Faculty
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Jason B. Weinberg |
Pathogenesis of Persistent Viral Infections
Some viruses are capable of persisting for extended periods of time in their host, producing either an ongoing low-grade infection or a true latent infection. Our research interests focus on interactions between persistent viruses and host inflammatory responses. Because of the strict species specificity of many human viruses, it can be difficult to completely study all aspects of their pathogenesis. We use two mouse pathogens – mouse adenovirus type 1 (MAV-1) and murine gammaherpesvirus 68 (MHV-68) – to study issues of viral persistence, host responses to infection, and interactions between the two processes.
Acute respiratory infection with a human adenovirus presents with varying severity, ranging from mild upper respiratory tract infections to more severe pneumonia and bronchiolitis obliterans. Adenovirus infection of immunocompromised patients can be particularly devastating, often resulting in rapidly disseminated infection and death. Emerging evidence suggests a role for persistent adenovirus infection in chronic lung diseases such as chronic obstructive lung disease (COPD) and asthma. Using MAV-1 infection of laboratory mice, we hope to define mechanisms by which host inflammatory responses are induced by viral infection and the contributions that specific components of these host responses make to the control of acute viral infection. To determine the ability of persistent adenovirus infection to modulate host responses to subsequent stimuli, we analyze pulmonary inflammation and airway hyperreactivity induced in mice persistently infected with MAV-1 following challenges with unrelated infectious or allergic stimuli. Information derived from these studies will enhance the understanding of the pathogenesis of both adenovirus infection and adenovirus-associated chronic lung disease. In addition, implicating a specific viral pathogen in the pathogenesis of chronic lung disease will provide opportunities to develop novel prevention or treatment strategies.
The human gammaherpesviruses are Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8). Each human gammaherpesvirus is closely associated with a number of malignancies, particularly in immunosuppressed transplant recipients or individuals with immunosuppression due to concurrent infection with human immunodeficiency virus. Like other herpesviruses, the gammaherpesviruses are characterized by their ability to establish life-long latency in host cells. Reactivation from latency and subsequent lytic viral replication is an essential component of the gammaherpesvirus life cycle, allowing the virus to spread to other cells within the host or to other susceptible hosts. Specific exogenous stimuli that trigger reactivation are not yet well defined, but clinical and experimental evidence suggests that coinfection with a second pathogen may serve as a stimulus for reactivation in a host latently infected with a gammaherpesvirus. Using a mouse model of coinfection, our laboratory tests the hypothesis that acute infection with a second pathogen is capable of inducing reactivation of latent MHV-68. We hope to define the roles of select chemokines and cytokines in MHV-68 reactivation.
Selected Publications:
Weinberg, JB, Lutzke, ML, Kunkel, SL and Rochford, R. Elevated chemokine responses are maintained in lungs after clearance of viral infection. Journal of Virology 2002; 76(20): 10518-10523.
Weinberg, JB, Lutzke, ML, Alfinito, R and Rochford, R. Mouse strain differences in the chemokine response to acute lung infection with a murine gammaherpesvirus. Viral Immunology 2004; 17(1): 69-77.
Weinberg, JB, Stempfle, GS, Wilkinson JE, Younger JG and Spindler, KR. Acute respiratory infection with mouse adenovirus type 1. Virology 2005; 340:245-254.
Cadillac, JM, Sigler, RE, Weinberg, JB, Lutzke, ML and Rochford, R. Gammaherpesvirus-induced lung pathology is altered in the absence of macrophages. Lung 2005, 183:239-251.
Weinberg, JB, Jensen, DR, Gralinski, LE, Lake, AR, Stempfle, GS and Spindler, KR. Contributions of E1A to mouse adenovirus type 1 pathogenesis following intranasal inoculation. Virology, in press.
