Keywords: Viral pathogenesis, virus-host interactions, genetics of virulence, vaccine development
My laboratory is interested in understanding the interactions between viruses and the infected host that lead either to virus-induced disease or to resolution of the viral infection. Our current studies are focused on mouse pathogenesis models using alphaviruses (Genus: Togaviridae, Family: Alphavirus), mosquito borne RNA viruses that are a significant cause of encephalitis and infectious arthritis in humans. Several aspects of alphavirus biology make them tools useful for studying viral pathogenesis. The alphavirus genome is extremely amenable to genetic manipulation due to the existence of full length infectious viral cDNA clones. These infectious clones permit the introduction of defined genetic changes into the alphavirus genome for the purpose of evaluating the role of specific viral genetic elements in viral replication or virulence. The infectious clone technology also permits the construction of virus based expression vectors for tracking viral replication within the infected animal or for use in gene delivery. Alphaviruses also cause a spectrum of diseases in mice that include encephalitis and arthritis/arthralgia. Due to the availability of a wide range of genetically modified mice lacking specific immune mediators, it is possible to manipulate both the virus and the infected animal in order to define the role of viral and/or host factors in the pathogenesis of virus-induced diseases.
Figure 1. Ross River virus (RRV) replication in joint associated tissues of infected mice. 14 day old mice were infected subcutaneously with 103 pfu of a recombinant RRV expressing green fluorescent protein. Frozen sections were analyzed by fluorescent microscopy. Green cells indicate viral infection. 200 x magnification. A. Synovial cavity in foot, 48 hours post infection. B. Synovial cavity in ankle, 48 hours post infection. C. Synovial cavity in knee, 48 hours post infection. D. Periosteum adjacent to knee, 72 hours post infection.
Figure 2. Ross River virus (RRV)-induced inflammation in joint-associated tissues. 14 day old mice were either mock infected or infected with 103 pfu of RRV subcutaneously. On day 7 post infection, hind limbs were sectioned and H+E stained. Periosteum adjacent to ankle joint of RRV infected mouse exhibits inflammation (lower panel), while the ankle of the mock infected animal appears normal. 200x magnification.
Our laboratory has developed two different model systems involving alphavirus infection of mice to study the pathogenesis of alphavirus-induced encephalitis and arthritis. The first model involves the use of two closely related alphaviruses, one of which causes lethal encephalitis in mice while the other is avirulent. We have begun using infectious cDNA clones of these two viruses to map viral genetic elements that are involved in the development of disease. The long term goals of these studies is to define the mechanisms by which these virulence determinants act to promote virus-induced disease and to evaluate the role of specific host immune factors in protecting against viral disease. The second model system focuses on identifying viral and host determinants that are involved in the development of virus-induced arthritis. Ross River virus, an Australian virus associated with several thousand cases of infectious poly-arthritis a year, causes a macrophage-mediated inflammatory disease in the muscle and joints of infected mice. This system provided us with a useful model to investigate the viral and host genetic elements that lead to virus-induced arthritis and should also increase our understanding of the basic mechanisms involved in the generation and resolution of the inflammatory response to viral infection.
In addition to studying viral pathogenesis, we are also extremely interested in using alphavirus-based vectors for gene delivery. We are currently attempting to develop replicon-based vaccines against several hemorrhagic fever viruses. These studies are focused on modifying both the replicons and the expressed antigens to generate an optimal host immune response.
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Mark Heise in UNC Genetics News
April 19, 2021
Department of Genetics Publications for April 4-17, 2021
Department of Genetics faculty, postdocs, students and collaborators published fifteen papers during April 4-17, 2021. Targeting Chikungunya Virus Replication by Benzoannulene Inhibitors. Ahmed SK, Haese NN, Cowan JT, Pathak V, Moukha-Chafiq O, Smith VJ, Rodzinak KJ, Ahmad F, Zhang S, Bonin KM, Streblow AD, Streblow CE, Kreklywich CN, Morrison C, Sarkar S, Moorman N, …
April 5, 2021
Department of Genetics Publications for March 21-April 3, 2021
Department of Genetics faculty, postdocs, students and collaborators published fifteen papers during March 21-April 3, 2021.
March 20, 2021
Department of Genetics Publications for March 7-20, 2021
Department of Genetics faculty, postdocs, students and collaborators published ten papers during March 7-20, 2021.
March 8, 2021
Department of Genetics Publications for February 21 – March 6, 2021
Department of Genetics faculty, postdocs, students and collaborators published twelve papers during February 21 – March 6, 2021.
February 22, 2021
Department of Genetics Publications for February 7-20, 2021
Department of Genetics faculty, postdocs, students and collaborators published seven papers during February 7-20, 2021
February 8, 2021
Department of Genetics Publications for Jan. 24 – Feb. 6, 2021
Department of Genetics faculty, postdocs, students and collaborators published twenty papers during Jan. 24 – Feb. 6, 2021.
January 11, 2021
Department of Genetics Publications for Dec. 27, 2020 – Jan. 9, 2021
Department of Genetics faculty, postdocs, students and collaborators published nine papers during Dec. 27, 2020 – Jan. 9, 2021.
January 4, 2021
Department of Genetics Publications for December 13-26, 2020
Department of Genetics faculty, postdocs, students and collaborators published nine papers during Dec. 13-26, 2020.
November 2, 2020
Department of Genetics Publications for October 11-31, 2020
Department of Genetics faculty, postdocs, students and collaborators published 18 papers during October 11-31, 2020. Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer. Fernandez-Martinez A, Krop IE, Hillman DW, Polley MY, Parker JS, Huebner L, Hoadley KA, …
October 1, 2020
Mark Heise, PhD Awarded New R01 Grant from NIAID
Dr. Mark Heise (Professor, Genetics and Microbiology & Immunology) was awarded a new R01 grant from the National Institute of Allergy and Infectious Disease (NIAID) for his project titled “Genetic Analysis of COVID-19 Susceptibility and Resistance Determinants in the Collaborative Cross”.