Carcinoembryonic antigens are targeted by diverse strains of typable and non‐typable Haemophilus influenzae

Abstract

SummaryHaemophilus influenzae (Hi), a commensal of the human respiratory mucosa, is an important cause of localized and systemic infections. We show that distinct strains belonging to typable (THi) and nontypable (NTHi) H. influenzae target human carcinoembryonic antigens (the membrane associated CEA family of cell adhesion molecules, are now termed CEACAMs). All strains of H. influenzae biogroup aegyptius (Hi-aeg) and more than 70% of THi and NTHi strains tested specifically recognize CEACAMIFc soluble constructs. Furthermore, transfection of Chinese hamster ovary cells with human CEACAM1 cDNA alone was sufficient for promoting Hi interactions with the transfected cells. The majority of the Hi-aeg strains tested interacted with soluble constructs containing only the N-terminal domain. In contrast, several THi and NTHi strains reacted with soluble constructs only when additional extracellular A and B domains of the receptor were present. The use of monoclonal antibodies confirmed that THi and NTHi strains also interact primarily at the N-domain. We used site-directed mutants of CEACAM1 that contained substitutions at surface exposed amino acids and a molecular model of the N-domain to identify the residues involved in interactions with Hi ligands. The studies show that a common region exposed at the CFG face of the molecule is targeted by diverse Hi strains. However, mutation at distinct sites within this area affected the interactions of distinct strains signifying the potential for tissue tropism via this receptor. Analyses of the molecular basis of interaction with human cell lines and purified CEA show that Hi strains, especially those belonging to Hi-aeg, interact with multiple CEACAMs. Because Neisseria meningitidis (Nm) strains are also known to bind at the CFG face of the receptor, we used Nm and Hi strains in co-infection experiments and demonstrate competition between these mucosal pathogens in colonization of target cells via CEACAMs.

Glycosylation Alters Dimerization Properties of a Cell-surface Signaling Protein, Carcinoembryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1)

“…It is likely that this complex set of effects arises as a result of the numerous homophilic and heterophilic interactions that CEACAM1 can have with itself and other members of the CEACAM superfamily. The N-terminal Ig variable (Ig V ) domain of CEACAM1 has been suggested to be the basis of cis and trans homo-dimer formation (20), as well as interactions with other molecules (21)(22)(23)(24). There are crystal structures of the Ig V domain expressed in Escherichia coli, which have led to the suggestion of two distinct dimerization interfaces (24,25).…”

CEACAM1 Dynamics during Neisseria gonorrhoeae Suppression of CD4+ T Lymphocyte Activation

“…Moreover, when combined with their phenomenal ability to alter its surface structures (41), their subversion of CEACAM1 coinhibitory function suggests that the bacteria persist by stealth, both escaping and actively suppressing the adaptive immune response. Considering that other human restricted-pathogens including Neisseria meningitidis (16), Haemophilus influenzae (57), and Moraxella catarrhalis (58), each bind CEACAM1, it is enticing to speculate that these pathogens also share this effective evolutionary strategy.…”

Temporal upregulation of host surface receptors provides a window of opportunity for bacterial adhesion and disease

“…Also, selective FimH-binding mannosides have been indicated in preventing UTIs in a preclinical murine model [106]. In vitro studies have found that anti-CEACAM antibodies block the adhesion of M. catarrhalis, N. meningitidis and NTHi to airway epithelial cells [39,71,107]. Also, NTHi adherence to A549 alveolar epithelial cells in vitro was shown to be inhibited in a dose-dependent manner with increasing concentrations of anti-ICAM-1 monoclonal antibodies [52].…”