The overall focus of this grant is acute lung injury and multiple organ failure in bacterial sepsis. Our hypothesis is that a pre-existing viral infection can alter the outcome of sepsis and increase lung injury. We have already shown that a preceding adenoviral infection markedly increases the severity of sepsis in an animal model. We also made the novel observation that a preceding adenoviral infection triggers a resistance (tolerance) to tumor necrosis factor ( (TNF(). The animals exposed to adenovirus are resistant to the effects of TNF( but they make TNF( in normal amounts in response to lipopolysaccharide (LPS). This was true, both with the wild type virus and with an adenoviral vector (deleted in the known adenovirus immunosuppressive proteins E1 and E3). Retained TNF( production after LPS stimulation makes the adenovirus-induced tolerance distinct from LPS tolerance (which blocks subsequent TNF( production). The presence of TNF( tolerance is important because excessive TNF( in the non-resistant state is an important mediator of tissue injury. On the other hand, TNF( and responsiveness to TNF( are essential for optimal clearance of bacterial infections. These observations suggest that the development of TNF( tolerance after a viral infection may contribute to increased incidence, and impaired resolution, of bacterial infections. A second novel finding, suggested by the preliminary data, is that a preceding adenoviral infection interferes with NF(B signaling and decreases production of anti-apoptotic proteins. This may contribute to the increased severity of sepsis by increasing tissue injury. We feel that TNF( tolerance and alterations in survival pathways are important components of virus-induced immunosuppression that can lead to increased severity of sepsis.
Our specific aims to evaluate this hypothesis are as follows: 1. Determine the effects of prior exposure to adenovirus on bacterial sepsis and acute lung injury. 2. Determine the effects of prior exposure to adenovirus on TNF( receptor signaling and survival pathways. 3. Determine the mechanisms leading to TNF( tolerance after exposure to adenovirus. These studies may provide important clues to understand the well-described clinical effects of some viruses on subsequent bacterial infections. ? ?
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