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.
|Truchan, Hilary K; Cockburn, Chelsea L; Hebert, Kathryn S et al. (2016) The Pathogen-Occupied Vacuoles of Anaplasma phagocytophilum and Anaplasma marginale Interact with the Endoplasmic Reticulum. Front Cell Infect Microbiol 6:22|
|Truchan, Hilary K; VieBrock, Lauren; Cockburn, Chelsea L et al. (2016) Anaplasma phagocytophilum Rab10-dependent parasitism of the trans-Golgi network is critical for completion of the infection cycle. Cell Microbiol 18:260-81|
|Seidman, David; Hebert, Kathryn S; Truchan, Hilary K et al. (2015) Essential domains of Anaplasma phagocytophilum invasins utilized to infect mammalian host cells. PLoS Pathog 11:e1004669|
|Beyer, Andrea R; Truchan, Hilary K; May, Levi J et al. (2015) The Anaplasma phagocytophilum effector AmpA hijacks host cell SUMOylation. Cell Microbiol 17:504-19|
|Beyer, Andrea R; Carlyon, Jason A (2015) Of goats and men: rethinking anaplasmoses as zoonotic infections. Lancet Infect Dis 15:619-20|
|Oki, Aminat T; Seidman, David; Lancina 3rd, Michael G et al. (2015) Dendrimer-enabled transformation of Anaplasma phagocytophilum. Microbes Infect 17:817-22|
|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|
|Ojogun, Nore; Kahlon, Amandeep; Ragland, Stephanie A et al. (2012) Anaplasma phagocytophilum outer membrane protein A interacts with sialylated glycoproteins to promote infection of mammalian host cells. Infect Immun 80:3748-60|
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