Abstract
Dynamic reorganization of the actin cytoskeleton dictates plasma membrane morphogenesis and is frequently subverted by bacterial pathogens for entry and colonization of host cells. The human-adapted bacterial pathogen Neisseria gonorrhoeae can colonize and replicate when cultured with human macrophages, however the basic understanding of how this process occurs is incomplete. N. gonorrhoeae is the etiological agent of the sexually transmitted disease gonorrhea and tissue resident macrophages are present in the urogenital mucosa, which is colonized by the bacteria. We uncovered that when gonococci colonize macrophages, they can establish an intracellular or a cell surface-associated niche that support bacterial replication independently. Unlike other intracellular bacterial pathogens, which enter host cells as single bacterium, establish an intracellular niche and then replicate, gonococci invade human macrophages as a colony. Individual diplococci are rapidly phagocytosed by macrophages and transported to lysosomes for degradation. However, we found that surface-associated gonococcal colonies of various sizes can invade macrophages by triggering actin skeleton rearrangement resulting in plasma membrane invaginations that slowly engulf the colony. The resulting intracellular membrane-bound organelle supports robust bacterial replication. The gonococci-occupied vacuoles evaded fusion with the endosomal compartment and were enveloped by a network of actin filaments. We demonstrate that gonococcal colonies invade macrophages via a process mechanistically distinct from phagocytosis that is regulated by the actin nucleating factor FMNL3 and is independent of the Arp2/3 complex. Our work provides insights into the gonococci life-cycle in association with human macrophages and defines key host determinants for macrophage colonization.
Highlights
The betaproteobacteria Neisseria gonorrhoeae (N.g) is a highly adapted human colonizer and the etiological agent of the sexually transmitted disease gonorrhea
The human-adapted bacterial pathogen Neisseria gonorrhoeae and causative agent of gonorrhea can invade the submucosa of the urogenital tract where it encounters tissue-resident innate immune sentinels, such as macrophages and neutrophils
We uncovered that N. gonorrhoeae establishes two distinct subcellular niches that support bacterial replication autonomously–one niche was on the macrophage surface and another one was intracellular
Summary
The betaproteobacteria Neisseria gonorrhoeae (N.g) is a highly adapted human colonizer and the etiological agent of the sexually transmitted disease gonorrhea. Gonococci colonization of the urogenital tract often trigger a localized inflammatory response, which in acute symptomatic infections can progress to the production of purulent exudate that contains gonococci, innate immune cells (macrophages and polymorphonuclear leukocytes- PMNs) and exfoliated epithelial cells [4,5]. Neutrophils recruitment is a central event in gonorrhea progression; the role of tissue resident macrophages, comprising ~10% of total leukocytes isolated from the genitourinary mucosa [4], as well as macrophages recruited to sites of acute gonococcal infections [5] remain underexplored. Important work using human cervical tissue explants demonstrated that N.g colonizes and invades the ectocervical, transformation zone and endocervical region of the female cervix [22], which contain high concentrations of macrophages [23]. The mechanism of macrophage colonization by gonococci as well as the identity and subcellular localization of the gonococci-occupied niche remain important open questions
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