Infection and Immunity
Infection and Immunity
3 years ago

Ehrlichia activation of Wnt-PI3K-mTOR signaling inhibits autolysosome generation and autophagic destruction by the mononuclear phagocyte.

Das, McBride, Velayutham, Lina, Luo
In multicellular organisms, autophagy is induced as an innate defense mechanism. Notably, the obligate intracellular bacterium, Ehrlichia chaffeensis, resides in early endosome-like vacuoles and circumvents lysosomal fusion through an unknown mechanism, thereby avoiding destruction in the autophagolysosome. In this study, we reveal that Wnt signaling plays a crucial role in inhibition of lysosomal fusion and autolysosomal destruction of ehrlichiae. During early infection, autophagosomes fuse with ehrlichial vacuoles to form an amphisome indicated by presence of autophagy markers such as LC3, Beclin-1 and p62. LC3 colocalized with ehrlichial morulae on days 1, 2 and 3 post infection, and increased LC3II levels were detected during infection, reaching a maximal level on day 3. Ehrlichial vacuoles did not colocalize with the lysosomal marker LAMP2, and lysosomes were redistributed and dramatically reduced in the infected cells. An inhibitor specific for the Wnt receptor signaling component, Dishevelled, induced lysosomal fusion with ehrlichial inclusions, corresponding with p62 degradation, and promoted transcription factor EB (TFEB) nuclear localization. E. chaffeensis infection activated the PI3K-Akt-mTOR pathway, and activation was induced by three ehrlichial TRP effectors, with TRP120 inducing the strongest activation. Moreover, induction of GSK3 using a Wnt inhibitor and siRNA knockdown of critical components of PI3K-GSK3-mTOR signaling decreased ehrlichial survival. This study reveals Ehrlichia exploitation of the evolutionarily conserved Wnt pathway to inhibit autolysosome generation, thereby evading this important innate immune defense mechanism.

Publisher URL: http://doi.org/10.1128/IAI.00690-17

DOI: 10.1128/IAI.00690-17

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