Coxsackievirus B3 causes myocarditis, pancreatitis and meningo-encephalitis but, despite the resulting human morbidity and mortality, neither a treatment, nor a vaccine, is available. My lab has shown that the metabolic status of the host cell plays a key role in determining the outcome of CVB3 infection and, in the previous period of support, we identified stem cells as early targets of CVB3 infection. In this renewal application, I propose 4 Specific Aims, focusing on the following topics : 1. Bone marrow is the main repository of stem cells in the adult, and we show herein that CVB naturally infects ~1% of bone marrow cells in vivo. We shall identify and characterize the bone marrow cells that become infected;and will evaluate the biological implications of this infection. 2. We shall determine the role of cellular activation in regulating CVB3 infection in the heart. We shall use a variety of methods to ask: are proliferating cells targeted? Are myocardial stem cells a preferred site of infection? Does prior myocardial damage alter viral replication in the heart, and does this exacerbate the viral myocarditis? 3. The innate immune response to picornaviruses in general, and to enteroviruses in particular, is poorly understood. We shall investigate the innate responses to CVB3 infection in lymphoid tissues (spleen &lymph nodes). What responses are mounted? Which of the many innate molecular sensors are involved? How does activation of the innate system affect the outcome of subsequent CVB3 infection? 4. Many virus infections induce very strong T cell responses, but CVB3 appears not to do so;neither CD4+ nor CD8+ T cells are strongly activated during wtCVB3 infection. We shall use novel methods to map, kinetically and anatomically, the presentation of CVB3-encoded MHC class I &class II epitopes, and will ask how the innate responses to CVB3 infection affect the subsequent development of adaptive T cell immunity.
Coxsackieviruses infect millions of people each year in the USA. In most cases, the infections cause little harm, but in some cases - especially in very young children - the diseases can be serious, and sometimes fatal. This research will help us understand how these viruses cause disease, and will provide clues about how to prevent or treat these dangerous infections.
|Robinson, Scott M; Tsueng, Ginger; Sin, Jon et al. (2014) Coxsackievirus B exits the host cell in shed microvesicles displaying autophagosomal markers. PLoS Pathog 10:e1004045|
|Althof, Nadine; Harkins, Stephanie; Kemball, Christopher C et al. (2014) In vivo ablation of type I interferon receptor from cardiomyocytes delays coxsackieviral clearance and accelerates myocardial disease. J Virol 88:5087-99|
|Althof, Nadine; Whitton, J Lindsay (2013) Coxsackievirus B3 infects the bone marrow and diminishes the restorative capacity of erythroid and lymphoid progenitors. J Virol 87:2823-34|
|Ruller, Chelsea M; Tabor-Godwin, Jenna M; Van Deren Jr, Donn A et al. (2012) Neural stem cell depletion and CNS developmental defects after enteroviral infection. Am J Pathol 180:1107-20|
|Alirezaei, Mehrdad; Flynn, Claudia T; Wood, Malcolm R et al. (2012) Pancreatic acinar cell-specific autophagy disruption reduces coxsackievirus replication and pathogenesis in vivo. Cell Host Microbe 11:298-305|
|Kemball, Christopher C; Flynn, Claudia T; Hosking, Martin P et al. (2012) Wild-type coxsackievirus infection dramatically alters the abundance, heterogeneity, and immunostimulatory capacity of conventional dendritic cells in vivo. Virology 429:74-90|
|Alirezaei, Mehrdad; Flynn, Claudia T; Whitton, J Lindsay (2012) Interactions between enteroviruses and autophagy in vivo. Autophagy 8:973-5|
|Tsueng, Ginger; Tabor-Godwin, Jenna M; Gopal, Aparajita et al. (2011) Coxsackievirus preferentially replicates and induces cytopathic effects in undifferentiated neural progenitor cells. J Virol 85:5718-32|
|Alirezaei, Mehrdad; Kemball, Christopher C; Whitton, J Lindsay (2011) Autophagy, inflammation and neurodegenerative disease. Eur J Neurosci 33:197-204|
|Tabor-Godwin, Jenna M; Ruller, Chelsea M; Bagalso, Nolan et al. (2010) A novel population of myeloid cells responding to coxsackievirus infection assists in the dissemination of virus within the neonatal CNS. J Neurosci 30:8676-91|
Showing the most recent 10 out of 38 publications