Innate Recognition by Neutrophil Granulocytes Differs between Neisseria gonorrhoeae Strains Causing Local or Disseminating Infections

Abstract

Members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family serve as cellular receptors for Neisseria gonorrhoeae. More specifically, neisserial colony opacity (Opa CEA ) proteins bind to epithelial CEACAMs (CEACAM1, CEA, CEACAM6) to promote bacterial colonization of the mucosa. In contrast, recognition by CEACAM3, expressed by human granulocytes, results in uptake and destruction of Opa CEA -expressing bacteria. Therefore, CEACAM3-mediated uptake might limit the spread of gonococci. However, some strains can cause disseminating gonococcal infections (DGIs), and it is currently unknown how these strains escape detection by granulocyte CEACAM3. Therefore, the opa gene loci from N. gonorrhoeae strain VP1, which was derived from a patient with disseminated gonococcal disease, were cloned and constitutively expressed in Escherichia coli. Similar to Opa proteins of the nondisseminating strain MS11, the majority of Opa proteins from strain VP1 bound epithelial CEACAMs and promoted CEACAM-initiated responses by epithelial cells. In sharp contrast to the Opa proteins of strain MS11, the Opa proteins of strain VP1 failed to interact with the human granulocyte receptor CEACAM3. Accordingly, bacteria expressing VP1 Opa proteins were not taken up by primary human granulocytes and did not trigger a strong oxidative burst. Analysis of Opa variants from four additional clinical DGI isolates again demonstrated a lack of CEACAM3 binding. In summary, our results reveal that particular N. gonorrhoeae strains express an Opa protein repertoire allowing engagement of epithelial CEACAMs for successful mucosal colonization, while avoiding recognition and elimination via CEACAM3-mediated phagocytosis. A failure of CEACAM3-mediated innate immune detection might be linked to the ability of gonococci to cause disseminated infections.

Adaptation to Host-Specific Bacterial Pathogens Drives Rapid Evolution of a Human Innate Immune Receptor

“…On the other hand, avoidance of recognition by CEACAM3 allows evasion of opsonin-independent phagocytosis mediated by this granulocyte receptor. In line with this idea, our detailed analysis of numerous pathogen adhesins detects a clear bias of CEACAM1 versus CEACAM3-binding in Opa and OMP P1 adhesins and confirms earlier studies [27,58]. A strong indication that CEACAM3-based detection is to the disadvantage of the pathogen is the fact that selective CEACAM3-binding adhesins, which lack binding to the epithelial CEACAMs such as CEACAM1 or CEA, do not seem to exist.…”

“…In this species, a single strain contains up to 11 distinct gene loci encoding CEACAM-binding adhesins, the so-called colony opacity-associated (Opa) proteins [25]. For two strains, the CEACAM-binding profile of the complete Opa protein repertoire has been analyzed [26,27]. In each case, 10 out of 11 Opa proteins bound to epithelial CEACAMs, while only few adhesins (3 or 1 out of 11) were also recognized by CEACAM3 [27].…”

“…For two strains, the CEACAM-binding profile of the complete Opa protein repertoire has been analyzed [26,27]. In each case, 10 out of 11 Opa proteins bound to epithelial CEACAMs, while only few adhesins (3 or 1 out of 11) were also recognized by CEACAM3 [27]. This finding indicates that pathogens evolve adhesins with a preference for binding to epithelial CEACAMs and avoiding the granulocyte phagocytic receptor CEACAM3.…”

CEACAM3—A Prim(at)e Invention for Opsonin-Independent Phagocytosis of Bacteria

“…Selective expression of CEACAM3, but not CEACAM1 or CEACAM6, in murine promyelocytic cells can recapitulate major features of neutrophil activation in response to CEACAM-binding bacteria such as oxidative burst and degranulation (55). Furthermore, microbes expressing particular adhesins, which bind CEACAM1, but not CEACAM3, are hardly phagocytosed by primary human granulocytes in the absence of opsonins (56). Therefore, the immediate and dramatic phagocytic response of human granulocytes exposed to CEACAM-binding bacteria can be mainly attributed to CEACAM3.…”

Animal Models of Immunity to Female Genital Tract Infections and Vaccine Development

“…Several mechanisms reduce phagocytic uptake of N. gonorrhoeae. LOS sialylation significantly reduces opsonic uptake by phagocytes through the C3b receptor (Gill et al, 1996;Rest and Frangipane, 1992;Ram et al, 1998b;Kim et al, 1992), and although nonopsonic uptake occurs by the binding of Opa proteins to CEACAMs, phase variation of opa genes produces subpopulations of Opa-negative gonococci and gonococci that express Opa proteins that do not bind to neutrophil CEACAMS and are thus protected from neutrophil uptake and killing (Ball and Criss, 2013;Fischer and Rest, 1988;Roth et al, 2013a). The gonococcus also has a remarkable capacity to resist neutrophil killing.…”