Dissertation/Thesis Abstract

Mechanisms of Hematopoietic Alteration in Experimental Anaplasma phagocytophilum Infection
by Johns, Jennifer Lynn, Ph.D., University of California, Davis, 2011, 121; 3474401
Abstract (Summary)

Infection with Anaplasma phagocytophilum, a gram-negative, LPS-negative, obligate intracellular bacteria, results in clinical disease in humans and domestic animal species. Hematologic disturbances caused by infection include multiple peripheral blood cytopenias that are consistently seen in natural infection of humans and animals as well as experimental murine infection. Utilizing an established mouse model of A. phagocytophilum infection, we first quantified alterations in bone marrow (BM) and splenic hematopoietic progenitor cells (HPCs) and lineage-committed cells. BM cytokine production and CXCL12 mRNA expression were also determined. Infection resulted in peripheral bicytopenia, markedly decreased numbers of lineage-committed HPCs in the BM, and a largely myelosuppressive BM cytokine environment. Concurrently, lineage-committed HPCs in the spleen increased. CXCL12 mRNA production in BM cells was significantly decreased. Hematopoietic lineage assessment demonstrated decreased erythroid cells and B lymphocytes in the BM and increased granulocytic cells. Additionally, splenomegaly developed and was due to lymphoid hyperplasia and increased hematopoiesis, largely increased erythropoiesis.

Next, we determined the effect of acute infection on BM hematopoietic stem and progenitor cell (HSPC) proliferation and mobilization to the periphery. Lineage- c-Kit+ HSPCs were enumerated and proliferation determined. Increased BM proliferation of HSPCs began at 2 days post-infection followed by HSPC mobilization and splenic homing. Proliferation of resident HSPCs contributed to increased splenic HSPC numbers. CXCL12 mRNA and protein were quantified in BM and spleen. CXCR4 surface, intracellular and total protein expression in sorted BM and splenic HSPCs was determined. BM CXCL12 mRNA and protein levels were decreased at 4-8 days post-infection concurrent with HSPC mobilization. CXCR4 protein parameters were decreased in BM HSPCs throughout infection. Reduction of CXCL12/CXCR4 signaling occurs simultaneously with HSPC mobilization from BM.

In total, the findings indicate that acute A. phagocytophilum infection induces multiple hematopoietic alterations including lineage shifts in BM, alterations in BM cytokine milieu, and quantitative and functional changes in BM and peripheral HSPC populations including increased mobilization to the periphery. Simultaneous downregulation of CXCL12/CXCR4 signaling occurs via multiple alterations in both receptor and ligand expression. As BM HSPCs will respond to a CXCL12 concentration gradient by mobilizing when BM CXCL12 levels decrease, the data strongly suggest that perturbed CXCL12 signaling induces HSPC mobilization during acute A. phagocytophilum infection.

Indexing (document details)
Advisor: Borjesson, Dori
Commitee: Angelastro, James, Nolta, Jan
School: University of California, Davis
Department: Comparative Pathology
School Location: United States -- California
Source: DAI-B 73/01, Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Pathology, Veterinary services, Immunology
Keywords: Anaplasma phagocytophilum, Bone marrow, Hematopoiesis
Publication Number: 3474401
ISBN: 9781124907321
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