The Nontypeable Haemophilus influenzae Major Adhesin Hia Is a Dual-Function Lectin That Binds to Human-Specific Respiratory Tract Sialic Acid Glycan Receptors

Abstract

NTHi is a human-adapted pathogen that colonizes the human respiratory tract. Strains of NTHi express multiple adhesins; however, there is a unique, mutually exclusive relationship between the major adhesins Hia and HMW1 and HMW2 (HMW1/2). Approximately 25% of NTHi strains express Hia, a phase-variable autotransporter protein that has a critical role in colonization of the host nasopharynx. The remaining 75% of strains express HMW1/2. Previous work has shown that the HMW1 and HMW2 proteins mediate binding to 2-3- and 2-6-linked sialic acid glycans found in the human respiratory tract. Here, we show that the high-affinity binding domain of Hia, binding domain 1 (BD1), is responsible for binding to α2-6-sialyllactosamine (2-6 SLN) glycans. BD1 is highly specific for glycans that incorporate the form of sialic acid expressed by humans, N-acetylneuraminic acid (Neu5Ac). We further show that Hia has lower-affinity binding activity for 2-3-linked sialic acid and that this binding activity is mediated via a distinct domain. Thus, Hia with its dual binding activities functionally mimics the combined activities of the HMW1 and HMW2 adhesins. In addition, we show that Hia has a role in biofilm formation by strains of NTHi that express the adhesin. Knowledge of the binding affinity of this major NTHi adhesin and putative vaccine candidate will direct and inform development of future vaccines and therapeutic strategies for this important pathogen. IMPORTANCE Host-adapted bacterial pathogens like NTHi have evolved specific mechanisms to colonize their restricted host niche. Relatively few of the adhesins expressed by NTHi have been characterized as regards their binding affinity at the molecular level. In this work, we show that the major NTHi adhesin Hia preferentially binds to Neu5Ac-α2-6-sialyllactosamine, the form of sialic acid expressed in humans. The receptors targeted by Hia in the human airway mirror those targeted by influenza A virus and indicates the broad importance of sialic acid glycans as receptors for microbes that colonize the human airway.

Phase Variation in HMW1A Controls a Phenotypic Switch in Haemophilus influenzae Associated with Pathoadaptation during Persistent Infection

“…The fact that high antibody titers are present even at the time of initial lower airway infection makes it unclear what advantage high levels of HMW may confer at early stages of infection. One possibility could relate to (at least for some alleles) HMW1 showing preferential binding to 2-3-linked sialic acid glycans that are predominant in the lower respiratory tract (57). Here, we show a phase-variable decrease of HMW levels over time in independent sets of serial COPD isolates, supporting this as being common during NTHi persistence within the COPD lung environment.…”

Epidemiology, Treatments, and Vaccine Development for Antimicrobial-Resistant Neisseria gonorrhoeae: Current Strategies and Future Directions

“…Another example is with carbamazepine and methyldopa, an anti-epileptic and anti-hypertensive drug. When used for cervical cell infection by MDR N. gonorrhoeae , prevention and cure was found via blocking of the I-domain of the gonococcal complement receptor 3 domain [ 85 ].…”

CEACAM1 Activation by CbpF-Expressing E. coli

“…Our results demonstrate the production of the first functional full length CbpF-expressing recombinant E. coli , and one of the few full-length recombinant TAAs studied ( Grosskinsky et al., 2007 ; Atack et al., 2020 ). To the best of our knowledge, it is the only full-length recombinant TAA CEACAM-activating ligand produced ( Nordstrom et al., 2004 ; Tan et al., 2005 ; Hallstrom et al., 2011 ; Brewer et al., 2019 ; Mikula et al., 2019 ).…”