains are serially passaged under production conditions, which frequ ... Full text Link to item Cite

Club cells surviving influenza A virus infection induce temporary nonspecific antiviral immunity.

Journal Article Proc Natl Acad Sci U S A · April 5, 2016 A brief window of antigen-nonspecific protection has been observed after influenza A virus (IAV) infection. Although this temporary immunity has been assumed to be the result of residual nonspecific inflammation, this period of induced immunity has not bee ... Full text Link to item Cite

Targeting Viral Proteostasis Limits Influenza Virus, HIV, and Dengue Virus Infection.

Journal Article Immunity · January 19, 2016 Viruses are obligate parasites and thus require the machinery of the host cell to replicate. Inhibition of host factors co-opted during active infection is a strategy hosts use to suppress viral replication and a potential pan-antiviral therapy. To define ... Full text Link to item Cite

Replication-Competent Influenza B Reporter Viruses as Tools for Screening Antivirals and Antibodies.

Journal Article J Virol · December 2015 Influenza B virus is a human pathogen responsible for significant health and economic burden. Research into this pathogen has been limited by the lack of reporter viruses. Here we describe the development of both a replication-competent fluorescent influen ... Full text Link to item Cite

Mutational Analysis of Measles Virus Suggests Constraints on Antigenic Variation of the Glycoproteins.

Journal Article Cell Rep · June 9, 2015 Measles virus undergoes error-prone replication like other RNA viruses, but over time, it has remained antigenically monotypic. The constraints on the virus that prevent the emergence of antigenic variants are unclear. As a first step in understanding this ... Full text Link to item Cite

Long-term survival of influenza virus infected club cells drives immunopathology.

Journal Article J Exp Med · August 25, 2014 Respiratory infection of influenza A virus (IAV) is frequently characterized by extensive immunopathology and proinflammatory signaling that can persist after virus clearance. In this report, we identify cells that become infected, but survive, acute influ ... Full text Link to item Cite

Genome-wide mutagenesis of influenza virus reveals unique plasticity of the hemagglutinin and NS1 proteins.

Journal Article Proc Natl Acad Sci U S A · December 10, 2013 The molecular basis for the diversity across influenza strains is poorly understood. To gain insight into this question, we mutagenized the viral genome and sequenced recoverable viruses. Only two small regions in the genome were enriched for insertions, t ... Full text Link to item Cite

Identification and comparative analysis of hepatitis C virus-host cell protein interactions.

Journal Article Mol Biosyst · December 2013 Hepatitis C virus (HCV) alters the global behavior of the host cell to create an environment conducive to its own replication, but much remains unknown about how HCV proteins elicit these changes. Thus, a better understanding of the interface between the v ... Full text Link to item Cite

Hemagglutinin stalk-based universal vaccine constructs protect against group 2 influenza A viruses.

Journal Article J Virol · October 2013 Current influenza virus vaccines contain H1N1 (phylogenetic group 1 hemagglutinin), H3N2 (phylogenetic group 2 hemagglutinin), and influenza B virus components. These vaccines induce good protection against closely matched strains by predominantly elicitin ... Full text Link to item Cite

In vivo bioluminescent imaging of influenza a virus infection and characterization of novel cross-protective monoclonal antibodies.

Journal Article J Virol · August 2013 Influenza A virus is a major human pathogen responsible for seasonal epidemics as well as pandemic outbreaks. Due to the continuing burden on human health, the need for new tools to study influenza virus pathogenesis as well as to evaluate new therapeutics ... Full text Link to item Cite

Colocalization of different influenza viral RNA segments in the cytoplasm before viral budding as shown by single-molecule sensitivity FISH analysis.

Journal Article PLoS Pathog · 2013 The Influenza A virus genome consists of eight negative sense, single-stranded RNA segments. Although it has been established that most virus particles contain a single copy of each of the eight viral RNAs, the packaging selection mechanism remains poorly ... Full text Link to item Cite

Lipids at the interface of virus-host interactions.

Journal Article Curr Opin Microbiol · August 2012 Viruses physically and metabolically remodel the host cell to establish an optimal environment for their replication. Many of these processes involve the manipulation of lipid signaling, synthesis, and metabolism. An emerging theme is that these lipid-modi ... Full text Link to item Cite

Molecular determinants and dynamics of hepatitis C virus secretion.

Journal Article PLoS Pathog · January 2012 The current model of hepatitis C virus (HCV) production involves the assembly of virions on or near the surface of lipid droplets, envelopment at the ER in association with components of VLDL synthesis, and egress via the secretory pathway. However, the ce ... Full text Link to item Cite

A physical interaction network of dengue virus and human proteins.

Journal Article Mol Cell Proteomics · December 2011 Dengue virus (DENV), an emerging mosquito-transmitted pathogen capable of causing severe disease in humans, interacts with host cell factors to create a more favorable environment for replication. However, few interactions between DENV and human proteins h ... Full text Link to item Cite

Dengue virus and autophagy.

Journal Article Viruses · August 2011 Several independent groups have published that autophagy is required for optimal RNA replication of dengue virus (DENV). Initially, it was postulated that autophagosomes might play a structural role in replication complex formation. However, cryo-EM tomogr ... Full text Link to item Cite

Multifaceted roles for lipids in viral infection.

Journal Article Trends Microbiol · July 2011 Viruses have evolved complex and dynamic interactions with their host cell. In recent years we have gained insight into the expanding roles for host lipids in the virus life cycle. In particular, viruses target lipid signaling, synthesis, and metabolism to ... Full text Link to item Cite

Dengue virus-induced autophagy regulates lipid metabolism.

Journal Article Cell Host Microbe · November 18, 2010 Autophagy influences numerous cellular processes, including innate and adaptive immunity against intracellular pathogens. However, some viruses, including dengue virus (DENV), usurp autophagy to enhance their replication. The mechanism for a positive role ... Full text Link to item Cite

Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis.

Journal Article Proc Natl Acad Sci U S A · October 5, 2010 Dengue virus (DENV) modifies cellular membranes to establish its sites of replication. Although the 3D architecture of these structures has recently been described, little is known about the cellular pathways required for their formation and expansion. In ... Full text Link to item Cite

RNA interference and single particle tracking analysis of hepatitis C virus endocytosis.

Journal Article PLoS Pathog · December 2009 Hepatitis C virus (HCV) enters hepatocytes following a complex set of receptor interactions, culminating in internalization via clathrin-mediated endocytosis. However, aside from receptors, little is known about the cellular molecular requirements for infe ... Full text Link to item Cite

Roles for endocytic trafficking and phosphatidylinositol 4-kinase III alpha in hepatitis C virus replication.

Journal Article Proc Natl Acad Sci U S A · May 5, 2009 Hepatitis C virus (HCV) reorganizes cellular membranes to establish sites of replication. The required host pathways and the mechanism of cellular membrane reorganization are poorly characterized. Therefore, we interrogated a customized small interfering R ... Full text Link to item Cite

Antisense to transforming growth factor-beta(1) facilitates the apoptosis of macrophages in rat vein grafts.

Journal Article J Vasc Res · 2008 BACKGROUND: The success of peripheral vein grafts is limited by intimal hyperplasia. Transforming growth factor (TGF)-beta(1) has effects on cell proliferation, apoptosis and extracellular matrix synthesis. We have previously observed positive changes in v ... Full text Link to item Cite

Transforming growth factor-beta1 antisense treatment of rat vein grafts reduces the accumulation of collagen and increases the accumulation of h-caldesmon.

Journal Article J Vasc Surg · May 2006 BACKGROUND: The main cause of occlusion and vein graft failure after peripheral and coronary arterial reconstruction is intimal hyperplasia. Transforming growth factor beta-1 (TGF-beta1) is a pleiotropic cytokine known to have powerful effects on cell grow ... Full text Link to item Cite