Edward Vizcarra

All Publications

• Multi-modal analysis reveals tumor and immune features distinguishing EBV-positive and EBV-negative post-transplant lymphoproliferative disorders. Cell reports. Medicine Toh, J., Reitsma, A. J., Tajima, T., Younes, S. F., Ezeiruaku, C., Jenkins, K. C., Peña, J. K., Zhao, S., Wang, X., Lee, E. Y., Glass, M. C., Kalesinskas, L., Ganesan, A., Liang, I., Pai, J. A., Harden, J. T., Vallania, F., Vizcarra, E. A., Bhagat, G., Craig, F. E., Swerdlow, S. H., Morscio, J., Dierickx, D., Tousseyn, T., Satpathy, A. T., Krams, S. M., Natkunam, Y., Khatri, P., Martinez, O. M. 2024: 101851

  Abstract

  The oncogenic Epstein-Barr virus (EBV) can drive tumorigenesis with disrupted host immunity, causing malignancies including post-transplant lymphoproliferative disorders (PTLDs). PTLD can also arise in the absence of EBV, but the biological differences underlying EBV(+) and EBV(-) B cell PTLD and the associated host-EBV-tumor interactions remain poorly understood. Here, we reveal the core differences between EBV(+) and EBV(-) PTLD, characterized by increased expression of genes related to immune processes or DNA interactions, respectively, and the augmented ability of EBV(+) PTLD B cells to modulate the tumor microenvironment through elaboration of monocyte-attracting cytokines/chemokines. We create a reference resource of proteins distinguishing EBV(+) B lymphoma cells from EBV(-) B lymphoma including the immunomodulatory molecules CD300a and CD24, respectively. Moreover, we show that CD300a is essential for maximal survival of EBV(+) PTLD B lymphoma cells. Our comprehensive multi-modal analyses uncover the biological underpinnings of PTLD and offer opportunities for precision therapies.

  View details for DOI 10.1016/j.xcrm.2024.101851

  View details for PubMedID 39657667

• Revolutionizing Postdoctoral Training Using the Social Ecological Model: Insights and Experiences from the Propel Scholars GEN BIOTECHNOLOGY Hayes, C. A., Headley, C. A., Nava, A. R., Vizcarra, E. A., Garcia, K. C., Mullen, M. S., Morales, J., Venida, A. C., Follis, S. 2024

  View details for DOI 10.1089/genbio.2024.0014

  View details for Web of Science ID 001283346900001

• Harnessing preexisting influenza virus-specific immunity increases antibody responses against SARS-CoV-2. Journal of virology Dulin, H., Barre, R. S., Xu, D., Neal, A., Vizcarra, E., Chavez, J., Ulu, A., Yang, M., Khan, S. R., Wuang, K., Bhakta, N., Chea, C., Wilson, E. H., Martinez-Sobrido, L., Hai, R. 2024: e0157123

  Abstract

  IMPORTANCE: Increased globalization and changes in human interactions with wild animals has increased the likelihood of the emergence of novel viruses with pandemic potential. Vaccines can be effective in preventing severe disease caused by pandemic viruses. However, it takes time to develop protective immunity via prime-boost vaccination. More effective vaccine designs should quickly induce protective immunity. We propose leveraging preexisting immunity to a different pathogen to boost protection against emerging viruses. We targeted SARS-CoV-2 as a representative pandemic virus and generated a fusion protein vaccine that combines the nucleoprotein from influenza A virus and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Our vaccine design significantly increased the production of RBD-specific antibodies in mice that had previously been exposed to influenza virus, compared to those without previous exposure. This enhanced immunity reduced SARS-CoV-2 replication in mice. Our results offer a vaccine design that could be valuable in a future pandemic setting.

  View details for DOI 10.1128/jvi.01571-23

  View details for PubMedID 38206036

• An ex vivo model of Toxoplasma recrudescence reveals developmental plasticity of the bradyzoite stage. mBio Vizcarra, E. A., Goerner, A. L., Ulu, A., Hong, D. D., Bergersen, K. V., Talavera, M. A., Le Roch, K., Wilson, E. H., White, M. W. 2023: e0183623

  Abstract

  The recrudescence of Toxoplasma cysts is the cause of clinical disease in the immunocompromised. Although Toxoplasma has been a useful parasite model for decades because it is relatively easy to genetically modify and culture, attempts to generate and study the recrudescence of tissue cysts have come up short with cell culture-adapted strains generating low numbers of tissue cysts in vivo. Taking advantage of a new ex vivo model of Toxoplasma recrudescence that uses a Type II ME49 strain unadapted to cell culture, we determined the cell biology, gene expression, and host cell dependency that define bradyzoite-cyst reactivation. Bradyzoite infection of fibroblasts and astrocytes produced sequential tachyzoite growth stages with pre-programmed kinetics; thus, an initial fast-growing stage was followed by a slow-growing replicating form. In vivo infections demonstrated that only fast growth tachyzoites, and not parasites post-growth shift, led to successful parasite dissemination to the brain and peripheral organs. In astrocytes, cells that reside in the central nervous system (CNS), bradyzoites initiated an additional recrudescent pathway involving brady-brady replication, which is a pathway not observed in fibroblasts. To investigate the molecular basis of growth and cell-dependent reactivation pathways, single-cell mRNA sequencing was performed on recrudescing parasites, revealing distinct gene signatures of these parasite populations and confirming multifunctionality of the original ex vivo bradyzoite population. This revised model of Toxoplasma recrudescence uncovers previously unknown complexity in the clinically important bradyzoite stage of the parasite, which opens the door to further study these novel developmental features of the Toxoplasma intermediate life cycle. IMPORTANCE The classical depiction of the Toxoplasma lifecycle is bradyzoite excystation conversion to tachyzoites, cell lysis, and immune control, followed by the reestablishment of bradyzoites and cysts. In contrast, we show that tachyzoite growth slows independent of the host immune response at a predictable time point following excystation. Furthermore, we demonstrate a host cell-dependent pathway of continuous amplification of the cyst-forming bradyzoite population. The developmental plasticity of the excysted bradyzoites further underlines the critical role the cyst plays in the flexibility of the lifecycle of this ubiquitous parasite. This revised model of Toxoplasma recrudescence uncovers previously unknown complexity in the clinically important bradyzoite stage of the parasite, which opens the door to further study these novel developmental features of the Toxoplasma intermediate life cycle.

  View details for DOI 10.1128/mbio.01836-23

  View details for PubMedID 37675999

• Group 1 metabotropic glutamate receptor expression defines a T cell memory population during chronic Toxoplasma infection that enhances IFN-gamma and perforin production in the CNS. Brain, behavior, and immunity Vizcarra, E. A., Ulu, A., Landrith, T. A., Qiu, X., Godzik, A., Wilson, E. H. 2023

  Abstract

  Within the brain, a pro-inflammatory response is essential to prevent clinical disease due to Toxoplasma gondii reactivation. Infection in the immunocompromised leads to lethal Toxoplasmic encephalitis while in the immunocompetent, there is persistent low-grade inflammation which is devoid of clinical symptoms. This signifies that there is a well-balanced and regulated inflammatory response to T. gondii in the brain. T cells are the dominant immune cells that prevent clinical disease, and this is mediated through the secretion of effector molecules such as perforins and IFN-gamma. The presence of cognate antigen, the expression of survival cytokines, and the alteration of the epigenetic landscape drive the development of memory T cells. However, specific extrinsic signals that promote the formation and maintenance of memory T cells within tissue are poorly understood. During chronic infection, there is an increase in extracellular glutamate that, due to its function as an excitatory neurotransmitter, is normally tightly controlled in the CNS. Here we demonstrate that CD8+ T cells from the T. gondii-infected brain parenchyma are enriched for metabotropic glutamate receptors (mGluR's). Characterization studies determined that mGluR+ expression by CD8+ T cells defines a distinct memory population at the transcriptional and protein level. Finally, using receptor antagonists and agonists we demonstrate mGluR signaling is required for optimal CD8+ T cell production of the effector cytokine IFNgamma. This work suggests that glutamate is an important environmental signal of inflammation that promotes T cell function. Understanding glutamate's influence on T cells in the brain can provide insights into the mechanisms that govern protective immunity against CNS-infiltrating pathogens and neuroinflammation.

  View details for DOI 10.1016/j.bbi.2023.08.015

  View details for PubMedID 37604212

• A genetic tool for the longitudinal study of a subset of post-inflammatory reactive astrocytes CELL REPORTS METHODS Agnew-Svoboda, W., Ubina, T., Figueroa, Z., Wong, Y., Vizcarra, E. A., Roebini, B., Wilson, E. H., Fiacco, T. A., Riccomagno, M. M. 2022; 2 (8): 100276

  Abstract

  Astrocytes are vital support cells that ensure proper brain function. In brain disease, astrocytes reprogram into a reactive state that alters many of their cellular roles. A long-standing question in the field is whether downregulation of reactive astrocyte (RA) markers during resolution of inflammation is because these astrocytes revert back to a non-reactive state or die and are replaced. This has proven difficult to answer mainly because existing genetic tools cannot distinguish between healthy versus RAs. Here we describe the generation of an inducible genetic tool that can be used to specifically target and label a subset of RAs. Longitudinal analysis of an acute inflammation model using this tool revealed that the previously observed downregulation of RA markers after inflammation is likely due to changes in gene expression and not because of cell death. Our findings suggest that cellular changes associated with astrogliosis after acute inflammation are largely reversible.

  View details for DOI 10.1016/j.crmeth.2022.100276

  View details for Web of Science ID 000907949400012

  View details for PubMedID 36046623

  View details for PubMedCentralID PMC9421582

• Correction: CD4+ T cells promote humoral immunity and viral control during Zika virus infection. PLoS pathogens Elong Ngono, A., Young, M. P., Bunz, M., Xu, Z., Hattakam, S., Vizcarra, E., Regla-Nava, J. A., Tang, W. W., Yamabhai, M., Wen, J., Shresta, S. 2019; 15 (5): e1007821

  Abstract

  [This corrects the article DOI: 10.1371/journal.ppat.1007474.].

  View details for DOI 10.1371/journal.ppat.1007821

  View details for PubMedID 31136625

  View details for PubMedCentralID PMC6538173

• A longitudinal systems immunologic investigation of acute Zika virus infection in an individual infected while traveling to Caracas, Venezuela. PLoS neglected tropical diseases Carlin, A. F., Wen, J., Vizcarra, E. A., McCauley, M., Chaillon, A., Akrami, K., Kim, C., Ngono, A. E., Lara-Marquez, M. L., Smith, D. M., Glass, C. K., Schooley, R. T., Benner, C., Shresta, S. 2018; 12 (12): e0007053

  Abstract

  Zika virus (ZIKV) is an emerging mosquito-borne flavivirus linked to devastating neurologic diseases. Immune responses to flaviviruses may be pathogenic or protective. Our understanding of human immune responses to ZIKV in vivo remains limited. Therefore, we performed a longitudinal molecular and phenotypic characterization of innate and adaptive immune responses during an acute ZIKV infection. We found that innate immune transcriptional and genomic responses were both cell type- and time-dependent. While interferon stimulated gene induction was common to all innate immune cells, the upregulation of important inflammatory cytokine genes was primarily limited to monocyte subsets. Additionally, genomic analysis revealed substantial chromatin remodeling at sites containing cell-type specific transcription factor binding motifs that may explain the observed changes in gene expression. In this dengue virus-experienced individual, adaptive immune responses were rapidly mobilized with T cell transcriptional activity and ZIKV neutralizing antibody responses peaking 6 days after the onset of symptoms. Collectively this study characterizes the development and resolution of an in vivo human immune response to acute ZIKV infection in an individual with pre-existing flavivirus immunity.

  View details for DOI 10.1371/journal.pntd.0007053

  View details for PubMedID 30596671

  View details for PubMedCentralID PMC6329527

• Deconvolution of pro- and antiviral genomic responses in Zika virus-infected and bystander macrophages. Proceedings of the National Academy of Sciences of the United States of America Carlin, A. F., Vizcarra, E. A., Branche, E., Viramontes, K. M., Suarez-Amaran, L., Ley, K., Heinz, S., Benner, C., Shresta, S., Glass, C. K. 2018; 115 (39): E9172-E9181

  Abstract

  Genome-wide investigations of host-pathogen interactions are often limited by analyses of mixed populations of infected and uninfected cells, which lower sensitivity and accuracy. To overcome these obstacles and identify key mechanisms by which Zika virus (ZIKV) manipulates host responses, we developed a system that enables simultaneous characterization of genome-wide transcriptional and epigenetic changes in ZIKV-infected and neighboring uninfected primary human macrophages. We demonstrate that transcriptional responses in ZIKV-infected macrophages differed radically from those in uninfected neighbors and that studying the cell population as a whole produces misleading results. Notably, the uninfected population of macrophages exhibits the most rapid and extensive changes in gene expression, related to type I IFN signaling. In contrast, infected macrophages exhibit a delayed and attenuated transcriptional response distinguished by preferential expression of IFNB1 at late time points. Biochemical and genomic studies of infected macrophages indicate that ZIKV infection causes both a targeted defect in the type I IFN response due to degradation of STAT2 and reduces RNA polymerase II protein levels and DNA occupancy, particularly at genes required for macrophage identity. Simultaneous evaluation of transcriptomic and epigenetic features of infected and uninfected macrophages thereby reveals the coincident evolution of dominant proviral or antiviral mechanisms, respectively, that determine the outcome of ZIKV exposure.

  View details for DOI 10.1073/pnas.1807690115

  View details for PubMedID 30206152

  View details for PubMedCentralID PMC6166801

• An IRF-3-, IRF-5-, and IRF-7-Independent Pathway of Dengue Viral Resistance Utilizes IRF-1 to Stimulate Type I and II Interferon Responses. Cell reports Carlin, A. F., Plummer, E. M., Vizcarra, E. A., Sheets, N., Joo, Y., Tang, W., Day, J., Greenbaum, J., Glass, C. K., Diamond, M. S., Shresta, S. 2017; 21 (6): 1600-1612

  Abstract

  Interferon-regulatory factors (IRFs) are a family of transcription factors (TFs) that translate viral recognition into antiviral responses, including type I interferon (IFN) production. Dengue virus (DENV) and other clinically important flaviviruses are suppressed by type I IFN. While mice lacking the type I IFN receptor (Ifnar1-/-) succumb to DENV infection, we found that mice deficient in three transcription factors controlling type I IFN production (Irf3-/-Irf5-/-Irf7-/- triple knockout [TKO]) survive DENV challenge. DENV infection of TKO mice resulted in minimal type I IFN production but a robust type II IFN (IFN-γ) response. Using loss-of-function approaches for various molecules, we demonstrate that the IRF-3-, IRF-5-, IRF-7-independent pathway predominantly utilizes IFN-γ and, to a lesser degree, type I IFNs. This pathway signals via IRF-1 to stimulate interleukin-12 (IL-12) production and IFN-γ response. These results reveal a key antiviral role for IRF-1 by activating both type I and II IFN responses during DENV infection.

  View details for DOI 10.1016/j.celrep.2017.10.054

  View details for PubMedID 29117564

  View details for PubMedCentralID PMC5696617

• Mapping and Role of the CD8+ T Cell Response During Primary Zika Virus Infection in Mice. Cell host & microbe Elong Ngono, A., Vizcarra, E. A., Tang, W. W., Sheets, N., Joo, Y., Kim, K., Gorman, M. J., Diamond, M. S., Shresta, S. 2017; 21 (1): 35-46

  Abstract

  CD8+ T cells may play a dual role in protection against and pathogenesis of flaviviruses, including Zika virus (ZIKV). We evaluated the CD8+ T cell response in ZIKV-infected LysMCre+IFNARfl/fl C57BL/6 (H-2b) mice lacking the type I interferon receptor in a subset of myeloid cells. In total, 26 and 15 CD8+ T cell-reactive peptides for ZIKV African (MR766) and Asian (FSS13025) lineage strains, respectively, were identified and validated. CD8+ T cells from infected mice were polyfunctional and mediated cytotoxicity. Adoptive transfer of ZIKV-immune CD8+ T cells reduced viral burdens, whereas their depletion led to higher tissue burdens, and CD8-/- mice displayed higher mortality with ZIKV infection. Collectively, these results demonstrate that CD8+ T cells protect against ZIKV infection. Further, this study provides a T cell competent mouse model for investigating ZIKV-specific T cell responses.

  View details for DOI 10.1016/j.chom.2016.12.010

  View details for PubMedID 28081442

  View details for PubMedCentralID PMC5234855