Scholars@Duke
Dennis Ko

Dennis Ko

Associate Professor in Molecular Genetics and Microbiology
Molecular Genetics and Microbiology
dennis.ko@duke.edu
0049 CARL Building, Box 3053, 213 Research Drive, Durham, NC 27710

Selected Publications

Context-specific eQTLs reveal causal genes underlying shared genetic architecture of critically ill COVID-19 and idiopathic pulmonary fibrosis.

Journal Article medRxiv · July 14, 2024 Most genetic variants identified through genome-wide association studies (GWAS) are suspected to be regulatory in nature, but only a small fraction colocalize with expression quantitative trait loci (eQTLs, variants associated with expression of a gene). T ... Full text Link to item Cite

Nuclear factor kappa B-dependent persistence of Salmonella Typhi and Paratyphi in human macrophages.

Journal Article mBio · April 10, 2024 UNLABELLED: Salmonella serovars Typhi and Paratyphi cause a prolonged illness known as enteric fever, whereas other serovars cause acute gastroenteritis. Mechanisms responsible for the divergent clinical manifestations of nontyphoidal and enteric fever Sal ... Full text Link to item Cite

Targeting senescent hepatocytes using the thrombomodulin-PAR1 inhibitor vorapaxar ameliorates NAFLD progression.

Journal Article Hepatology · October 1, 2023 BACKGROUND AND AIMS: Senescent hepatocytes accumulate in parallel with fibrosis progression during NASH. The mechanisms that enable progressive expansion of nonreplicating cell populations and the significance of that process in determining NASH outcomes a ... Full text Link to item Cite

The RNA helicase DDX39B activates FOXP3 RNA splicing to control T regulatory cell fate.

Journal Article Elife · June 1, 2023 Genes associated with increased susceptibility to multiple sclerosis (MS) have been identified, but their functions are incompletely understood. One of these genes codes for the RNA helicase DExD/H-Box Polypeptide 39B (DDX39B), which shows genetic and func ... Full text Link to item Cite

Human variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation.

Journal Article Cell Genom · May 10, 2023 Human genetic diversity can reveal critical factors in host-pathogen interactions. This is especially useful for human-restricted pathogens like Salmonella enterica serovar Typhi (S. Typhi), the cause of typhoid fever. One key defense during bacterial infe ... Full text Link to item Cite

GABA signaling triggered by TMC-1/Tmc delays neuronal aging by inhibiting the PKC pathway in C. elegans.

Journal Article Sci Adv · December 21, 2022 Aging causes functional decline and degeneration of neurons and is a major risk factor of neurodegenerative diseases. To investigate the molecular mechanisms underlying neuronal aging, we developed a new pipeline for neuronal proteomic profiling in young a ... Full text Link to item Cite

The bacterial effector GarD shields Chlamydia trachomatis inclusions from RNF213-mediated ubiquitylation and destruction.

Journal Article Cell Host Microbe · December 14, 2022 Chlamydia trachomatis is the leading cause of sexually transmitted bacterial infections and a major threat to women's reproductive health in particular. This obligate intracellular pathogen resides and replicates within a cellular compartment termed an inc ... Full text Link to item Cite

The Awesome Power of Human Genetics of Infectious Disease.

Journal Article Annu Rev Genet · November 30, 2022 Since the identification of sickle cell trait as a heritable form of resistance to malaria, candidate gene studies, linkage analysis paired with sequencing, and genome-wide association (GWA) studies have revealed many examples of genetic resistance and sus ... 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

Identification of a Germline Pyrin Variant in a Metastatic Melanoma Patient With Multiple Spontaneous Regressions and Immune-related Adverse Events.

Journal Article J Immunother · July 2022 The mechanisms underlying tumor immunosurveillance and their association with the immune-related adverse events (irAEs) associated with checkpoint inhibitor immunotherapies remain poorly understood. We describe a metastatic melanoma patient exhibiting mult ... Full text Open Access Link to item Cite

Integration of the Salmonella Typhimurium Methylome and Transcriptome Reveals That DNA Methylation and Transcriptional Regulation Are Largely Decoupled under Virulence-Related Conditions.

Journal Article mBio · June 28, 2022 Despite being in a golden age of bacterial epigenomics, little work has systematically examined the plasticity and functional impacts of the bacterial DNA methylome. Here, we leveraged single-molecule, real-time sequencing (SMRT-seq) to examine the m6A DNA ... Full text Link to item Cite

Human genetic diversity regulating the TLR10/TLR1/TLR6 locus confers increased cytokines in response to Chlamydia trachomatis.

Journal Article HGG Adv · January 13, 2022 Human genetic diversity can have profound effects on health outcomes upon exposure to infectious agents. For infections with Chlamydia trachomatis (C. trachomatis), the wide range of genital and ocular disease manifestations are likely influenced by human ... Full text Link to item Cite

Variation in Leishmania chemokine suppression driven by diversification of the GP63 virulence factor.

Journal Article PLoS Negl Trop Dis · October 2021 Leishmaniasis is a neglected tropical disease with diverse outcomes ranging from self-healing lesions, to progressive non-healing lesions, to metastatic spread and destruction of mucous membranes. Although resolution of cutaneous leishmaniasis is a classic ... Full text Link to item Cite

ARHGEF26 enhances Salmonella invasion and inflammation in cells and mice.

Journal Article PLoS Pathog · July 2021 Salmonella hijack host machinery in order to invade cells and establish infection. While considerable work has described the role of host proteins in invasion, much less is known regarding how natural variation in these invasion-associated host proteins af ... Full text Link to item Cite

An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility.

Journal Article Genome Med · May 17, 2021 BACKGROUND: While genome-wide associations studies (GWAS) have successfully elucidated the genetic architecture of complex human traits and diseases, understanding mechanisms that lead from genetic variation to pathophysiology remains an important challeng ... Full text Open Access Link to item Cite

These Are the Genes You're Looking For: Finding Host Resistance Genes.

Journal Article Trends Microbiol · April 2021 Humanity's ongoing struggle with new, re-emerging and endemic infectious diseases serves as a frequent reminder of the need to understand host-pathogen interactions. Recent advances in genomics have dramatically advanced our understanding of how genetics c ... Full text Link to item Cite

Th17 Immunity in the Colon Is Controlled by Two Novel Subsets of Colon-Specific Mononuclear Phagocytes.

Conference Front Immunol · 2021 Intestinal immunity is coordinated by specialized mononuclear phagocyte populations, constituted by a diversity of cell subsets. Although the cell subsets constituting the mononuclear phagocyte network are thought to be similar in both small and large inte ... Full text Link to item Cite

Variation inLeishmaniachemokine suppression driven by diversification of the GP63 virulence factor

Journal Article · 2021 Leishmaniasis is a neglected tropical disease with diverse infection outcomes ranging from self-healing lesions, to progressive non-healing lesion, to metastatic spread and destruction of mucous membranes. Although resolution of cutaneous leishmaniasis is ... Full text Cite

Integration of the Salmonella Typhimurium methylome and transcriptome reveals DNA methylation and transcriptional regulation are largely decoupled under virulence-related conditions

Journal Article · 2021 Despite being in a golden age of bacterial epigenomics, little work has systematically examined the plasticity and functional impacts of the bacterial DNA methylome. Here, we leveraged SMRT sequencing to examine the m 6 A DNA methylome of two Salmonella en ... Full text Cite

An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility.

Journal Article medRxiv · December 22, 2020 While genome-wide associations studies (GWAS) have successfully elucidated the genetic architecture of complex human traits and diseases, understanding mechanisms that lead from genetic variation to pathophysiology remains an important challenge. Methods a ... Full text Link to item Cite

Modeling of variables in cellular infection reveals CXCL10 levels are regulated by human genetic variation and the Chlamydia-encoded CPAF protease.

Journal Article Sci Rep · October 26, 2020 Susceptibility to infectious diseases is determined by a complex interaction between host and pathogen. For infections with the obligate intracellular bacterium Chlamydia trachomatis, variation in immune activation and disease presentation are regulated by ... Full text Open Access Link to item Cite

The Salmonella Secreted Effector SarA/SteE Mimics Cytokine Receptor Signaling to Activate STAT3.

Journal Article Cell Host Microbe · January 8, 2020 Bacteria masterfully co-opt and subvert host signal transduction. As a paradigmatic example, Salmonella uses two type-3 secretion systems to inject effector proteins that facilitate Salmonella entry, establishment of an intracellular niche, and modulation ... Full text Link to item Cite

ARHGEF26 enhancesSalmonellainvasion and inflammation in cells and mice

Journal Article · 2020 Salmonella hijack host machinery in order to invade cells and establish infection. While considerable work has described the role of host proteins in invasion, much less is known regarding how natural variation in these invasion-associated host proteins af ... Full text Cite

The genetic architecture of human infectious diseases and pathogen-induced cellular phenotypes

Journal Article · 2020 Here, we develop a genetics-anchored framework to decipher mechanisms of infectious disease (ID) risk and infer causal effect on potential complications. We perform transcriptome-wide association studies (TWAS) of 35 ID traits in 27,615 individuals in a br ... Full text Cite

Pathogen-encoded evasion of CXCL10 and T cell responses

Journal Article · February 22, 2019 Abstract Clearance of intracellular pathogens, such as Leishmania (L.) major , depends on a well-regulated adaptive T cell response. Here we describe a pathogen-encoded mechanism to alter T cell recruitment by suppressing CXCL10, a chemokine that recruits ... Full text Open Access Cite

Pathogen Evasion of Chemokine Response Through Suppression of CXCL10.

Journal Article Front Cell Infect Microbiol · 2019 UNLABELLED: Clearance of intracellular pathogens, such as Leishmania (L.) major, depends on an immune response with well-regulated cytokine signaling. Here we describe a pathogen-mediated mechanism of evading CXCL10, a chemokine with diverse antimicrobial ... Full text Link to item Cite

Methylthioadenosine Suppresses Salmonella Virulence.

Journal Article Infect Immun · September 2018 In order to deploy virulence factors at appropriate times and locations, microbes must rapidly sense and respond to various metabolite signals. Previously, we showed a transient elevation of the methionine-derived metabolite methylthioadenosine (MTA) conce ... Full text Link to item Cite

An Atlas of Genetic Variation Linking Pathogen-Induced Cellular Traits to Human Disease.

Journal Article Cell Host Microbe · August 8, 2018 Pathogens have been a strong driving force for natural selection. Therefore, understanding how human genetic differences impact infection-related cellular traits can mechanistically link genetic variation to disease susceptibility. Here we report the Hi-HO ... Full text Open Access Link to item Cite

Salmonella Activation of STAT3 Signaling by SarA Effector Promotes Intracellular Replication and Production of IL-10.

Journal Article Cell Rep · June 19, 2018 Salmonella enterica is an important foodborne pathogen that uses secreted effector proteins to manipulate host pathways to facilitate survival and dissemination. Different S. enterica serovars cause disease syndromes ranging from gastroenteritis to typhoid ... Full text Link to item Cite

Systematic detection of positive selection in the human-pathogen interactome and lasting effects on infectious disease susceptibility.

Journal Article PLoS One · 2018 Infectious disease has shaped the natural genetic diversity of humans throughout the world. A new approach to capture positive selection driven by pathogens would provide information regarding pathogen exposure in distinct human populations and the constan ... Full text Link to item Cite

A real-time PCR assay for quantification of parasite burden in murine models of leishmaniasis.

Journal Article PeerJ · 2018 Eukaryotic parasites in the genus Leishmania place approximately 350 million people per year at risk of disease. In addition to their global health significance, Leishmania spp. have served as an important model for delineating basic concepts in immunology ... Full text Link to item Cite

Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol.

Journal Article Proc Natl Acad Sci U S A · September 12, 2017 Risk, severity, and outcome of infection depend on the interplay of pathogen virulence and host susceptibility. Systematic identification of genetic susceptibility to infection is being undertaken through genome-wide association studies, but how to expedit ... Full text Open Access Link to item Cite

Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk.

Journal Article Cell · March 23, 2017 Multiple sclerosis (MS) is an autoimmune disorder where T cells attack neurons in the central nervous system (CNS) leading to demyelination and neurological deficits. A driver of increased MS risk is the soluble form of the interleukin-7 receptor alpha cha ... Full text Link to item Cite

Human genetic and metabolite variation reveals that methylthioadenosine is a prognostic biomarker and an inflammatory regulator in sepsis.

Journal Article Sci Adv · March 2017 Sepsis is a deleterious inflammatory response to infection with high mortality. Reliable sepsis biomarkers could improve diagnosis, prognosis, and treatment. Integration of human genetics, patient metabolite and cytokine measurements, and testing in a mous ... Full text Open Access Link to item Cite

A whole animal chemical screen approach to identify modifiers of intestinal neutrophilic inflammation.

Journal Article FEBS J · February 2017 By performing two high-content small molecule screens on dextran sodium sulfate- and trinitrobenzene sulfonic acid-induced zebrafish enterocolitis models of inflammatory bowel disease, we have identified novel anti-inflammatory drugs from the John Hopkins ... Full text Link to item Cite

Multiple Surface Regions on the Niemann-Pick C2 Protein Facilitate Intracellular Cholesterol Transport.

Journal Article J Biol Chem · November 6, 2015 The cholesterol storage disorder Niemann-Pick type C (NPC) disease is caused by defects in either of two late endosomal/lysosomal proteins, NPC1 and NPC2. NPC2 is a 16-kDa soluble protein that binds cholesterol in a 1:1 stoichiometry and can transfer chole ... Full text Link to item Cite

CPAG: software for leveraging pleiotropy in GWAS to reveal similarity between human traits links plasma fatty acids and intestinal inflammation.

Journal Article Genome Biol · September 15, 2015 Meta-analyses of genome-wide association studies (GWAS) have demonstrated that the same genetic variants can be associated with multiple diseases and other complex traits. We present software called CPAG (Cross-Phenotype Analysis of GWAS) to look for simil ... Full text Open Access Link to item Cite

Calcineurin orchestrates dimorphic transitions, antifungal drug responses and host-pathogen interactions of the pathogenic mucoralean fungus Mucor circinelloides.

Journal Article Mol Microbiol · September 2015 Calcineurin plays essential roles in virulence and growth of pathogenic fungi and is a target of the natural products FK506 and Cyclosporine A. In the pathogenic mucoralean fungus Mucor circinelloides, calcineurin mutation or inhibition confers a yeast-loc ... Full text Link to item Cite

Expression Divergence of Duplicate Genes in the Protein Kinase Superfamily in Pacific Oyster.

Journal Article Evol Bioinform Online · 2015 Gene duplication has been proposed to serve as the engine of evolutionary innovation. It is well recognized that eukaryotic genomes contain a large number of duplicated genes that evolve new functions or expression patterns. However, in mollusks, the evolu ... Full text Link to item Cite

Analysis of a food-borne fungal pathogen outbreak: virulence and genome of a Mucor circinelloides isolate from yogurt.

Journal Article mBio · July 8, 2014 Food-borne pathogens are ongoing problems, and new pathogens are emerging. The impact of fungi, however, is largely underestimated. Recently, commercial yogurts contaminated with Mucor circinelloides were sold, and >200 consumers became ill with nausea, vo ... Full text Link to item Cite

A cellular genome-wide association study reveals human variation in microtubule stability and a role in inflammatory cell death.

Journal Article Mol Biol Cell · January 2014 Pyroptosis is proinflammatory cell death that occurs in response to certain microbes. Activation of the protease caspase-1 by molecular platforms called inflammasomes is required for pyroptosis. We performed a cellular genome-wide association study (GWAS) ... Full text Open Access Link to item Cite

The marriage of quantitative genetics and cell biology: a novel screening approach reveals people have genetically encoded variation in microtubule stability.

Journal Article Bioarchitecture · 2014 Microtubules play a central role in many essential cellular processes, including chromosome segregation, intracellular transport, and cell polarity. As these dynamic polymers are crucial components of eukaryotic cellular architecture, we were surprised by ... Full text Link to item Cite

An enzyme that inactivates the inflammatory mediator leukotriene b4 restricts mycobacterial infection.

Journal Article PLoS One · 2013 While tuberculosis susceptibility has historically been ascribed to failed inflammation, it is now known that an excess of leukotriene A4 hydrolase (LTA4H), which catalyzes the final step in leukotriene B4 (LTB4) synthesis, produces a hyperinflammatory sta ... Full text Open Access Link to item Cite

Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death.

Journal Article Proc Natl Acad Sci U S A · August 28, 2012 Genome-wide association studies can identify common differences that contribute to human phenotypic diversity and disease. When genome-wide association studies are combined with approaches that test how variants alter physiology, biological insights can em ... Full text Link to item Cite

Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections.

Journal Article Cell · February 3, 2012 Susceptibility to tuberculosis is historically ascribed to an inadequate immune response that fails to control infecting mycobacteria. In zebrafish, we find that susceptibility to Mycobacterium marinum can result from either inadequate or excessive acute i ... Full text Link to item Cite

A suppressor/enhancer screen in Drosophila reveals a role for wnt-mediated lipid metabolism in primordial germ cell migration.

Journal Article PLoS One · 2011 Wnt proteins comprise a large family of secreted ligands implicated in a wide variety of biological roles. WntD has previously been shown to inhibit the nuclear accumulation of Dorsal/NF-κB protein during embryonic dorsal/ventral patterning and the adult i ... Full text Link to item Cite

A suppressor/enhancer screen in Drosophila reveals a role for Wnt-mediated lipid metabolism in primordial germ cell migration

Journal Article PLoS ONE · 2011 Wnt proteins comprise a large family of secreted ligands implicated in a wide variety of biological roles. WntD has previously been shown to inhibit the nuclear accumulation of Dorsal/NF-κB protein during embryonic dorsal/ventral patterning and the adult i ... Full text Cite

Expression of the Salmonella spp. virulence factor SifA in yeast alters Rho1 activity on peroxisomes.

Journal Article Mol Biol Cell · October 15, 2010 The Salmonella typhimurium effector protein SifA regulates the assembly and tubulation of the Salmonella phagosome. SifA localizes to the phagosome and interacts with the membrane via its prenylated tail. SifA is a structural homologue of another bacterial ... Full text Link to item Cite

GWAS analyzer: integrating genotype, phenotype and public annotation data for genome-wide association study analysis.

Journal Article Bioinformatics · February 15, 2010 MOTIVATION: Genome-wide association studies are beginning to elucidate how our genetic differences contribute to susceptibility and severity of disease. While computational tools have previously been developed to support various aspects of genome-wide asso ... Full text Link to item Cite

A genome-wide in vitro bacterial-infection screen reveals human variation in the host response associated with inflammatory disease.

Journal Article Am J Hum Genet · August 2009 Recent progress in cataloguing common genetic variation has made possible genome-wide studies that are beginning to elucidate the causes and consequences of our genetic differences. Approaches that provide a mechanistic understanding of how genetic variant ... Full text Link to item Cite

A conserved acidic patch in the Myb domain is required for activation of an endogenous target gene and for chromatin binding.

Journal Article Mol Cancer · October 7, 2008 The c-Myb protein is a transcriptional regulator initially identified by homology to the v-Myb oncoprotein, and has since been implicated in human cancer. The most highly conserved portion of the c-Myb protein is the DNA-binding domain which consists of th ... Full text Link to item Cite

Cell-autonomous death of cerebellar purkinje neurons with autophagy in niemann-pick type C disease

Journal Article PLoS Genetics · July 1, 2005 Niemann-Pick type C is a neurodegenerative lysosomal storage disorder caused by mutations in either of two genes, npc1 and npc2. Cells lacking Npc1, which is a transmembrane protein related to the Hedgehog receptor Patched, or Npc2, which is a secreted cho ... Full text Cite

The integrity of a cholesterol-binding pocket in Niemann-Pick C2 protein is necessary to control lysosome cholesterol levels.

Journal Article Proc Natl Acad Sci U S A · March 4, 2003 The neurodegenerative disease Niemann-Pick Type C2 (NPC2) results from mutations in the NPC2 (HE1) gene that cause abnormally high cholesterol accumulation in cells. We find that purified NPC2, a secreted soluble protein, binds cholesterol specifically wit ... Full text Link to item Cite

Dynamic movements of organelles containing Niemann-Pick C1 protein: NPC1 involvement in late endocytic events.

Journal Article Mol Biol Cell · March 2001 People homozygous for mutations in the Niemann-Pick type C1 (NPC1) gene have physiological defects, including excess accumulation of intracellular cholesterol and other lipids, that lead to drastic neural and liver degeneration. The NPC1 multipass transmem ... Full text Link to item Cite

A surface of Escherichia coli sigma 70 required for promoter function and antitermination by phage lambda Q protein.

Journal Article Genes Dev · October 15, 1998 The sigma initiation factor sigma70 of Escherichia coli acts not only in promoter recognition and DNA strand opening, but also to mediate the transformation of RNA polymerase (RNAP) to an antiterminating form by the phage lambda gene Q protein. Q is able t ... Full text Link to item Cite

Antitermination by bacteriophage lambda Q protein.

Journal Article Cold Spring Harb Symp Quant Biol · 1998 Full text Link to item Cite

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

Dataset Diversity in the human genome is one factor that confers resistance and susceptibility to infectious diseases. This is observed most dramatically during pandemics, where individuals exhibit large differences in risk and clinical outcomes against a pathogen ... Full text Cite