Cytomegalovirus (CMV) is the most common opportunistic infection in solid organ transplant recipients, particularly in lung transplant recipients (LTRs). Active CMV infection is associated with acute and chronic rejection (bronchiolitis obliterans syndrome), with donor+/recipient- (D+R-) mismatched lung transplant recipients (LTRs) at highest risk for CMV disease and increased mortality. The mechanisms by which D+R- LTRs develop and maintain protective CMV-specific T cell immunity, particularly within the lung allograft, remain incompletely understood. Our preliminary data reveal a striking induction of the transcription factor T-bet, a central regulator of Type-1 immunity in mice, during human primary CMV infection. Our central hypothesis states that optimal protective CMV-specific effector memory (TEM) is T-bet-dependent/polyfunctional, and necessary for viral host defense in the lung and other tissues during acute and chronic infection. To test this hypothesis, in SA1 we will determine the role of T-bet in the regulation of TEM cell function and host defense during human and murine CMV infection. Because we unexpectedly detect CMV-specific CCR7+ TCM cells in human and murine lung airways during active infection, we will determine the relationship between TCM and T-bet+TEM cells, and the role of TCM cells in pulmonary host defense in SA2. Our preliminary data indicates the immunodominance of CMV-specific CD8+ T cell memory changes over time. In SA3, we will determine whether differential CMV-specific T-bet+TEM cell responses predict acute primary/short-term versus long-term CMV protection in the absence of antiviral therapy. Our proposal is an extension and expansion of CMV-specific immune studies currently being conducted in D+R- LTRs by the Pl and his team under an active R21 award (R21 A1072537-O1A1). The PI, John McDyer, MD, is a K08 awardee, transplant pulmonologist, and immunologist, who is strongly committed to understanding CMV pathogenesis, viral immunity, and treatment of CMV infection in lung transplant recipients. He has assembled an expert team of collaborators/consultants in virology, biostatistics, flow cytometry/CMV immunity, and has established a murine CMV (MCMV) model of infection in his laboratory to complement human studies and further test mechanisms in MCMV host defense. This award will provide a foundation for novel translational work in a unique human CMV infection model, and along with MCMV model studies, address clinically relevant issues in viral host defense. Improved knowledge and analysis of CMV-specific immunity in high-risk LTRs may enhance our clinical ability to risk-stratify these challenging patients, and potentially impact future antiviral therapy practices.
Cytomegalovirus (CMV) is the most common infection in solid organ transplant recipients, particularly lung transplant recipients, and is associated with increased risk for organ allograft rejection and mortality, though it is unclear why. Understanding the host immune response to CMV during and after acute infection, and the factors that regulate these responses in transplant recipients, will improve our knowledge of CMV infection and immunity. New knowledge may improve the ability to monitor high-risk patients and develop new treatment strategies, perhaps leading to better outcomes in lung transplant or other solid organ transplant recipients.
|Popescu, Iulia; Pipeling, Matthew R; Mannem, Hannah et al. (2016) IL-12-Dependent Cytomegalovirus-Specific CD4+ T Cell Proliferation, T-bet Induction, and Effector Multifunction during Primary Infection Are Key Determinants for Early Immune Control. J Immunol 196:877-90|
|Lendermon, Elizabeth A; Dodd-o, Jeffrey M; Coon, Tiffany A et al. (2015) CD8(+)IL-17(+) T Cells Mediate Neutrophilic Airway Obliteration in T-bet-Deficient Mouse Lung Allograft Recipients. Am J Respir Cell Mol Biol 52:622-33|
|Shah, Pali D; Zhong, Qiong; Lendermon, Elizabeth A et al. (2015) Hyperexpansion of Functional Viral-Specific CD8+ T Cells in Lymphopenia-Associated MCMV Pneumonitis. Viral Immunol 28:255-64|
|Popescu, Iulia; Pipeling, Matthew R; Shah, Pali D et al. (2014) T-bet:Eomes balance, effector function, and proliferation of cytomegalovirus-specific CD8+ T cells during primary infection differentiates the capacity for durable immune control. J Immunol 193:5709-5722|
|George, M Patricia; Masur, Henry; Norris, Karen A et al. (2014) Infections in the immunosuppressed host. Ann Am Thorac Soc 11 Suppl 4:S211-20|
|Morrell, Matthew R; Pilewski, Joseph M; Gries, Cynthia J et al. (2014) De novo donor-specific HLA antibodies are associated with early and high-grade bronchiolitis obliterans syndrome and death after lung transplantation. J Heart Lung Transplant 33:1288-94|
|Miller, Hannah L; Shah, Pali D; Orens, Jonathan B et al. (2013) Prevention of airway allograft tolerance by polyinosinic:polycytidylic acid requires type I interferon responsiveness for mouse airway obliteration. J Heart Lung Transplant 32:914-24|
|Akulian, J A; Pipeling, M R; John, E R et al. (2013) High-quality CMV-specific CD4+ memory is enriched in the lung allograft and is associated with mucosal viral control. Am J Transplant 13:146-56|
|Dodd-o, J M; Lendermon, E A; Miller, H L et al. (2011) CD154 blockade abrogates allospecific responses and enhances CD4(+) regulatory T-cells in mouse orthotopic lung transplant. Am J Transplant 11:1815-24|
|Pipeling, Matthew R; John, Emily R; Orens, Jonathan B et al. (2011) Primary cytomegalovirus phosphoprotein 65-specific CD8+ T-cell responses and T-bet levels predict immune control during early chronic infection in lung transplant recipients. J Infect Dis 204:1663-71|
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