The specific innate immune receptor CEACAM3 triggers neutrophil bactericidal activities via a Syk kinase-dependent pathway

Abstract

SummaryThe human-restricted pathogens Neisseria gonorrhoeae, Neisseria meningitidis, Haemophilus influenzae and Moraxella catarrhalis colonize host tissues via carcinoembryonic antigen-related cellular adhesion molecules (CEACAMs). One such receptor, CEACAM3, acts in a host-protective manner by orchestrating the capture and engulfment of invasive bacteria by human neutrophils. Herein, we show that bacterial binding to CEACAM3 causes recruitment of the cytoplasmic tyrosine kinase Syk, resulting in the phosphorylation of both CEACAM3 and Syk. This interaction is specific for the immunoreceptor tyrosine-based activation motif (ITAM) in the CEACAM3 cytoplasmic domain. While dispensable for the phagocytic uptake of single bacteria by CEACAM3, Syk is necessary for internalization when cargo size increases or when the density of CEACAMbinding ligand on the cargo surface is below a critical threshold. Moreover, Syk engagement is required for an effective bacterial killing response, including the neutrophil oxidative burst and degranulation functions in response to N. gonorrhoeae. These data reveal CEACAM3 as a specific innate immune receptor that mediates the opsonin-independent clearance of CEACAM-binding bacteria via Syk, a molecular trigger for functional immunoreceptor responses of both the adaptive (TCR, BCR, FcR) and innate (Dectin-1, CEACAM3) immune systems.

Selection for a CEACAM Receptor-Specific Binding Phenotype during Neisseria gonorrhoeae Infection of the Human Genital Tract

“…We hypothesized that the high prevalence of Opa expression in our LPCIs suggests that Opa proteins facilitate infection. However, since each Opa variant may have a different spectrum of CEACAM binding, since the spectrum of binding has the potential to drastically affect the host cellular response to infection (28,30,32,38,43,44,47), and since the pattern of CEACAM expression varies between sexes and cell types, we sought to characterize the binding specificity of each N. gonorrhoeae isolate.…”

“…However, expression of human CEACAM1 in a mouse allowed persistent colonization by N. meningitidis (37), and a mouse model expressing human CEACAM5 showed increased gonococcal recovery from the lower genital tract (38). In contrast, Opa binding to neutrophil CEACAM3 drives inflammation and gonococcal clearance (39)(40)(41)(42)(43)(44)(45)(46)(47). The specific contribution of Opa binding to individual CEACAMs for N. gonorrhoeae colonization and pathogenesis in humans and how differences in CEACAM distribution between the sexes might affect the outcome of infection have not been addressed.…”

Colonization of healthy children by Moraxella catarrhalis is characterized by genotype heterogeneity, virulence gene diversity and co-colonization with Haemophilus influenzae

“…In detail, both species can bind to carcinoembryonic antigen-related cell adhesion molecules (CEACAM)-1, which is a receptor for the OMPs UspA1 and P5 of M. catarrhalis and H. influenzae, respectively (Hill et al, 2001). CEACAM-1 is a specific innate immune receptor and although the CEACAM-binding ligands of respiratory pathogens are structurally diverse, they target a common site on the receptor (Hill et al, 2005;Sarantis & Gray-Owen, 2007). However, competition for binding sites could be outweighed by non-receptor-mediated factors associated with co-colonization events.…”

Rho GTPases as pathogen targets: Focus on curable sexually transmitted infections

“…Rac1 and Cdc42 also participate in the activation of proinflammatory cytokines via a cascade of cellular stress response kinases, leading to the activation of JNK/AP1 via p21-activated kinase1 (PAK), 69 in addition to their roles in bacteria internalization. [70][71][72][73][74] Rho GTPases in porin-mediated neisseria entry Porins are the major component of the outer membrane of pathogenic Neisseria species. In primary cervical epithelial cells, bacterial entry involves the binding of PorB, pili and lipooligosacharide to complement receptor type 3.…”