Subversion of cellular autophagy by Anaplasma phagocytophilum.
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.
Niu
Hua
H
Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA.
Yamaguchi
Mamoru
M
Rikihisa
Yasuko
Y
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
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