Human cytomegalovirus (CMV), like other beta herpes viruses, has the ability to become latent following primary infection. CMV can later reactivate from latency, and following reactivation is a well known pathogen in immmunosuppressed transplant and AIDS patients. We have recently demonstrated that critically ill surgical patients can also reactivate latent CMV, and that it appears to be a pulmonary pathogen in these patients, with worsened morbidity and possibly mortality. Unfortunately, the trigger for this reactivation remains unknown. A number of stimuli have been related to reactivation, including immunosuppression, allogeneic stimulation from transplant, cytokine stimulation, and bacterial sepsis. Using an animal model, we have recently demonstrated that intra-abdominal bacterial sepsis can cause distant reactivation of latent CMV in lungs of immunocompetent mice. Further, we have shown that this reactivation occurs in multiple organs, suggesting the possible involvement of a circulating mediator. Several inflammatory mediators released during sepsis, including endotoxin and tumor necrosis factor, have been shown to be stimulatory to CMV replication, and thus might be responsible for reactivation in this model. In addition, these mediators are known to cause significant local end organ inflammation, and our preliminary data suggests that this local inflammation may contribute to reactivation of CMV from latency. Finally, our preliminary data also suggests that reactivation of CMV from latency also causes pathology in the immunocompetent host. This proposal, therefore, will focus on determining the mechanisms by which bacterial sepsis induces reactivation of latent CMV in lungs of immunocompetent hosts. Based upon our preliminary data, we will test the hypothesis that inflammatory mediators induced by sepsis, acting either systemically or locally, stimulate CMV reactivation from latency.
In Specific Aim I, we will evaluate the role of systemic and local inflammation in reactivation of latent CMV.
Specific Aim II will investigate the role of nuclear factor kappa B activation in sepsis-triggered reactivation.
In Specific Aim III, we will further investigate the injurious effects of pulmonary CMV reactivation. The long-term goals of our laboratory are to elucidate the critical cellular and molecular factors mediating CMV reactivation from latency in critically ill surgical patients, and to utilize these data in directing therapy to ameliorate CMV disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM066115-01A1
Application #
6610118
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2003-05-08
Project End
2008-04-30
Budget Start
2003-05-08
Budget End
2004-04-30
Support Year
1
Fiscal Year
2003
Total Cost
$292,050
Indirect Cost
Name
Ohio State University
Department
Surgery
Type
Schools of Medicine
DUNS #
071650709
City
Columbus
State
OH
Country
United States
Zip Code
43210
Mansfield, Sara A; Cook, Charles H (2017) Antiviral prophylaxis of cytomegalovirus reactivation in immune competent patients-the jury remains out. J Thorac Dis 9:2221-2223
Griessl, Marion; Gutknecht, Michael; Cook, Charles H (2017) Determination of suitable reference genes for RT-qPCR analysis of murine Cytomegalovirus in vivo and in vitro. J Virol Methods 248:100-106
Trgovcich, Joanne; Kincaid, Michelle; Thomas, Alicia et al. (2016) Cytomegalovirus Reinfections Stimulate CD8 T-Memory Inflation. PLoS One 11:e0167097
Mansfield, Sara; Dwivedi, Varun; Byrd, Sara et al. (2016) Broncholaveolar lavage to detect cytomegalovirus infection, latency, and reactivation in immune competent hosts. J Med Virol 88:1408-16
Mansfield, Sara; Grießl, Marion; Gutknecht, Michael et al. (2015) Sepsis and cytomegalovirus: foes or conspirators? Med Microbiol Immunol 204:431-7
Guidry, Christopher A; Mansfield, Sara A; Sawyer, Robert G et al. (2014) Resistant pathogens, fungi, and viruses. Surg Clin North Am 94:1195-218
Raghavan, Bindu; Cook, Charles H; Trgovcich, Joanne (2014) The carboxy terminal region of the human cytomegalovirus immediate early 1 (IE1) protein disrupts type II inteferon signaling. Viruses 6:1502-24
Juranic Lisnic, Vanda; Babic Cac, Marina; Lisnic, Berislav et al. (2013) Dual analysis of the murine cytomegalovirus and host cell transcriptomes reveal new aspects of the virus-host cell interface. PLoS Pathog 9:e1003611
Campbell, Jonathan; Trgovcich, Joanne; Kincaid, Michelle et al. (2012) Transient CD8-memory contraction: a potential contributor to latent cytomegalovirus reactivation. J Leukoc Biol 92:933-7
Cook, Charles H; Limaye, Ajit P (2012) Cytomegalovirus serostatus and outcome during critical illness. Crit Care Med 40:2740; author reply 2740-1

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