Anaplasma phagocytophilum is a tick-borne obligate intracellular bacterial pathogen and the agent of granulocytic anaplasmosis in humans and animals. A. phagocytophilum primarily infects neutrophils (PMNs), subverting normal PMN apoptosis and killing mechanisms to facilitate bacterial proliferation. In contrast to endotoxin-positive bacterial infections, A. phagocytophilum infection induces neutropenia despite increased bone marrow (BM) granulopoiesis. The implication is that this granulocytotropic pathogen may fundamentally alter the upstream regulation of PMN mobilization, the downstream regulation of PMN release from BM and the systemic trafficking and homing of PMN during infection. Neutropenia and hematopoietic alterations likely contribute to the serious clinical complications of A. phagocytophilum infection, including opportunistic infections, but the mechanisms involved in altered PMN trafficking during A. phagocytophilum infection are largely unknown. Our global hypothesis is that A. phagocytophilum infection and pathogen replication perturb normal PMN trafficking and may ultimately facilitate pathogen-PMN interaction and enhance bacterial propagation. Infection-induced production of granulocyte colony stimulating factor (G-CSF) and interleukin-8 (IL-8) will be investigated as upstream regulators of PMN mobilization from BM via effects on intermediate signaling and integrin-mediated interactions. Systemic PMN trafficking and splenic homing will be defined using sophisticated imaging strategies. Mechanisms of PMN trafficking including chemotactic gradients and integrin-mediated interactions in the spleen will be determined. Our goal is to define mechanisms of infection-induced PMN trafficking and to determine their role in the innate immune response and clinical consequences of disease. The K01 award would support Dr. Jennifer Johns'career development as a postdoctoral DVM, PhD and prepare her for independent research. Dr. Johns is an experienced, board-certified veterinary clinical pathologist with a specific interest in hematologic and hematopoietic alterations in infectious disease and a commitment to advanced biomedical research. Five years of mentored support is requested.

Public Health Relevance

Anaplasma phagocytophilum is an obligate intracellular bacteria and the agent of Granulocytic Anaplasmosis in animals and humans. Infection with A. phagocytophilum causes multiple hematologic abnormalities, including neutropenia, that contribute to serious clinical complications including opportunistic infection and death. The goals of this project are to define the mechanisms by which PMN trafficking is dysregulated during infection and to determine the effect of PMN trafficking dysregulation on pathogen persistence or clearance.

Agency
National Institute of Health (NIH)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01OD011150-05
Application #
8724577
Study Section
Comparative Medicine Review Committee (RIRG)
Program Officer
Fuchs, Bruce
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304