Anaplasmataceae: Dichotomous Autophagic Interplay for Infection

Abstract

Autophagy is a vital conserved degradative process that maintains cellular homeostasis by recycling or eliminating dysfunctional cellular organelles and proteins. More recently, autophagy has become a well-recognized host defense mechanism against intracellular pathogens through a process known as xenophagy. On the host-microbe battlefield many intracellular bacterial pathogens have developed the ability to subvert xenophagy to establish infection. Obligately intracellular bacterial pathogens of the Anaplasmataceae family, including Ehrlichia chaffeensis, Anaplasma phaogocytophilium and Orientia tsutsugamushi have developed a dichotomous strategy to exploit the host autophagic pathway to obtain nutrients while escaping lysosomal destruction for intracellular survival within the host cell. In this review, the recent findings regarding how these master manipulators engage and inhibit autophagy for infection are explored. Future investigation to understand mechanisms used by Anaplasmataceae to exploit autophagy may advance novel antimicrobial therapies and provide new insights into how intracellular microbes exploit autophagy to survive.

Keywords: Anaplasma; Anaplasmataceae; Ehrlichia; autolysosome; autophagy; effector; phagolysosome; xenophagy.

Figure 1

A. phagocytophilum interplay with the autophagic pathway. (1) A. phagocytophilum selectively recruits Rab GTPases Rab4A, Rab10, Rab11A, Rab14, Rab22A, Rab35 which regulate endocytic recycling and Rab1 which regulates vesicular protein transport from the endoplasmic reticulum (ER) to the Golgi compartment. (2) T4SS effector Ats-1 is translocated from the ApV into the host cell cytoplasm and (3) directly interacts with autophagsome initiation complex (Atg14-Beclin 1-Vps34) to initiate omegasome formation in the ER. (4) Isolation membrane elongates and (5) double-membrane autophagosome decorated with LC3 form. (6) Autophagosomes are recruited to the ApV that fuse to release autophagic body content. (7) A. phagocytopilum blocks lysosomal fusion potentially by preventing endosomal maturation and/or through other unknown mechanisms.

Figure 2

E. chaffeensis interplay with the autophagic pathway. (1) E. chaffeensis dense-cored cells express effectors important for Wnt signaling including T1SS effectors TRP120 and TRP32. E. chaffeensis stimulates phagocytosis for entry through interaction between TRP120 and the Fzd receptor/co-receptor complex. (2) E. chaffeensis-mediated Wnt-PI3K/Akt signaling stimulates increased levels of phospho-GSK3-β reducing TSC2 and increasing Rheb activity leading to mTOR activation. (3) E. chaffeensis T4SS effector Etf-1 is secreted into the host cell cytoplasm and interacts with Beclin1, PI3CK complex and Rab5-GTP to stimulate phagophore formation. (4) ATG5 and LC3 engage to induce autophagosome formation in a class III PtdIns3K-dependent manner. (5) E. chaffeensis T4SS effector Etf-2 localizes to E. chaffeensis vacuole membrane and binds to RAB5-GTP to delay endosome maturation. (6) Autophagosomes displaying Beclin1, LC3II and p62/SQSTM1 fuse with E. chaffeensis inclusions to form amphisomes. (7) mTOR activation leads to TFEB phosphorylation and inhibition of TFEB nuclear translocation. Inhibition of TFEB nuclear translocation prevents transcription of genes involved in lysosomal biogenesis and (8) increased phospho-p70 S6 kinase activity inhibits autolysosome formation.

Figure 3

Degradation of E. chaffeensis by antibody-TRIM21-mediated selective autophagy. Ehrlichiae opsonized with E. chaffeensis-OMP-1 specific antibody are internalized by unknown uptake mechanism. Intracellular antibody-opsonized ehrlichiae are recognized by cytosolic Fc receptor TRIM21. (1) Induction of TRIMosome formation and selective autophagy occurs through recruitment of autophagy regulators, ULK1, Beclin 1, ATG16L and autophagy effectors LC3/GABARAP and p62/SQSTM1. (2) E. chaffeensis-Ab/TRIM21 complex stimulates rapid immune signaling and a proinflammatory response through accumulation of K48 and K63 polyUb chains and activation and nuclear translocation of NF-κB and IRF.