Professor of Immunology & Microbiology, University of Colorado Anschutz School of Medicine
Arthropods, including mosquitoes, sand flies, and ticks, often bite humans to obtain blood meals. During feeding, these arthropods can transmit infectious pathogens, such as RNA viruses and protozoan parasites, to humans that cause devastating diseases (e.g. chikungunya, dengue, leishmaniasis, malaria). Our laboratory seeks to improve our knowledge of the molecular pathogenesis of these infections (i.e. what are the critical host-pathogen interactions that contribute to protection or pathology?). This knowledge may improve our ability to prevent and treat these diseases through the development of vaccines as well as pathogen- or host-targeted therapeutics.
Mosquito-transmitted RNA viruses include flaviviruses, such as Dengue virus and West Nile virus, bunyaviruses, such as Rift Valley fever virus, and alphaviruses, such as chikungunya virus, Ross River virus, and Venezuelan equine encephalitis virus. Chikungunya virus, Ross River virus, and related arthritogenic alphaviruses cause explosive epidemics that can involve thousands to millions of infected patients. Chikungunya, which translates as “disease that bends up the joints”, is characterized by an abrupt onset of fever with severe joint pain, and the pain may persist for weeks to years. Chronic chikungunya joint disease, and the chronic rheumatological diseases caused by the related arthritogenic alphaviruses, may result from persistent infection in musculoskeletal tissues. To investigate the molecular pathogenesis of these infections, we use genetic strategies, molecular and cellular approaches, and mouse models of acute and chronic chikungunya virus or Ross River virus infection. Using these systems, we study viral interactions with the host immune response. We are particularly interested in defining mechanisms of activation and resolution of virus-induced inflammatory responses, immunological mechanisms that control virus clearance versus virus persistence, and viral genetic determinants that counteract host anti-viral responses and promote persistent infection. The mouse models we use enable us to utilize transgenic and knockout strains to study the role of specific host genes in the disease process and investigate the genetics of host susceptibility to acute and chronic infection. Additionally, due to the well-established alphavirus reverse genetics system, we are able to easily manipulate the genome of the virus. Taken together, these advantages provide a highly tractable system to establish mechanisms by which viral interactions with the host lead to disease. In addition, we utilize cell culture-based and animal infection models to test novel anti-virals and immunomodulatory therapeutics against acute and chronic CHIKV/RRV infection.
Arthropod-transmitted protozoan parasites include Leishmania (the causative agents of leishmaniasis), Trypanosoma (the causative agents of Sleeping sickness and Chagas' disease) and Plasmodium (the causative agents of malaria). Leishmaniasis is a major global health problem that affects more than 12 million people worldwide. Leishmania parasites are endemic in Asia, the Middle East, sub-Saharan Africa, and South America. These obligate intracellular parasites are transmitted to humans by infected sand flies and cause a spectrum of clinical manifestations that includes cutaneous leishmaniasis (localized lesions of the skin), mucocutaneous leishmaniasis (mucosal lesions; nose, mouth, throat) and visceral leishmaniasis (parasite infection and disease in visceral organs including the liver, spleen, bone marrow, and lymphatic system). We are interested in defining interactions between leishmania parasites and host macrophage that influence host innate and adaptive immune responses, and ultimately parasite clearance versus persistence. In addition, we aim to define parasite-encoded factors that determine parasite resistance or susceptibility to oxidative/nitrosative stress, a major host defense mechanism employed by infected macrophages. To accomplish these goals we use cell culture and murine infection models. We also use a variety of genetic tools to manipulate the genome of these organisms.
Graduate Student, Graduate Program in Immunology
Kelsey is interested in innate immune mechanisms that mediate control of alphavirus infection, and defining viral determinants that counteract these host responses. Her research aims to define mechanisms by which monocytes contribute to the control of acute alphavirus infection and how pathogenic strains of Ross River virus evade this control. Kelsey is the recipient of an NIH-NIAID F31 fellowship.
Professional Research Assistant
Nick studies the role of Arginase 1 and iNOS in alphavirus pathogenesis. Nick also investigates novel therapeutics against alphavirus infection.
|Mary McCarthy, PhD|
Mary is interested in defining immunological mechanisms that determine the clearance or persistence of arthritogenic alphaviruses, and elucidating mechanisms by which pathogenic alphaviruses evade or suppress the development of adaptive immune responses in the draining lymph node. Mary is the recipient of an NIH-NIAID F32 fellowship.
|Bennett Davenport, PhD|
Bennett is interested in understanding Leishmania immunopathogenesis and defining anti-oxidative/anti-nitrosative stress pathways deployed by Leishmania parasites in defense against host macrophage anti-parasitic responses. In addition, Bennett studies the role of CD8 T cells in clearance of alphavirus infection and is evaluating novel therapeutic strategies to prevent or mitigate persistent alphavirus infection. Bennett is the recipient of a T32 fellowship in Rheumatology for his work on immunological control of alphavirus infection.
|Katie Carpentier, PhD|
Katie is interested in innate immunity against virus infection. She is working to define innate immune mechanisms that mediate clearance of arboviruses from the circulation and to determine mechanisms by which determinants in the CHIKV E2 glycoprotein and 3’ UTR allow for evasion of innate immunity. In addition, Katie also evaluates novel direct acting antiviral therapeutics against alphavirus infection. Katie is the recipient of an NIH-NIAID T32 fellowship in Immunology.
Henri J. Jupille, PhD
Kristina S. Burrack, PhD
David W. Hawman, PhD