title: Subversion of cellular autophagy by Anaplasma phagocytophilum.
abstract: Anaplasma phagocytophilum, the causative agent of human granulocytic anaplasmosis, is an obligatory intracellular pathogen. After entry into host cells, the bacterium is diverted from the endosomal pathway and replicates in a membrane-bound compartment devoid of endosomal or lysosomal markers. Here, we show that several hallmarks of early autophagosomes can be identified in A. phagocytophilum replicative inclusions, including a double-lipid bilayer membrane and colocalization with GFP-tagged LC3 and Beclin 1, the human homologues of Saccharomyces cerevisiae autophagy-related proteins Atg8 and Atg6 respectively. While the membrane-associated form of LC3, LC3-II, increased during A. phagocytophilum infection, A. phagocytophilum-containing inclusions enveloped with punctate GFP-LC3 did not colocalize with a lysosomal marker. Stimulation of autophagy by rapamycin favoured A. phagocytophilum infection. Inhibition of the autophagosomal pathway by 3-methyladenine did not inhibit A. phagocytophilum internalization, but reversibly arrested its growth. Although autophagy is considered part of the innate immune system that clears a variety of intracellular pathogens, our study implies that A. phagocytophilum subverts this system to establish itself in an early autophagosome-like compartment segregated from lysosomes to facilitate its proliferation.
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Niu
authors.forename: Mamoru
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Rikihisa
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000378:metabolism; D041081:Anaplasma phagocytophilum / Q000276:immunology* / Q000502:physiology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000032:analysis; D001343:Autophagy / Q000276:immunology*; D000071186:Beclin-1; D002460:Cell Line; D000882:Haplorhini; D006801:Humans; D002479:Inclusion Bodies / Q000737:chemistry / Q000382:microbiology*; D007425:Intracellular Membranes / Q000737:chemistry / Q000648:ultrastructure; D008051:Lipid Bilayers; D008565:Membrane Proteins / Q000032:analysis; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000032:analysis; D020123:Sirolimus / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008051:Lipid Bilayers; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C025946:3-methyladenine; D000225:Adenine; D020123:Sirolimus