Campus Box 7292
Chapel Hill, NC 27599-7292
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. RossRiver 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. RossRiver 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. RossRiver 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.
Morrison TE, Oko L, Montgomery SA, Whitmore AC, Lotstein AR, Gunn BM, Elmore SA, Heise MT. (2011). A mouse model of chikungunya virus-induced musculoskeletal inflammatory disease: evidence of arthritis, tenosynovitis, myositis, and persistence.
Am J Pathol. 178(1):32-40.
Simmons JD, Wollish AC, Heise MT (2010). A determinant of Sindbis virus neurovirulence enables efficient disruption of Jak/STAT signaling. J Virol. 84(21):11429-39.
Cruz CC, Suthar MS, Montgomery SA, Shabman R, Simmons J, Johnston RE, Morrison TE, Heise MT (2010). Modulation of type I IFN induction by a virulence determinant within the alphavirus nsP1 protein. Virology. 399(1):1-10.
Simmons JD, White LJ, Morrison TE, Montgomery SA, Whitmore AC, Johnston RE, Heise MT (2009). Venezuelan equine encephalitis virus disrupts STAT1 signaling by distinct mechanisms independent of host shutoff. J Virol. 83(20):10571-81.
Rogers KM, Heise M (2009). Modulation of cellular tropism and innate antiviral response by viral glycans. J Innate Immun. 1(5):405-12.
Sheahan T, Morrison TE, Funkhouser W, Uematsu S, Akira S, Baric RS, Heise MT (2008). MyD88 is required for protection from lethal infection with a mouse-adapted SARS-CoV. PLoS Pathog. 4(12):e1000240.
Shabman RS, Rogers KM, Heise MT (2008). Ross River virus envelope glycans contribute to type I interferon production in myeloid dendritic cells. J Virol. 82(24):12374-83.
Morrison TE, Simmons JD, Heise MT (2008). Complement receptor 3 promotes severe ross river virus-induced disease. J Virol. 82(22):11263-72.
Morrison TE, Fraser RJ, Smith PN, Mahalingam S, Heise MT (2007). Complement contributes to inflammatory tissue destruction in a mouse model of Ross River virus-induced disease. J Virol. 81(10):5132-43.
Shabman RS, Morrison TE, Moore C, White L, Suthar MS, Hueston L, Rulli N, Lidbury B, Ting JP, Mahalingam S, Heise MT (2007). Differential induction of type I interferon responses in myeloid dendritic cells by mosquito and mammalian-cell-derived alphaviruses. J Virol. 81(1):237-47.
Morrison TE, Whitmore AC, Shabman RS, Lidbury BA, Mahalingam S, Heise MT (2006). Characterization of Ross River virus tropism and virus-induced inflammation in a mouse model of viral arthritis and myositis. J Virol. 80(2):737-49.
Suthar MS, Shabman R, Madric K, Lambeth C, Heise MT (2005). Identification of adult mouse neurovirulence determinants of the Sindbis virus strain AR86. J Virol. 79(7):4219-28.