Epithelial Haven and Autophagy Breakout in Gonococci Infection

Abstract

The World Health Organization (WHO) has estimated that in 2016, there were 87 million new cases of gonorrhea. Gonorrhea is caused by the sexually transmitted human-exclusive agent Neisseria gonorrhoeae, a Gram-negative diplococcus that causes cervicitis in females and urethritis in males and may lead to more severe complications. Currently, there is no vaccine against N. gonorrhoeae. Its resistance to antibiotics has been increasing in the past few years, reducing the range of treatment options. N. gonorrhoeae requires a surface protein/receptor (Opa proteins, porin, Type IV pili, LOS) to adhere to and invade epithelial cells. During invasion and transcytosis, N. gonorrhoeae is targeted by the autophagy pathway, a cellular maintenance process which balances sources of energy at critical times by degrading damaged organelles and macromolecules in the lysosome. Autophagy is an important host defense mechanism which targets invading pathogens. Based on transmission electron microscopy (TEM) analysis, the intracellular bacteria occupy the autophagosome, a double-membraned vesicle that is formed around molecules or microorganisms during macroautophagy and fuses with lysosomes for degradation. Most of the gonococci end up in autolysosomes for degradation, but a subpopulation of the intracellular bacteria inhibits the maturation of the autophagosome and its fusion with lysosomes by activating mTORC1 (a known suppressor of the autophagy signaling), thus escaping autophagic elimination. This mini review focuses on the cellular features of N. gonorrhoeae during epithelial cell invasion, with a particular focus on how N. gonorrhoeae evades the autophagy pathway.

Keywords: N. gonorrhoeae; autophagy; epithelial cell; epithelial cell invasion; intracellular pathogen.

FIGURE 1

(A) Gonococci (in red) adhere to the cellular membrane and form a microcolony, triggering the autophagy pathway through CD46-cyt1/GOPC, which recruits the Beclin-1/Vps34 complex. (B) Bacteria become enveloped in the autophagosome (blue arrow). (C) The autophagosome fuses with the lysosome in order to kill the bacteria. (D) Gonococci evade the autophagy pathway by inducing the cleavage of the CD46-cyt ectodomain via metalloproteinases and by inducing the cleavage and release of the cytoplasmic tail via presenilin/y-secretase, decreasing intracellular CD46-cyt1 and the cell’s ability to initiate autophagy (pink arrow). (E) Bacteria secrete IgAP, (orange arrow) which cleaves LAMP1, resulting in remodeling of the lysosomal membranes and prevention of autophagosome/lysosome fusion, therefore increasing the survival of the gonococci. (F) Gonococci activate mTORC1 (green arrow), therefore suppressing autophagy signaling (purple arrow).