Scholars@Duke
Ashley St John

Ashley St John

Adjunct Associate Professor in the Department of Pathology
Pathology
ashley.st.john@duke.edu
Box 3010 Med Ctr, Durham, NC 27710
156 Jones Bldg, Durham, NC 27710

Selected Publications

NKT cells promote Th1 immune bias to dengue virus that governs long-term protective antibody dynamics.

Journal Article J Clin Invest · August 1, 2024 NKT cells are innate-like T cells, recruited to the skin during viral infection, yet their contributions to long-term immune memory to viruses are unclear. We identified granzyme K, a product made by cytotoxic cells including NKT cells, as linked to induct ... Full text Link to item Cite

AI is a viable alternative to high throughput screening: a 318-target study.

Journal Article Sci Rep · April 2, 2024 High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can acce ... Full text Open Access Link to item Cite

Mucosal SARS-CoV-2 vaccination of rodents elicits superior systemic T central memory function and cross-neutralising antibodies against variants of concern.

Journal Article EBioMedicine · January 2024 BACKGROUND: COVID-19 vaccines used in humans are highly effective in limiting disease and death caused by the SARS-CoV-2 virus, yet improved vaccines that provide greater protection at mucosal surfaces, which could reduce break-through infections and subse ... Full text Link to item Cite

Exacerbated Zika virus-induced neuropathology and microcephaly in fetuses of dengue-immune nonhuman primates.

Journal Article Sci Transl Med · October 25, 2023 Zika virus (ZIKV) is a mosquito-borne flavivirus that can vertically transmit from mother to fetus, potentially causing congenital defects, including microcephaly. It is not fully understood why some fetuses experience severe complications after in utero e ... Full text Link to item Cite

Mast cell activation in lungs during SARS-CoV-2 infection associated with lung pathology and severe COVID-19.

Journal Article J Clin Invest · October 2, 2023 Lung inflammation is a hallmark of Coronavirus disease 2019 (COVID-19) in patients who are severely ill, and the pathophysiology of disease is thought to be immune mediated. Mast cells (MCs) are polyfunctional immune cells present in the airways, where the ... Full text Link to item Cite

Promises and challenges of mucosal COVID-19 vaccines.

Journal Article Vaccine · June 19, 2023 Coronavirus disease-2019 (COVID-19) is an ongoing pandemic caused by the newly emerged virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, COVID-19 vaccines are given intramuscularly and they have been shown to evoke systemic imm ... Full text Link to item Cite

New perspectives on the origins and heterogeneity of mast cells.

Journal Article Nat Rev Immunol · January 2023 Featured Publication Mast cells are immune cells of the haematopoietic lineage that are now thought to have multifaceted functions during homeostasis and in various disease states. Furthermore, while mast cells have been known for a long time to contribute to allergic disease ... Full text Link to item Cite

Dengue: Update on Clinically Relevant Therapeutic Strategies and Vaccines.

Journal Article Current treatment options in infectious diseases · January 2023 Dengue viruses (DENV) continue to circulate worldwide, resulting in a significant burden on human health. There are four antigenically distinct serotypes of DENV, an infection of which could result in a potentially life-threatening disease. Current treatme ... Full text Cite

Conventional and non-conventional antigen presentation by mast cells.

Journal Article Discov Immunol · 2023 Mast cells (MCs) are multifunctional immune cells that express a diverse repertoire of surface receptors and pre-stored bioactive mediators. They are traditionally recognized for their involvement in allergic and inflammatory responses, yet there is a grow ... Full text Link to item Cite

Transitional premonocytes emerge in the periphery for host defense against bacterial infections.

Journal Article Sci Adv · March 4, 2022 Circulating Ly6Chi monocytes often undergo cellular death upon exhaustion of their antibacterial effector functions, which limits their capacity for subsequent macrophage differentiation. This shrouds the understanding on how the host replaces the tissue-r ... Full text Link to item Cite

Dengue virus infection modifies mosquito blood-feeding behavior to increase transmission to the host.

Journal Article Proc Natl Acad Sci U S A · January 18, 2022 Mosquito blood-feeding behavior is a key determinant of the epidemiology of dengue viruses (DENV), the most-prevalent mosquito-borne viruses. However, despite its importance, how DENV infection influences mosquito blood-feeding and, consequently, transmiss ... Full text Link to item Cite

Animals as potential reservoirs for dengue transmission: A systematic review.

Journal Article One Health · June 2021 Dengue is a rapidly spreading mosquito-borne flavivirus infection that is prevalent in tropical and sub-tropical regions. Humans are known to be the main reservoir host maintaining the epidemic cycles of dengue but it is unclear if dengue virus is also mai ... Full text Link to item Cite

Signatures of mast cell activation are associated with severe COVID-19.

Journal Article medRxiv · June 1, 2021 Lung inflammation is a hallmark of Coronavirus disease 2019 (COVID-19) in severely ill patients and the pathophysiology of disease is thought to be immune-mediated. Mast cells (MCs) are polyfunctional immune cells present in the airways, where they respond ... Full text Link to item Cite

Maternal Immunity and Vaccination Influence Disease Severity in Progeny in a Novel Mast Cell-Deficient Mouse Model of Severe Dengue.

Journal Article Viruses · May 12, 2021 Sub-neutralizing concentrations of antibodies in dengue infected patients is a major risk factor for the development of dengue hemorrhagic fever and dengue shock syndrome. Here, we describe a mouse model with a deficiency in mast cells (MCs) in addition to ... Full text Link to item Cite

Coding and non-coding roles of MOCCI (C15ORF48) coordinate to regulate host inflammation and immunity.

Journal Article Nat Commun · April 9, 2021 Mito-SEPs are small open reading frame-encoded peptides that localize to the mitochondria to regulate metabolism. Motivated by an intriguing negative association between mito-SEPs and inflammation, here we screen for mito-SEPs that modify inflammatory outc ... Full text Link to item Cite

Immunological and Pathological Landscape of Dengue Serotypes 1-4 Infections in Immune-Competent Mice.

Journal Article Front Immunol · 2021 Dengue virus (DENV), a Flavivirus, causes a broad spectrum of disease in humans with key clinical signs including thrombocytopenia, vascular leakage and hemorrhaging. A major obstacle to understanding DENV immunity has been the lack of a validated immune-c ... Full text Link to item Cite

Th1-Polarized, Dengue Virus-Activated Human Mast Cells Induce Endothelial Transcriptional Activation and Permeability.

Journal Article Viruses · December 2, 2020 Dengue virus (DENV), an arbovirus, strongly activates mast cells (MCs), which are key immune cells for pathogen immune surveillance. In animal models, MCs promote clearance of local peripheral DENV infections but, conversely, also promote pathological vasc ... Full text Link to item Cite

Fetal mast cells mediate postnatal allergic responses dependent on maternal IgE.

Journal Article Science · November 20, 2020 Featured Publication Mast cells (MCs) are central effector cells in allergic reactions that are often mediated by immunoglobulin E (IgE). Allergies commonly start at an early age, and both MCs and IgE are detectable in fetuses. However, the origin of fetal IgE and whether feta ... Full text Link to item Cite

Protective and pathogenic roles for mast cells during viral infections.

Journal Article Curr Opin Immunol · October 2020 Mast cells (MCs) are long-lived immune cells. They are armed with preformed mediators within granules that can be instantaneously released in response to an invading pathogen, including certain viruses. At the skin and mucosae, they initiate innate immune ... Full text Link to item Cite

Combinatorial Single-Cell Analyses of Granulocyte-Monocyte Progenitor Heterogeneity Reveals an Early Uni-potent Neutrophil Progenitor.

Journal Article Immunity · August 18, 2020 Granulocyte-monocyte progenitors (GMPs) have been previously defined for their potential to generate various myeloid progenies such as neutrophils and monocytes. Although studies have proposed lineage heterogeneity within GMPs, it is unclear if committed p ... Full text Link to item Cite

Early Insights into Immune Responses during COVID-19.

Journal Article J Immunol · August 1, 2020 Featured Publication Coronavirus disease-2019 (COVID-19) is caused by the newly emerged virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and was recently declared as a pandemic by the World Health Organization. In its severe form, the disease is characterized ... Full text Link to item Cite

Risk factors and biomarkers of severe dengue.

Journal Article Curr Opin Virol · August 2020 Dengue virus infects several million people each year. Although usually a self-limiting disease, some patients can develop life-threatening severe complications, characterized by plasma leakage, hemorrhaging, and shock. The signs and symptoms of severe dis ... Full text Link to item Cite

Serum chymase levels correlate with severe dengue warning signs and clinical fluid accumulation in hospitalized pediatric patients.

Journal Article Sci Rep · July 16, 2020 Dengue induces a spectrum of severity in humans from the milder dengue fever to severe disease, or dengue hemorrhagic fever (DHF). Chymase is a candidate biomarker that may aid dengue prognosis. This prospective study aimed to identify whether warning sign ... Full text Link to item Cite

ELKS1 controls mast cell degranulation by regulating the transcription of Stxbp2 and Syntaxin 4 via Kdm2b stabilization.

Journal Article Sci Adv · July 2020 ELKS1 is a protein with proposed roles in regulated exocytosis in neurons and nuclear factor κB (NF-κB) signaling in cancer cells. However, how these two potential roles come together under physiological settings remain unknown. Since both regulated exocyt ... Full text Link to item Cite

Novel mucosal adjuvant, mastoparan-7, improves cocaine vaccine efficacy.

Journal Article NPJ Vaccines · February 5, 2020 Cocaine is one of the most potent and addictive psychostimulants known and there are no available pharmacotherapies to treat cocaine addiction. Here we describe a novel cocaine vaccine employing the mucosal adjuvant and mast cell-activating oligopeptide, m ... Full text Link to item Cite

Novel mucosal adjuvant, mastoparan-7, improves cocaine vaccine efficacy.

Journal Article NPJ Vaccines · 2020 Cocaine is one of the most potent and addictive psychostimulants known and there are no available pharmacotherapies to treat cocaine addiction. Here we describe a novel cocaine vaccine employing the mucosal adjuvant and mast cell-activating oligopeptide, m ... Full text Open Access Link to item Cite

Cross-Reactive Immunity Among Flaviviruses.

Journal Article Front Immunol · 2020 Flaviviruses consist of significant human pathogens responsible for hundreds of millions of infections each year. Their antigenic relationships generate immune responses that are cross-reactive to multiple flaviviruses and their widespread and overlapping ... Full text Link to item Cite

Dengue Viruses (Flaviviridae)

Chapter · January 1, 2020 Dengue fever/dengue hemorrhagic fever is the most important arboviral disease of humans. In the past 50 years, there has been a dramatic global re-emergence of dengue fever with expanding geographic distribution of both the viruses and the mosquito vectors ... Full text Cite

Therapeutics for Dengue

Journal Article Current Treatment Options in Infectious Diseases · September 15, 2019 Full text Cite

Dengue virus-elicited tryptase induces endothelial permeability and shock.

Journal Article J Clin Invest · July 2, 2019 Featured Publication Dengue virus (DENV) infection causes a characteristic pathology in humans involving dysregulation of the vascular system. In some patients with dengue hemorrhagic fever (DHF), vascular pathology can become severe, resulting in extensive microvascular perme ... Full text Link to item Cite

Peripheral serotonin causes dengue virus-induced thrombocytopenia through 5HT2 receptors.

Journal Article Blood · May 23, 2019 Dengue virus (DENV) is the most prevalent vector-borne viral pathogen, infecting millions of patients annually. Thrombocytopenia, a reduction in circulating platelet counts, is the most consistent sign of DENV-induced disease, independent of disease severi ... Full text Link to item Cite

Adaptive immune responses to primary and secondary dengue virus infections.

Journal Article Nat Rev Immunol · April 2019 Featured Publication Dengue is the leading mosquito-borne viral illness infecting humans. Owing to the circulation of multiple serotypes, global expansion of the disease and recent gains in vaccination coverage, pre-existing immunity to dengue virus is abundant in the human po ... Full text Link to item Cite

Immune synapses between mast cells and γδ T cells limit viral infection.

Journal Article J Clin Invest · March 1, 2019 Featured Publication Mast cells (MCs) are immune sentinels, but whether they also function as antigen-presenting cells (APCs) remains elusive. Using mouse models of MC deficiency, we report on MC-dependent recruitment and activation of multiple T cell subsets to the skin and d ... Full text Link to item Cite

Japanese encephalitis virus neuropenetrance is driven by mast cell chymase.

Journal Article Nat Commun · February 11, 2019 Japanese encephalitis virus (JEV) is a leading cause of viral encephalitis. However, the mechanisms of JEV penetration of the blood-brain-barrier (BBB) remain poorly understood. Mast cells (MCs) are granulated innate immune sentinels located perivascularly ... Full text Link to item Cite

Maternal immunity and antibodies to dengue virus promote infection and Zika virus-induced microcephaly in fetuses.

Journal Article Sci Adv · February 2019 Featured Publication Zika virus (ZIKV), an emergent flaviviral pathogen, has been linked to microcephaly in neonates. Although the risk is greatest during the first trimester of pregnancy in humans, timing alone cannot explain why maternal ZIKV infection leads to severe microc ... Full text Link to item Cite

Necroptosis of infiltrated macrophages drives Yersinia pestis dispersal within buboes.

Journal Article JCI Insight · September 20, 2018 When draining lymph nodes become infected by Yersinia pestis (Y. pestis), a massive influx of phagocytic cells occurs, resulting in distended and necrotic structures known as buboes. The bubonic stage of the Y. pestis life cycle precedes septicemia, which ... Full text Link to item Cite

Immune responses to dengue virus in the skin.

Journal Article Open Biol · August 2018 Dengue virus (DENV) causes infection in humans and current estimates place 40% of the world population at risk for contracting disease. There are four DENV serotypes that induce a febrile illness, which can develop into a severe and life-threatening diseas ... Full text Link to item Cite

Flavivirus serocomplex cross-reactive immunity is protective by activating heterologous memory CD4 T cells.

Journal Article Sci Adv · July 2018 How previous immunity influences immune memory recall and protection against related flaviviruses is largely unknown, yet encounter with multiple flaviviruses in a lifetime is increasingly likely. Using sequential challenges with dengue virus (DENV), yello ... Full text Link to item Cite

Reprograming immunity to food allergens.

Journal Article J Allergy Clin Immunol · May 2018 A novel immune-modulatory therapy utilizing targeted delivery of cytokines to draining lymph nodes effectively reprograms Th2 allergic responses towards a Th1 and tolerogenic profile, resulting in protection from peanut antigen-induced anaphylaxis. ... Full text Link to item Cite

A preliminary study on efficacy of rupatadine for the treatment of acute dengue infection.

Journal Article Sci Rep · March 1, 2018 Currently there are no specific treatments available for acute dengue infection. We considered that rupatadine, a platelet-activating factor receptor inhibitor, might modulate dengue-associated vascular leak. The effects of rupatadine were assessed in vitr ... Full text Link to item Cite

Chymase Level Is a Predictive Biomarker of Dengue Hemorrhagic Fever in Pediatric and Adult Patients.

Journal Article J Infect Dis · November 27, 2017 BACKGROUND: Most patients with dengue experience mild disease, dengue fever (DF), while few develop the life-threatening diseases dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). No laboratory tests predict DHF or DSS. We evaluated whether th ... Full text Link to item Cite

Transcriptional Profiling Confirms the Therapeutic Effects of Mast Cell Stabilization in a Dengue Disease Model.

Journal Article J Virol · September 15, 2017 There are no approved therapeutics for the treatment of dengue disease despite the global prevalence of dengue virus (DENV) and its mosquito vectors. DENV infections can lead to vascular complications, hemorrhage, and shock due to the ability of DENV to in ... Full text Link to item Cite

Immune correlates of protection for dengue: State of the art and research agenda.

Conference Vaccine · August 24, 2017 Dengue viruses (DENV1-4) are mosquito-borne flaviviruses estimated to cause up to ∼400 million infections and ∼100 million dengue cases each year. Factors that contribute to protection from and risk of dengue and severe dengue disease have been studied ext ... Full text Link to item Cite

Cross-reactive antibodies enhance live attenuated virus infection for increased immunogenicity.

Journal Article Nat Microbiol · September 19, 2016 Vaccination has achieved remarkable successes in the control of childhood viral diseases. To control emerging infections, however, vaccines will need to be delivered to older individuals who, unlike infants, probably have had prior infection or vaccination ... Full text Link to item Cite

Molecular determinants of plaque size as an indicator of dengue virus attenuation.

Journal Article Sci Rep · May 17, 2016 The development of live viral vaccines relies on empirically derived phenotypic criteria, especially small plaque sizes, to indicate attenuation. However, while some candidate vaccines successfully translated into licensed applications, others have failed ... Full text Link to item Cite

Maternal Antibody-Mediated Disease Enhancement in Type I Interferon-Deficient Mice Leads to Lethal Disease Associated with Liver Damage.

Journal Article PLoS Negl Trop Dis · March 2016 Epidemiological studies have reported that most of the severe dengue cases occur upon a secondary heterologous infection. Furthermore, babies born to dengue immune mothers are at greater risk of developing severe disease upon primary infection with a heter ... Full text Link to item Cite

Neutrophils Self-Regulate Immune Complex-Mediated Cutaneous Inflammation through CXCL2.

Journal Article J Invest Dermatol · February 2016 Deposition of immune complexes (ICs) in tissues triggers acute inflammatory pathology characterized by massive neutrophil influx leading to edema and hemorrhage, and is especially associated with vasculitis of the skin, but the mechanisms that regulate thi ... Full text Link to item Cite

Dengue vascular leakage is augmented by mast cell degranulation mediated by immunoglobulin Fcγ receptors.

Journal Article Elife · March 18, 2015 Dengue virus (DENV) is the most significant human arboviral pathogen and causes ∼400 million infections in humans each year. In previous work, we observed that mast cells (MC) mediate vascular leakage during DENV infection in mice and that levels of MC act ... Full text Link to item Cite

Dengue vascular leakage is augmented by mast cell degranulation mediated by immunoglobulin Fcγ receptors

Journal Article eLife · March 18, 2015 Dengue virus (DENV) is the most significant human arboviral pathogen and causes ∼400 million infections in humans each year. In previous work, we observed that mast cells (MC) mediate vascular leakage during DENV infection in mice and that levels o ... Full text Cite

S1P-Dependent trafficking of intracellular yersinia pestis through lymph nodes establishes Buboes and systemic infection.

Journal Article Immunity · September 18, 2014 Pathologically swollen lymph nodes (LNs), or buboes, characterize Yersinia pestis infection, yet how they form and function is unknown. We report that colonization of the draining LN (dLN) occurred due to trafficking of infected dendritic cells and monocyt ... Full text Link to item Cite

Barriers to preclinical investigations of anti-dengue immunity and dengue pathogenesis.

Journal Article Nat Rev Microbiol · June 2013 Dengue virus (DENV) is a human pathogen that causes severe and potentially fatal disease in millions of individuals each year. Immune-mediated pathology is thought to underlie many of the complications of DENV infection in humans, but the notable limitatio ... Full text Link to item Cite

Innate immunity and its regulation by mast cells.

Journal Article J Immunol · May 1, 2013 Mast cells (MCs), which are granulated tissue-resident cells of hematopoietic lineage, constitute a major sensory arm of the innate immune system. In this review we discuss the evidence supporting the dual role of MCs, both as sentinels for invading pathog ... Full text Link to item Cite

Contributions of mast cells and vasoactive products, leukotrienes and chymase, to dengue virus-induced vascular leakage.

Journal Article Elife · April 30, 2013 Dengue Virus (DENV), a flavivirus spread by mosquito vectors, can cause vascular leakage and hemorrhaging. However, the processes that underlie increased vascular permeability and pathological plasma leakage during viral hemorrhagic fevers are largely unkn ... Full text Open Access Link to item Cite

Mast cell interleukin-10 drives localized tolerance in chronic bladder infection.

Journal Article Immunity · February 21, 2013 The lower urinary tract's virtually inevitable exposure to external microbial pathogens warrants efficient tissue-specialized defenses to maintain sterility. The observation that the bladder can become chronically infected in combination with clinical obse ... Full text Link to item Cite

Plasticity in mast cell responses during bacterial infections.

Journal Article Curr Opin Microbiol · February 2012 Mast cells (MCs) have been implicated in orchestrating the host's early innate immune and adaptive immune responses in several models of acute bacterial infections. Most of this activity results in early clearance of the bacteria and timely resolution of i ... Full text Link to item Cite

Synthetic mast-cell granules as adjuvants to promote and polarize immunity in lymph nodes.

Journal Article Nat Mater · January 22, 2012 Granules of mast cells (MCs) enhance adaptive immunity when, on activation, they are released as stable particles. Here we show that submicrometre particles modelled after MC granules augment immunity when used as adjuvants in vaccines. The synthetic parti ... Full text Link to item Cite

Mast cell modulation of the vascular and lymphatic endothelium.

Journal Article Blood · November 17, 2011 Mast cells (MCs) promote a wide range of localized and systemic inflammatory responses. Their involvement in immediate as well as chronic inflammatory reactions at both local and distal sites points to an extraordinarily powerful immunoregulatory capacity ... Full text Link to item Cite

Immune surveillance by mast cells during dengue infection promotes natural killer (NK) and NKT-cell recruitment and viral clearance.

Journal Article Proc Natl Acad Sci U S A · May 31, 2011 A wealth of evidence supports the essential contributions of mast cells (MCs) to immune defense against bacteria and parasites; however, the role of MCs in viral infections has not been defined. We now report that rodent, monkey, and human MCs are able to ... Full text Link to item Cite

Mast cell-orchestrated immunity to pathogens.

Journal Article Nat Rev Immunol · June 2010 Although mast cells were discovered more than a century ago, their functions beyond their role in allergic responses remained elusive until recently. However, there is a growing appreciation that an important physiological function of these cells is the re ... Full text Link to item Cite

Salmonella disrupts lymph node architecture by TLR4-mediated suppression of homeostatic chemokines.

Journal Article Nat Med · November 2009 We report that infection of draining lymph nodes (DLNs) by Salmonella typhimurium results in the specific downregulation of the homeostatic chemokines CCL21 and CXCL13, which are essential for normal DLN organization and function. Our data reveal that the ... Full text Link to item Cite

Mast cell-derived particles deliver peripheral signals to remote lymph nodes.

Journal Article J Exp Med · October 26, 2009 During infection, signals from the periphery are known to reach draining lymph nodes (DLNs), but how these molecules, such as inflammatory cytokines, traverse the significant distances involved without dilution or degradation remains unclear. We show that ... Full text Link to item Cite

Mast cells augment adaptive immunity by orchestrating dendritic cell trafficking through infected tissues.

Journal Article Cell Host Microbe · October 22, 2009 Mast cells (MCs) are best known for eliciting harmful reactions, mostly after primary immunity has been established. Here, we report that, during footpad infection with E. coli in MC-deficient mice, as compared to their MC-sufficient counterparts, the seru ... Full text Link to item Cite

The antiapoptotic protein Mcl-1 is essential for the survival of neutrophils but not macrophages.

Journal Article Blood · February 15, 2007 The antiapoptotic protein Mcl-1, a member of the Bcl-2 family, plays critical roles in promoting the survival of lymphocytes and hematopoietic stem cells. Although previous studies have implicated Mcl-1 in regulating the survival of neutrophils and macroph ... Full text Link to item Cite