Dr. Pergam completed an MPH degree and Infectious Diseases training at the University of Washington. This proposal describes a 5-year training program which will allow him to develop an independent academic career in clinical research studying the genetics of host immunity to cytomegalovirus (CMV) in transplant. This project will build on preliminary work evaluating the role of killer immunoglobulin-like receptors (KIR) in CMV infection in hematopoietic cell transplantation (HOT). CMV is the most common viral infection in HOT, with over 60% of seropositive recipients reactivating, and 9% developing life-threatening complications. Since natural killer (NK) cells recover quickly after transplantation, they may play an important role in the control of reactivation in the early post-transplant period. Our preliminary studies provide new evidence of an increased risk of invasive CMV disease.in recipients who receive only one donor activating KIR gene. We also show that individual donor KIR genes, particularly KIR3DS1, may decrease rates of both reactivation and invasive CMV disease. In addition, our data suggests that fewer cytotoxic CD56?"/KIR* natural killer cells in the post-HCT period increase the risk of CMV reactivation. In our first Aim, we will evaluate the associations between KIR and CMV quantitative phenotypes using a retrospective cohort of seropositive HOT recipients (Aim 1a). We will then sequence donor KIR3DL1/DS1 as a candidate gene, and assess it for associations with CMV pneumonia using a case control approach (Aim 1b). Finally, we will prospectively evaluate post-HCT NK cell and KIR reconstitution in the laboratory and determine how they affect CMV reactivation (Aim 2). Together, these studies will provide new insights into the role of NK cells in CMV immunobiology.

Public Health Relevance

CMV remains the most common viral infection in transplantation, and is associated with significant morbidity and mortality. Through these genetic studies we hope to identify better predictors for CMV reactivation and disease, which could help to alter donor selection, identify appropriate candidates for aggressive antiviral prophylaxis pre-transplant, and may eventually lead to a reduction in the burden of CMV complications in HCT.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL096831-04
Application #
8296656
Study Section
Special Emphasis Panel (ZHL1-CSR-R (M1))
Program Officer
Welniak, Lisbeth A
Project Start
2009-08-20
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$134,329
Indirect Cost
$9,950
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Miles-Jay, Arianna; Butler-Wu, Susan; Rowhani-Rahbar, Ali et al. (2015) Incidence rate of fluoroquinolone-resistant gram-negative rod bacteremia among allogeneic hematopoietic cell transplantation patients during an era of levofloxacin prophylaxis. Biol Blood Marrow Transplant 21:539-45
Chu, Helen Y; Englund, Janet A; Podczervinski, Sara et al. (2014) Nosocomial transmission of respiratory syncytial virus in an outpatient cancer center. Biol Blood Marrow Transplant 20:844-51
Travi, Giovanna; Pergam, Steven A (2014) Cytomegalovirus pneumonia in hematopoietic stem cell recipients. J Intensive Care Med 29:200-12
Boyle, Nicole M; Podczervinski, Sara; Jordan, Kim et al. (2014) Bacterial foodborne infections after hematopoietic cell transplantation. Biol Blood Marrow Transplant 20:1856-61
Pergam, S A; Limaye, A P; AST Infectious Diseases Community of Practice (2013) Varicella zoster virus in solid organ transplantation. Am J Transplant 13 Suppl 4:138-46
Milano, Filippo; Chien, Jason W; Riffkin, Ivy et al. (2012) Stable long-term pulmonary function after myeloablative double cord blood transplant. Biol Blood Marrow Transplant 18:309-13
Milano, Filippo; Pergam, Steven A; Xie, Hu et al. (2011) Intensive strategy to prevent CMV disease in seropositive umbilical cord blood transplant recipients. Blood 118:5689-96
Pergam, S A; Forsberg, C W; Boeckh, M J et al. (2011) Herpes zoster incidence in a multicenter cohort of solid organ transplant recipients. Transpl Infect Dis 13:15-23
Gooley, Ted A; Chien, Jason W; Pergam, Steven A et al. (2010) Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 363:2091-101
Pergam, S A; Limaye, A P; AST Infectious Diseases Community of Practice (2009) Varicella zoster virus (VZV) in solid organ transplant recipients. Am J Transplant 9 Suppl 4:S108-15

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