Doctoral Dissertations

Date of Award

8-2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Microbiology

Major Professor

Thandi M. Onami

Committee Members

Mark Y.Sangster, Barry T.Rouse, Tim E. Sparer, Chunlei Su

Abstract

Viruses replicating in the respiratory tract (RT) triggers a wide- range of cytokines and chemokines that have antiviral and pro-inflammatory features, instigating an efficient virus- specific B and T cell response that aids in virus- clearance. The majority of antibody secreting cells (ASCs) localizing in the upper RT secrete IgA that can effectively neutralize viruses. In addition, elements of B cell memory are generated that can provide protection from re-infection. Studies examining these aspects, following murine gammaherpesvirus 68 (MHV-68) infection comprise chapter 2 of the dissertation work. Our studies demonstrate that following MHV-68 infection, unlike influenza infection, resulted in a generalized deficiency of virus-specific IgA induction and deficient B cell memory establishment in the respiratory tract. The studies indicate that these aspects of B cell response are regulated by features of virus- replication in the RT. These studies lead to the speculation that these features of B cell response may represent an evolutionary adaptation of viruses that establish long-term latency and are transmitted periodically after reactivation and shedding in secretions.

Following cognate interactions with CD4+ T cells, the B cells undergo proliferation, isotype-switching and differentiate towards extrafollicular (low affinity, rapid) or germinal center pathway (high affinity). It is not clear what factors regulate these pathways of B cell differentiation, especially in the context of virus infection in the RT. Studies examining these aspects following influenza infection comprise chapter 3 of the dissertation work. Our studies establish a model for the investigation of host and viral factors that modulate the quality and effectiveness of the B cell response to influenza infection. The findings indicate that the strength of the extrafollicular B cell response depends on the nature of the infecting virus. We present evidence that this pathway of rapid antiviral antibody production relates to the production of non-specifically acting factors in the lung and also dependent of the cytokine profile of virus-specific CD4+T cells.

In summary, the current dissertation findings point out to an influence of virus and host associated factors in regulating features of B cell response in the RT.

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