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.
Highlights
Nontypeable Haemophilus influenzae (NTHi) is a human-adapted pathogen responsible for multiple acute and chronic infections of the respiratory tract, including otitis media (OM) [1], community-acquired pneumonia [2], and chronic obstructive pulmonary disease (COPD) exacerbations [3]
We recently demonstrated that HMW2, which is ϳ65% identical to HMW1, binds the related glycan ␣2-6-sialyllactosamine (2-6 SLN), with high specificity for 2-6 SLN containing N-acetylneuraminic acid (Neu5Ac), the form of sialic acid expressed by humans [20]
In this work, we demonstrated that the NTHi adhesin Hia is a lectin, with high specificity for host-specific glycans
Summary
Nontypeable Haemophilus influenzae (NTHi) is a human-adapted pathogen responsible for multiple acute and chronic infections of the respiratory tract, including otitis media (OM) [1], community-acquired pneumonia [2], and chronic obstructive pulmonary disease (COPD) exacerbations [3]. Many bacteria express virulence factors that belong to the autotransporter protein family These proteins have a diverse array of functions, including adhesion to host surfaces [12]. The remaining ϳ75% of NTHi strains express the HMW1 and 2 (HMW1/2) proteins [17], which have previously been demonstrated to be involved in adhesion of NTHi to human cells [18]. It is unclear why strains encode genes for Hia or HMW but never both. We present an investigation to identify and characterize the Hia cellular receptor
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