About

Professor Lee Gehrke's research focuses principally on RNA viruses that have a positive sense genome. These viruses store their genetic code in RNA, which is ready to be translated into protein immediately upon infection and uncoating. His work distinguishes positive sense RNA viruses from negative sense viruses, which require conversion into a positive strand for translation. RNA viruses are considered more serious human health threats than DNA viruses. The Gehrke lab develops improved models for studying infectious diseases by infecting embryonic stem (ES) and induced pluripotent stem (iPS) derived cells with BSL2 and BSL3 neurotropic flaviviruses, including Dengue, Zika, Powassan, Deer Tick, West Nile, and Japanese Encephalitis virus. Additionally, his team works on developing low-cost, rapid diagnostics to detect emerging virus infections across various virus families such as flaviviruses, alphaviruses, filoviruses, and coronaviruses.

Research topics

• Virology
• Biology
• Immunology
• Medicine
• Neuroscience
• Pathology
• Genetics

Selected publications

• Human Brain Organoids: A New Model to Study <em>Cryptococcus neoformans </em>Neurotropism

  Preprints.org · 2025-06-26 · 1 citations

  preprintOpen access

  With the rise in immunocompromised individuals and patients with immune-related comorbidities such as COVID-19, the rate of fungal infections is growing. This increase, along with the current plateau in anti-fungal drug development, has made understanding the pathogenesis and dissemination of these organisms more pertinent than ever. The mouse model of fungal infection, while informative on a basic science level, has severe limitations in terms of translation to the human disease. Here we present data supporting the implementation of the human cerebral organoid model, which is generated from human embryonic stem cells and accurately recapitulates relevant brain cell types and structures, to study fungal infection and dissemination to the central nervous system (CNS). This approach provides direct insight into the relevant pathogenesis of specific fungal organisms in human tissues where in vivo models are impossible. With this model system we assessed the specific brain tropisms and cellular effects of fungal pathogens known to cross the blood brain barrier (BBB) such as Cryptococcus neoformans. We determined the effects of this fungal pathogen has on the overall gross morphology, cellular architecture, and cytokine release from these model organoids. Furthermore, we demonstrated that C. neoformans penetrates and invades the organoid tissue and remains present throughout the course of infection. These results demonstrate the utility of this new model to the field and highlight the potential for this system to elucidate fungal pathogenesis to new therapeutic strategies to prevent and treat the disseminated stages of fungal diseases such as cryptococcal meningitis.

  PublisherOA PDFDOI

• Human Brain Organoids: A New Model to Study Cryptococcus neoformans Neurotropism

  Journal of Fungi · 2025-07-19 · 2 citations

  articleOpen access

  With the rise in immunocompromised individuals and patients with immune-related comorbidities such as COVID-19, the rate of fungal infections is growing. This increase, along with the current plateau in antifungal drug development, has made understanding the pathogenesis and dissemination of these organisms more pertinent than ever. The mouse model of fungal infection, while informative on a basic scientific level, has severe limitations in terms of translation to the human disease. Here we present data supporting the implementation of the human cerebral organoid model, which is generated from human embryonic stem cells and accurately recapitulates relevant brain cell types and structures, to study fungal infection and dissemination to the central nervous system (CNS). This approach provides direct insight into the relevant pathogenesis of specific fungal organisms in human tissues where in vivo models are impossible. With this model system we assessed the specific brain tropisms and cellular effects of fungal pathogens known to cross the blood–brain barrier (BBB), such as Cryptococcus neoformans. We determined the effects of this fungal pathogen on the overall gross morphology, cellular architecture, and cytokine release from these model organoids. Furthermore, we demonstrated that C. neoformans penetrates and invades the organoid tissue and remains present throughout the course of infection. These results demonstrate the utility of this new model to the field and highlight the potential for this system to elucidate fungal pathogenesis to develop new therapeutic strategies to prevent and treat the disseminated stages of fungal diseases such as cryptococcal meningitis.

  PublisherOA PDFDOI

• A human blood-brain barrier model reveals pericytes as critical regulators of viral neuroinvasion

  iScience · 2025-12-13 · 1 citations

  articleOpen access

  cellular interactions at the BBB. We used this model to evaluate the pathological consequences of BBB exposure to highly neuroinvasive flaviviruses. Our results identify a previously undescribed role for NCC-PCs in maintaining BMEC barrier integrity during infection and reducing the spread of viral infection to the CNS.

  PublisherDOI

• Oxidative Stress and Interferon Signaling Drive Differential Pathogenesis of Ancestral and Contemporary Zika Viruses in Human Cerebral Organoids

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-12 · 2 citations

  preprintOpen accessSenior authorCorresponding

  Neurotropic Zika viruses (ZIKV) cause serious human disease with pandemic potential. Pathogenesis severities resulting from Asian/American versus African ZIKV lineage infections range from mild to severe, respectively; however, mechanisms underlying differential ZIKV pathogenesis remain unclear, as do effective therapeutic strategies. The limitations of mechanistic understanding are due in part to the challenges of comparing data generated in disparate experimental models, as well as approaches that did not test both ancestral and contemporary ZIKV infections. The goal of this work was to define differential pathogenesis mechanisms among ancestral and contemporary ZIKVs by direct infection comparisons using a relevant human stem cell-derived cerebral organoid experimental model. While Asian/American ZIKV lineage infections enhanced antiviral and interferon gene expression responses that correlated with viral RNA clearance from organoid ventricles, ancestral African lineage ZIKV infections enhanced apoptotic and stress response signaling that correlated with diminished STAT2 signaling protein levels, ongoing ZIKV replication, and production of damaging reactive oxygen species (ROS). We discovered that, surprisingly, severe ancestral Zika virus pathogenesis was dramatically reduced by Trolox, a hydroxyl radical scavenger antioxidant, thereby confirming ROS imbalance as a major pathogenesis driver. These results demonstrate that ZIKV lineage infections and pathogenesis are differentiated by their signaling responses and suggest that preventing or controlling hydroxyl radical imbalance may offer therapeutic benefits to address microcephaly and Congenital Zika Virus Syndrome. One Sentence Summary: Differential signal transduction responses to lineage-specific Zika virus infections cause reduction-oxidation imbalance-mediated pathogenesis that is blocked by Trolox, an antioxidant.

  PublisherOA PDFDOI

• A novel human blood-brain barrier model reveals pericytes as critical regulators of viral neuroinvasion

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-03

  preprintOpen access

  Abstract The blood-brain barrier (BBB) plays a vital role in regulating the passage of biomolecules between the bloodstream and the central nervous system (CNS) while also protecting the CNS from pathogens. Pericytes reside at the interface between the endothelial cells that form the vessel walls and the brain parenchyma. These cells are critical for maintaining BBB integrity and play key roles in regulating vessel permeability, blood flow, and immune cell migration. In this study, we developed a novel serum-free protocol to generate neural crest cell-derived pericytes (NCC-PCs) from human pluripotent stem cells (hPSCs). These NCC-PCs enhance BMEC barrier function and can be co-cultured with hPSC-derived brain microvascular endothelial cells (BMECs) in a contact co-culture BBB model that recapitulates the in vivo cellular interactions at the BBB. We used this model to evaluate the pathological consequences of BBB cell infection by highly neuroinvasive flaviviruses. Our results identify a previously undescribed role for NCC-PCs in maintaining BMEC barrier integrity during infection and reducing the spread of viral infection to the CNS.

  PublisherOA PDFDOI

• Healthy adipocytes provide a protective environment by limiting viral infection through cell-cell communication

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-12

  preprintOpen access

  Abstract Adipocytes, long regarded primarily as energy storage cells, are increasingly recognized as active players in immune regulation. In metabolic disorders such as obesity and diabetes—conditions characterized by adipocyte dysfunction—patients often exhibit worsened outcomes following viral infections. However, the role of healthy adipocytes in modulating antiviral immunity remains poorly understood. Here, we demonstrate that healthy adipocytes secrete factors that confer antiviral protection to neighboring cells. We developed a fully human pluripotent stem cell (hPSC)-derived system including adipocytes, immune, and vascular cells to evaluate the antiviral capacity and infectivity of various cell types. Our cell system has the advantage of being of human origin, as opposed to animal models. Through our technological development, we have removed cell culture medium as a variable by adapting all cell types to a single base medium. We found that only adipocytes could induce an antiviral state in adjacent mural and immune cells. This unique immunomodulatory capacity is mediated, at least in part, by the STING-dependent secretion of low levels of interferon-alpha (IFN-α) from healthy adipocytes. Notably, pharmacological induction of metabolic dysfunction in adipocytes diminished their antiviral activity, revealing a previously unrecognized link between metabolic health and antiviral defense. These findings identify a novel role for adipocytes in orchestrating local antiviral responses and provide new insight into how metabolic dysfunction may compromise host defense during viral infections.

  PublisherOA PDFDOI

• SARS-CoV-2 infection of human pluripotent stem cell-derived vascular cells reveals smooth muscle cells as key mediators of vascular pathology during infection

  Nature Communications · 2024-12-30 · 4 citations

  articleOpen access

  Although respiratory symptoms are the most prevalent disease manifestation of infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), nearly 20% of hospitalized patients are at risk for thromboembolic events. This prothrombotic state is considered a key factor in the increased risk of stroke, which is observed clinically during both acute infection and long after symptoms clear. Here, we develop a model of SARS-CoV-2 infection using human-induced pluripotent stem cell-derived endothelial cells (ECs), pericytes (PCs), and smooth muscle cells (SMCs) to recapitulate the vascular pathology associated with SARS-CoV-2 exposure. Our results demonstrate that perivascular cells, particularly SMCs, are a susceptible vascular target for SARS-CoV-2 infection. Utilizing RNA sequencing, we characterize the transcriptomic changes accompanying SARS-CoV-2 infection of SMCs, PCs, and ECs. We observe that infected SMCs shift to a pro-inflammatory state and increase the expression of key mediators of the coagulation cascade. Further, we show human ECs exposed to the secretome of infected SMCs produce hemostatic factors that contribute to vascular dysfunction despite not being susceptible to direct infection. The findings here recapitulate observations from patient sera in human COVID-19 patients and provide mechanistic insight into the unique vascular implications of SARS-CoV-2 infection at a cellular level. This study uses a novel vascular model with human induced pluripotent stem cell-derived endothelial cells, pericytes, and smooth muscle cells to explore the vascular complications associated with SARS-CoV-2. It reveals that smooth muscle cells as the primary sites of infection and inflammation.

  PublisherOA PDFDOI

• Human otic progenitor cell models of congenital hearing loss reveal potential pathophysiologic mechanisms of Zika virus and cytomegalovirus infections

  mBio · 2024-03-05 · 10 citations

  articleOpen accessSenior author

  ABSTRACT Congenital hearing loss is a common chronic condition affecting children in both developed and developing nations. Viruses correlated with congenital hearing loss include human cytomegalovirus (HCMV) and Zika virus (ZIKV), which causes congenital Zika syndrome. The mechanisms by which HCMV and ZIKV infections cause hearing loss are poorly understood. It is challenging to study human inner ear cells because they are encased in bone and also scarce as autopsy samples. Recent advances in culturing human stem cell-derived otic progenitor cells (OPCs) have allowed us herein to describe successful in vitro infection of OPCs with HCMV and ZIKV, and also to propose potential mechanisms by which each viral infection could affect hearing. We find that ZIKV infection rapidly and significantly induces the expression of type I interferon and interferon-stimulated genes, while OPC viability declines, at least in part, from apoptosis. In contrast, HCMV infection did not appear to upregulate interferons or cause a reduction in cell viability, and instead disrupted expression of key genes and pathways associated with inner ear development and function, including Cochlin, nerve growth factor receptor, SRY-box transcription factor 11, and transforming growth factor-beta signaling. These findings suggest that ZIKV and HCMV infections cause congenital hearing loss through distinct pathways, that is, by inducing progenitor cell death in the case of ZIKV infection, and by disruption of critical developmental pathways in the case of HCMV infection. IMPORTANCE Congenital virus infections inflict substantial morbidity and devastating disease in neonates worldwide, and hearing loss is a common outcome. It has been difficult to study viral infections of the human hearing apparatus because it is embedded in the temporal bone of the skull. Recent technological advances permit the differentiation of otic progenitor cells (OPCs) from human-induced pluripotent stem cells. This paper is important for demonstrating that inner ear virus infections can be modeled in vitro using OPCs. We infected OPCs with two viruses associated with congenital hearing loss: human cytomegalovirus (HCMV), a DNA virus, or Zika virus (ZIKV), an RNA virus. An important result is that the gene expression and cytokine production profiles of HCMV/ZIKV-infected OPCs are markedly dissimilar, suggesting that mechanisms of hearing loss are also distinct. The specific molecular regulatory pathways identified in this work could suggest important targets for therapeutics.

  PublisherDOI

• Abortive infection of bat fibroblasts with SARS-CoV-2

  Proceedings of the National Academy of Sciences · 2024-10-14 · 7 citations

  articleOpen access

  Bats are tolerant to highly pathogenic viruses such as Marburg, Ebola, and Nipah, suggesting the presence of a unique immune tolerance toward viral infection. Here, we compared severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of human and bat ( Rhinolophus ferrumequinum ) pluripotent cells and fibroblasts. Since bat cells do not express an angiotensin-converting enzyme 2 (ACE2) receptor that allows virus infection, we transduced the human ACE2 (hA) receptor into the cells and found that transduced cells can be infected with SARS-CoV-2. Compared to human embryonic stem cells-hA, infected bat induced Pluripotent Stem Cells (iPSCs)-hA produced about a 100-fold lower level of infectious virus and displayed lower toxicity. In contrast, bat embryonic fibroblast-hA produced no infectious virus while being infectable and synthesizing viral RNA and proteins, suggesting abortive infection. Indeed, electron microscopy failed to detect virus-like particles in infected bat fibroblasts in contrast to bat iPSCs or human cells, consistent with the latter producing infectious viruses. This suggests that bat somatic but not pluripotent cells have an effective mechanism to control virus replication. Consistent with previous results by others, we find that bat cells have a constitutively activated innate immune system, which might limit SARS-CoV-2 infection compared to human cells.

  PublisherOA PDFDOI

• Integrative systems biology characterizes immune-mediated neurodevelopmental changes in murine Zika virus microcephaly

  iScience · 2023-05-19 · 8 citations

  articleOpen access

  Characterizing perturbation of molecular pathways in congenital Zika virus (ZIKV) infection is critical for improved therapeutic approaches. Leveraging integrative systems biology, proteomics, and RNA-seq, we analyzed embryonic brain tissues from an immunocompetent, wild-type congenital ZIKV infection mouse model. ZIKV induced a robust immune response accompanied by the downregulation of critical neurodevelopmental gene programs. We identified a negative correlation between ZIKV polyprotein abundance and host cell cycle-inducing proteins. We further captured the downregulation of genes/proteins, many of which are known to be causative for human microcephaly, including Eomesodermin/T-box Brain Protein 2 (EOMES/TBR2) and Neuronal Differentiation 2 (NEUROD2). Disturbances of distinct molecular pathways in neural progenitors and post-mitotic neurons may contribute to complex brain phenotype of congenital ZIKV infection. Overall, this report on protein- and transcript-level dynamics enhances understanding of the ZIKV immunopathological landscape through characterization of fetal immune response in the developing brain.

  PublisherOA PDFDOI

Recent grants

• MMDx: A rapid multiplexed matrix code diagnostic for real time epidemiology

  NIH · $1.6M · 2012–2018

• 3D Models of Engineered Human iPS Cells to Investigate Neurotropic Virus Infections

  NIH · $14.4M · 2017–2024

• NIH Grant R01GM042504

  NIH · $4.2M · 2005

• NIH Grant R21CA159132

  NIH · $374k · 2015

• 3D Models of Engineered Human iPS Cells to Investigate Neurotropic Virus Infections

  NIH · $3.5M · 2017–2022

Frequent coauthors

• Irene Bosch

  91 shared

• Stephen A. Jobling

  Agriculture and Food

  52 shared

• Lanny J. Rosenwasser

  University of Missouri–Kansas City

  43 shared

• Benjamin R. McDonald

  Brown University

  40 shared

• Rudolf Jaenisch

  Whitehead Institute for Biomedical Research

  39 shared

• Ann Durbin

  Harvard University

  37 shared

• L S Paik

  Harvard University

  36 shared

• Helena de Puig

  Massachusetts Institute of Technology

  35 shared

Labs

• Gehrke LabPI

Education

• Ph.D., Molecular Biology

  University of Wisconsin-Madison

  2002

• B.S., Biology

  University of California, San Diego

  1997