Mechanisms of Obligatory Intracellular Infection with Anaplasma phagocytophilum

Abstract

SUMMARY Anaplasma phagocytophilum persists in nature by cycling between mammals and ticks. Human infection by the bite of an infected tick leads to a potentially fatal emerging disease called human granulocytic anaplasmosis. A. phagocytophilum is an obligatory intracellular bacterium that replicates inside mammalian granulocytes and the salivary gland and midgut cells of ticks. A. phagocytophilum evolved the remarkable ability to hijack the regulatory system of host cells. A. phagocytophilum alters vesicular traffic to create an intracellular membrane-bound compartment that allows replication in seclusion from lysosomes. The bacterium downregulates or actively inhibits a number of innate immune responses of mammalian host cells, and it upregulates cellular cholesterol uptake to acquire cholesterol for survival. It also upregulates several genes critical for the infection of ticks, and it prolongs tick survival at freezing temperatures. Several host factors that exacerbate infection have been identified, including interleukin-8 (IL-8) and cholesterol. Host factors that overcome infection include IL-12 and gamma interferon (IFN-γ). Two bacterial type IV secretion effectors and several bacterial proteins that associate with inclusion membranes have been identified. An understanding of the molecular mechanisms underlying A. phagocytophilum infection will foster the development of creative ideas to prevent or treat this emerging tick-borne disease.

Autophagosomes induced by a bacterial Beclin 1 binding protein facilitate obligatory intracellular infection

“…By light microscopy, Ap inclusions appear as characteristic irregular clumps of various sizes because of dense aggregates of bacteria (a few to >50) inside inclusions called morula (morula means mulberry in Latin) (Fig. 4 A and B) (9). Immunofluorescence labeling showed the localization of Atg14L and DFCP1 to Ap inclusions (Fig.…”

“…Ap is a Gram-negative obligatory intracellular bacterium that belongs to the order Rickettsiales (9). Ap infects granulocytes and endothelial cells of various mammalian species (9). In humans, Ap causes an emerging and major tick-borne disease called human granulocytic anaplasmosis, an acute febrile disease that is potentially fatal, especially in elderly or immunocompromised individuals (10).…”

“…We have been studying the role of autophagy in Anaplasma phagocytophilum (Ap) infection. Ap is a Gram-negative obligatory intracellular bacterium that belongs to the order Rickettsiales (9). Ap infects granulocytes and endothelial cells of various mammalian species (9).…”

Expression, purification, and biological characterization of <i>Anaplasma phagocytophilum</i> enolase

“…A. phagocytophilum is primarily transmitted to humans via bites from infected ixodid ticks; however, transmission has also been reported to occur through blood transfusion and contact with infected mammal blood (2). After infection, the patient generally presents unexplained nonspecific symptoms such as fever, chills, headache, and myalgia, which may occur in the presence of abnormal laboratory features, which may include leukopenia, thrombocytopenia, and/or mildly elevated liver enzymes (3).…”

“…Within the vertebrate host, the bacteria colonizes neutrophils, but also infects other cells of myeloid and nonmyeloid origin. Of interest, it has also been reported to infect and multiply in several different ixodid tick tissues, including the midgut and salivary gland cells (2). Over recent decades, several molecules used by A. phagocytophilum to infect and multiply within vertebrate host cells have been well characterized (4).…”