Intercellular adhesion molecule 1 serves as a primary cognate receptor for the Type IV pilus of nontypeableHaemophilus influenzae

Abstract

Nontypeable Haemophilus influenzae (NTHI) utilizes the Type IV pilus (Tfp) to adhere to respiratory tract epithelial cells thus colonizing its human host; however the host cell receptor to which this adhesive protein binds is unknown. From a panel of receptors engaged by Tfp expressed by other bacterial species, we showed that the majority subunit of NTHI Tfp, PilA, bound to intercellular adhesion molecule 1 (ICAM1) and that this interaction was both specific and of high affinity. Further, Tfp-expressing NTHI inoculated on to polarized respiratory tract epithelial cells that expressed ICAM1 were significantly more adherent compared to Tfp-deficient NTHI or NTHI inoculated on to epithelial cells to which ICAM1 gene expression was silenced. Moreover, pre-incubation of epithelial cells with recombinant soluble PilA (rsPilA) blocked adherence of NTHI, an outcome that was abrogated by admixing rsPilA with ICAM1 prior to application on to the target cells. Epithelial cells infected with adenovirus or respiratory syncytial virus showed increased expression of ICAM1, this outcome supported augmented adherence of Tfp-expressing NTHI. Collectively, these data revealed the cognate receptor for NTHI Tfp as ICAM1 and promote continued development of a Tfp-targeted vaccine for NTHI-induced diseases of the airway wherein upper respiratory tract viruses play a key predisposing role.

Host–pathogen interactions of nontypeable Haemophilus influenzae: from commensal to pathogen

“…Potentially it is a way of selectively coping with the conditions faced during different stages of infection when the positioning and composition of the respiratory mucosal surface and epithelial cell changes, such as sloughing or other effects arising from virulence factors damaging host cells. Coincidentally, the upregulation of ICAM1 occurs during viral infection , which further supports the idea that NTHi may adaptively change its own membrane protein expression. This may match the conditions that arise from prior infections or invasions of the epithelial cell layer by different microbial agents.…”

“…The pilus of NTHi, specifically the pilus tip, PilA, was recently shown to bind intercellular adhesion molecule 1 (ICAM1) on the surface of epithelial cells . Pili occur on NTHi as well as on the typeable strains, where the pili are able to bind mucin .…”

Transcutaneous Immunization with a Band-Aid Prevents Experimental Otitis Media in a Polymicrobial Model

“…Moreover, protection against experimental OM afforded by immunization with rsPilA, chimV4, and IHF was consistent with our understanding of the functions of NTHI OMP P5, Tfp, and IHF in bacterial adherence, pathobiology, and biofilm formation. For example, NTHI Tfp engages ICAM-1, and OMP P5 engages both ICAM-1 and CEACAM-1, molecules whose expression levels on respiratory tract epithelial cells are increased in response to respiratory tract viral infection, including adenovirus (33)(34)(35). Moreover, Tfp and OMP P5 are essential for NTHI to adhere to the mucosal surface.…”

“…Moreover, Tfp and OMP P5 are essential for NTHI to adhere to the mucosal surface. Additionally, Tfp is required for NTHI to exhibit twitching motility, form biofilms, and persist within the chinchilla nasopharynx (34,36,37). Antibodies directed against an OMP P5-directed immunogen, called LB1, in addition to antibodies against PilA prevent adherence of NTHI to respiratory epithelial cells (37,38).…”

Viral–bacterial co-infections in the respiratory tract

“…Other URT viruses also enhance bacterial adherence to both primary and immortalized epithelial cells with distinct differences noted amongst epithelial cell types in terms of response to infection with RSV, parainfluenza virus-3 or influenza virus [29]. Novotny and Bakaletz [30] recently showed that both RSV and AV induced upregulated expression of the cell surface glycoprotein intercellular adhesion molecule 1 (ICAM-1) by primary respiratory tract epithelial cells and that ICAM1 served as a cognate ligand for the Type IV pilus of nontypeable H. influenzae, thus promoting adherence of this Gram negative pathogen. RSV infection also enhances adherence of P. aeruginosa to both normal and CF epithelial cells [31] and this effect can be extended to Gram positive Viral-bacterial superinfections of the airway Bakaletz 31 Table 1 Mechanisms by which viruses predispose to secondary bacterial infection Damage to airway epithelium/induction of hyperplasia/cell loss/exposure of basement membrane Diminished ciliary beat frequency/disruption of mucociliary clearance/altered mucus rheology Increased receptor availability on epithelial cells promotes augmented bacterial adherence Dysregulated activation, migration and function of antigen presenting cells (alveolar macrophages, dendritic cells, tissue resident macrophages and T-cells) Disruption of phagocyte function Abnormal expression of antimicrobial/host defense peptides Virus-induced type I interferons alter the phenotype of the immune response Enhanced production of inflammatory mediators (cytokines, chemokines, acute phase reactants) Generalized immunosuppression that leads to immune paralysis Virus-mediated release of bacteria from biofilms Viral dysregulation of nutritional immunity Virus induced alteration of the microbiome with increase in pathogens associated with secondary infections bacteria.…”