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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077431-04
Application #
7237232
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
Project Start
2004-09-15
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2009-06-30
Support Year
4
Fiscal Year
2007
Total Cost
$349,641
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Hansdottir, Sif; Monick, Martha M; Lovan, Nina et al. (2010) Vitamin D decreases respiratory syncytial virus induction of NF-kappaB-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state. J Immunol 184:965-74
Monick, Martha M; Powers, Linda S; Walters, Katherine et al. (2010) Identification of an autophagy defect in smokers' alveolar macrophages. J Immunol 185:5425-35
Hunninghake, Gary W; Doerschug, Kevin C; Nymon, Amanda B et al. (2010) Insulin-like growth factor-1 levels contribute to the development of bacterial translocation in sepsis. Am J Respir Crit Care Med 182:517-25
Groskreutz, Dayna J; Babor, Ellen C; Monick, Martha M et al. (2010) Respiratory syncytial virus limits alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha) phosphorylation to maintain translation and viral replication. J Biol Chem 285:24023-31
Groskreutz, Dayna J; Monick, Martha M; Babor, Ellen C et al. (2009) Cigarette smoke alters respiratory syncytial virus-induced apoptosis and replication. Am J Respir Cell Mol Biol 41:189-98
Ashare, Alix; Stanford, Clark; Hancock, Patricia et al. (2009) Chronic liver disease impairs bacterial clearance in a human model of induced bacteremia. Clin Transl Sci 2:199-205
Nyunoya, Toru; Monick, Martha M; Klingelhutz, Aloysius L et al. (2009) Cigarette smoke induces cellular senescence via Werner's syndrome protein down-regulation. Am J Respir Crit Care Med 179:279-87
Monick, Martha M; Powers, Linda S; Barrett, Christopher W et al. (2008) Constitutive ERK MAPK activity regulates macrophage ATP production and mitochondrial integrity. J Immunol 180:7485-96
Hansdottir, Sif; Monick, Martha M; Hinde, Sara L et al. (2008) Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense. J Immunol 181:7090-9
Yarovinsky, Timur O; Monick, Martha M; Husmann, Matthias et al. (2008) Interferons increase cell resistance to Staphylococcal alpha-toxin. Infect Immun 76:571-7

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