Abstract
The genus Anaplasma consists of tick-transmitted obligate intracellular bacteria that invade white or red blood cells to cause debilitating and potentially fatal infections. A. phagocytophilum, a human and veterinary pathogen, infects neutrophils to cause granulocytic anaplasmosis. A. marginale invades bovine erythrocytes. Evidence suggests that both species may also infect endothelial cells in vivo. In mammalian and arthropod host cells, A. phagocytophilum and A. marginale reside in host cell derived pathogen-occupied vacuoles (POVs). While it was recently demonstrated that the A. phagocytophilum-occupied vacuole (ApV) intercepts membrane traffic from the trans-Golgi network, it is unclear if it or the A. marginale-occupied vacuole (AmV) interacts with other secretory organelles. Here, we demonstrate that the ApV and AmV extensively interact with the host endoplasmic reticulum (ER) in endothelial, myeloid, and/or tick cells. ER lumen markers, calreticulin, and protein disulfide isomerase, and the ER membrane marker, derlin-1, were pronouncedly recruited to the peripheries of both POVs. ApV association with the ER initiated early and continued throughout the infection cycle. Both the ApV and AmV interacted with the rough ER and smooth ER. However, only derlin-1-positive rough ER derived vesicles were delivered into the ApV lumen where they localized with intravacuolar bacteria. Transmission electron microscopy identified multiple ER-POV membrane contact sites on the cytosolic faces of both species' vacuoles that corresponded to areas on the vacuoles' lumenal faces where intravacuolar Anaplasma organisms closely associated. A. phagocytophilum is known to hijack Rab10, a GTPase that regulates ER dynamics and morphology. Yet, ApV-ER interactions were unhindered in cells in which Rab10 had been knocked down, demonstrating that the GTPase is dispensable for the bacterium to parasitize the ER. These data establish the ApV and AmV as pathogen-host interfaces that directly engage the ER in vertebrate and invertebrate host cells and evidence the conservation of ER parasitism between two Anaplasma species.
Highlights
Anaplasma phagocytophilum and Anaplasma marginale are ticktransmitted obligate intracellular bacterial pathogens of the Family Anaplasmataceae that cause debilitating and potentially fatal diseases (Carlyon, 2012)
We demonstrated that the A. phagocytophilum-occupied vacuole (ApV) and A. marginale-occupied vacuole (AmV) engage the endoplasmic reticulum (ER) and that ER derived vesicles are delivered into their lumen in mammalian and tick host cells
This strategy is likely important to Anaplasma spp. intracellular survival, as it is initiated in the early hours following the bacterial entry event that generates the pathogen-occupied vacuoles (POVs) and continues throughout the entirety of the infection cycle
Summary
Anaplasma phagocytophilum and Anaplasma marginale are ticktransmitted obligate intracellular bacterial pathogens of the Family Anaplasmataceae that cause debilitating and potentially fatal diseases (Carlyon, 2012). A. phagocytophilum infects neutrophils to cause granulocytic anaplasmosis in humans and animals (Truchan et al, 2013). S. states, as well as Mexico, Central and South America, and the Caribbean Islands It infects erythrocytes, which can result in anemia, weight loss, reduced growth, and milk production, and abortion in pregnant cattle (Kocan et al, 2010; Suarez and Noh, 2011). Following resolution of acute disease, bovine anaplasmosis can remain chronic for the life of the animal and is estimated to cost the U.S and South American cattle industries hundreds of millions of dollars each year (Kocan et al, 2003; Suarez and Noh, 2011)
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