Faculty

Judith Aronson, M.D.

Professor
jaronson@utmb.edu
Department Microbiology & Immunology
Director of Autopsy
Vice Chair for Education
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Education:	M.D. | 1985 | University of North Carolina
	B.S. | 1980 | Yale University

Overview

Arenavirus pathogenesis.

Research Interests

The overarching research interest of the laboratory is the pathogenesis of viral diseases, with particular emphasis on arenavirus hemorrhagic fevers. Arenaviruses are single stranded RNA viruses with bisegmented ambisense genomes. They are the causative agents of a group of rodent-transmitted, human hemorrhagic fevers including Lassa fever, Argentine hemorrhagic fever, Bolivian hemorrhagic fever, Venezuelan hemorrhagic fever, and others. These viruses cause fulminating illnesses with few histopathologic clues as to speci?c target organ damage. Little is known about the pathogenesis of any of these potentially lethal diseases. To study the pathogenesis of this disease, my laboratory is using an established guinea pig model of Lassa fever based on the New World arenavirus Pichinde (PIC). Parental isolates of PIC are naturally attenuated in guinea pigs, but guinea pig passage-adapted PIC variants are extremely virulent in that species and non-pathogenic for humans. Pichinde virus disease in guinea pigs has pathologic and virologic features that strongly resemble human Lassa fever. To date, this is the safest, most convenient, and most accurate animal model of any human hemorrhagic fever. This system offers us the opportunity to study molecular determinants of virulence, immunity, and pathogenic mechanisms in the context of the pathobiologic "control" attenuated PIC. Current research projects and interests are listed below.

Molecular determinants of virulence in PIC passage pairs: Sequence analysis and reassortment genetics approaches are being used to map the important virulence determinants in the PIC genome. To date, major virulence determinants have been localized to the viral genomic S segment, which encodes envelope glycoproteins 1 and 2, and nucleoprotein. Using immunohistology, in situ hybridization and ?ow cytometry, we are comparing the tropisms and spread of attenuated vs. virulent PIC variants. Although both viruses are macrophage-tropic, the virulent PIC variant shows the ability to spread to a variety of different cell types in the liver, lung, adrenal gland, and intestine in the second week of infection. This "expanded tropism" property is clearly associated with S segment genes in that reassortant virus with the S segment from the virulent parent display the phenotype. A strong candidate virulence-associated mutation has been identi?ed in a hydrophilic domain of the viral surface-exposed glycoprotein 1. We believe this may have implications in terms of virus attachment to host cell receptors and/or cell-cell spread of virus. Ongoing studies are examining this possibility.

The role of cytokines in the pathogenesis of arenavirus disease: Evidence from human and experimental animal arenavirus infections suggests that proin?ammatory cytokines, especially tumor necrosis factor alpha, play a role in the terminal shock of arenavirus hemorrhagic fevers. We are interested in comparing the cytokine responses in animals infected with attenuated vs. virulent PIC. Since immunologic reagents for guinea pigs are generally not available, this aim necessitates the adaptation of bioassays or RT-PCR approaches to the identi?cation and quanti?cation of guinea pig cytokines. With Dr. Herzog, Shope, and others, we are involved in a multidisciplinary collaboration to develop agents that block the transke hypothesis that over-production of interferon may have toxic effects on the infected host. The abilities of attenuated and virulent PIC to induce and/or respond to the antiviral effects of interferon are also being compared. Outgrowths from this project will examine the role of other non-speci?c immune mechanisms in control of the disease.

Approaches for etiologic diagnosis of infectious diseases in formalin-? xed, paraffin-embedded tissue samples: In cases where infectious diseases are suspected, it is a common occurrence that frozen biopsy or autopsy tissue is not available, that culture facilities are not available at remote sites where tissue is obtained, or that suspected agents are not cultivable. For these reasons, it is important to develop techniques such as immunohistology, in situ hybridization, and in situ PCR, that can be applied to routinely processed tissue samples. The department's unique resources for automated immunohistology and in situ hybridization, serologic diagnosis of viral diseases, and the affiliation with the Center for Tropical Diseases place us in a unique position for developing methods for tissue-based diagnosis of tropical and emerging infectious diseases. To date, immunohistologic or in situ hybridization methods for the diagnosis of yellow fever, dengue fever, equine morbillivirus infection, White Water Arroyo virus infection, and lobomycosis have been developed.

Recent Publications

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