Ehrlichia secretes Etf-1 to induce autophagy and capture nutrients for its growth through RAB5 and class III phosphatidylinositol 3-kinase

Lin, Mingqun; Liu, Hongyan; Xiong, Qingming; Niu, Hua; Cheng, Zhihui; Yamamoto, Akitsugu; Rikihisa, Yasuko

Autophagy is induced in response to a variety of infections and is a critical innate immune mechanism for clearing intracellular infection. 106, 107 Thus, what is distinctive for the obligatory intracellular pathogen E. chaffeensis, compared with most other intracellular pathogens, is that infection-induced autophagy does not kill the pathogen; on the contrary, pathogen growth is autophagy dependent. Ehrlichial infection significantly increases cellular PtdIns3P levels at early stage of infection, and dramatic inhibition of ehrlichial growth results from the inhibition of autophagy induction by 3-MA or spautin-1 treatment, or knockdown of ATG5 or BECN1. The inhibition is not due to reduced viability of the host cells, or due to direct toxicity to bacteria. Conversely autophagy induction by rapamycin enhanced infection. How does host cellular autophagy facilitate ehrlichial proliferation? Gln is a primary energy and carbon source of E. chaffeensis that cannot utilize glucose. 53 The present study implies that autophagy supplies Gln for E. chaffeensis, because it acquires host preincorporated Gln in a class III PtdIns3K activity-dependent manner, and growth inhibition by autophagy inhibition was reversed by excess amino acid supplementation. Moreover, free Gln and Glu, which are the primary amino acids generated by the autophagic degradation of eukaryotic cytoplasm, 108 are also the primary amino acids that increased during exponential E. chaffeensis growth (Table 1) .