Anaplasma phagocytophilum is an obligate intracellular bacterium and rickettsial pathogen that invades neutrophils and endothelial cells to cause the emerging and potentially fatal infection, human granulocytic anaplasmosis (HGA). A. phagocytophilum converts its host neutrophil into a Trojan horse that facilitates pathogen replication and dissemination. The bacterium down-regulates the neutrophil antimicrobial response, raising susceptibility to opportunistic infections. Blocking A. phagocytophilum infection of neutrophils would prevent the stage of HGA associated with pathogen dissemination and increased risk of opportunistic infections. A. phagocytophilum infects microvascular endothelial cells of heart and liver. Endothelial cells are also implicated as the initial cell type that A. phagocytophilum infects following inoculation via tick feeding. Infected endothelial cells are capable of transferring the bacterium to neutrophils. Abrogating A. phagocytophilum invasion of endothelial cells would potentially prevent infection of major organs and initial establishment of infection. The overall goal of this project is to functionally characterize A. phagocytophilum oute membrane proteins that facilitate infection. We identified outer membrane protein A (OmpA) and Asp14 (14-kDa Ap surface protein) as the first two A. phagocytophilum proteins that are critical for invasion of myeloid and endothelial cells. Targeting OmpA and Asp14 nearly abolishes A. phagocytophilum infection of host cells.
In Aim 1, we will identify the OmpA and Asp14 domains that mediate A. phagocytophilum uptake and determine if either protein is sufficient for invasion.
In Aim 2, we will identify the host cell receptors of OmpA and Asp14.
In Aim 3, we will directly assess the relevance of OmpA and Asp14 to infectivity using novel transgenic A. phagocytophilum organisms that can be induced to express antisense RNA against ompA or asp14 to knock down OmpA or Asp14 expression. This research will provide a robust understanding of A. phagocytophilum cellular invasion and identify the first two invasin-receptor pairs for any Anaplasmataceae pathogen. As OmpA and Asp14 are conserved among several rickettsial pathogens, our work will provide direction for vaccine development against a subset of bacteria that causes HGA and other debilitating diseases. Lastly, our work will yield a valuable tool for assessing gene function in obligate intracellular bacteria.
Human granulocytic anaplasmosis (HGA) is an emerging, potentially fatal disease caused by a bacterium that invades blood vessel endothelial cells and white blood cells called neutrophils. We have identified two bacterial factors that are critical fo infection of both host cell types. The proposed research will determine how the two bacterial factors mediate infection. Doing so will aid the design of novel strategies for preventing HGA.
|Seidman, David; Ojogun, Nore; Walker, Naomi J et al. (2014) Anaplasma phagocytophilum surface protein AipA mediates invasion of mammalian host cells. Cell Microbiol 16:1133-45|
|Truchan, Hilary K; Seidman, David; Carlyon, Jason A (2013) Breaking in and grabbing a meal: Anaplasma phagocytophilum cellular invasion, nutrient acquisition, and promising tools for their study. Microbes Infect 15:1017-25|
|Kahlon, Amandeep; Ojogun, Nore; Ragland, Stephanie A et al. (2013) Anaplasma phagocytophilum Asp14 is an invasin that interacts with mammalian host cells via its C terminus to facilitate infection. Infect Immun 81:65-79|
|Troese, Matthew J; Kahlon, Amandeep; Ragland, Stephanie A et al. (2011) Proteomic analysis of Anaplasma phagocytophilum during infection of human myeloid cells identifies a protein that is pronouncedly upregulated on the infectious dense-cored cell. Infect Immun 79:4696-707|
|Ojogun, Nore; Barnstein, Brian; Huang, Bernice et al. (2011) Anaplasma phagocytophilum infects mast cells via alpha1,3-fucosylated but not sialylated glycans and inhibits IgE-mediated cytokine production and histamine release. Infect Immun 79:2717-26|
|Huang, Bernice; Hubber, Andree; McDonough, Justin A et al. (2010) The Anaplasma phagocytophilum-occupied vacuole selectively recruits Rab-GTPases that are predominantly associated with recycling endosomes. Cell Microbiol 12:1292-307|
|Huang, Bernice; Troese, Matthew J; Ye, Shaojing et al. (2010) Anaplasma phagocytophilum APH_1387 is expressed throughout bacterial intracellular development and localizes to the pathogen-occupied vacuolar membrane. Infect Immun 78:1864-73|
|Huang, Bernice; Troese, Matthew J; Howe, Dale et al. (2010) Anaplasma phagocytophilum APH_0032 is expressed late during infection and localizes to the pathogen-occupied vacuolar membrane. Microb Pathog 49:273-84|
|Troese, Matthew J; Carlyon, Jason A (2009) Anaplasma phagocytophilum dense-cored organisms mediate cellular adherence through recognition of human P-selectin glycoprotein ligand 1. Infect Immun 77:4018-27|
|Thomas, Rachael J; Dumler, J Stephen; Carlyon, Jason A (2009) Current management of human granulocytic anaplasmosis, human monocytic ehrlichiosis and Ehrlichia ewingii ehrlichiosis. Expert Rev Anti Infect Ther 7:709-22|
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