A Cation-Binding Surface Protein as a Vaccine Antigen To Prevent Moraxella catarrhalis Otitis Media and Infections in Chronic Obstructive Pulmonary Disease

Abstract

is an exclusively human respiratory tract pathogen that is a common cause of otitis media in children and respiratory tract infections in adults with chronic obstructive pulmonary disease. A vaccine to prevent these infections would have a major impact in reducing the substantial global morbidity and mortality in these populations. Through a genome mining approach, we identified AfeA, an ∼32 kDa substrate binding protein of an ABC transport system as an excellent candidate vaccine antigen. Recombinant AfeA was expressed and purified and binds ferric, ferrous, manganese and zinc ions as demonstrated by thermal shift assays. It is a highly conserved protein that is present in all strains of Immunization with recombinant, purified AfeA induces high titer antibodies that recognize the native protein. AfeA expresses abundant epitopes on the bacterial surface and induces protective responses in the mouse pulmonary clearance model following aerosol challenge with Finally, AfeA is expressed during human respiratory tract infection of adults with COPD. Based on these observations, AfeA is an excellent vaccine antigen to be included in a vaccine to prevent infections caused by.

Panel 8: Vaccines and immunology

“…catarrhalis vaccines.-Several surface proteins of M. catarrhalis are in various stages of preclinical development as vaccine antigens, reviewed recently by several groups [9,63,64] and summarized in the 2015 ISOM report [29]. Since the 2015 ISOM report, three new potential antigens have been identified, including two substrate binding proteins of ABC transporters (CysP, AfeA) and a peptide of lactoferrin binding protein A [65][66][67]. Each antigen expresses epitopes on the bacterial surface, is conserved among strains, and induces enhanced clearance in the mouse pulmonary clearance model following immunization.…”

Structural and functional insights into iron acquisition from lactoferrin and transferrin in Gram-negative bacterial pathogens

“…6 c), which suggests that AfeA is similar to YfeA in its ability to bind metal cations, like iron. AfeA was shown to bind ferric, ferrous, manganese, and zinc ions with a thermal shift assay in a previous study (Murphy et al 2017 ) thus it might play a role in transporting any or all of these metal cations.…”

“…6 c) are in identical positions in the binding cleft as the residues in the holo YfeA structure. Thermal shift assays (Murphy et al 2017 ) demonstrate that the M. catarrhalis AfeA is polyspecific, able to bind ferric, ferrous, manganese, and zinc ions. This is analogous to what has been demonstrated for YfeA (Radka et al 2017 ), indicating that AfeA and YfeA likely share the same mode of binding.…”

“…The structure of ModA is more similar to FbpA and both are known to bind to only one substrate. MolA, on the other hand, is a C-clamp protein like AfeA and both of these proteins are known to be polyspecific, binding more than one substrate (Murphy et al 2017 ; Tirado-Lee et al 2011 ). ModA has a significantly higher affinity to molybdate in the nM to low μM scale while MolA has a lower affinity in the 100 μM scale (Tirado-Lee et al 2011 ).…”

“…Based on the protein sequence, AfeA was previously predicted to be a lipoprotein and evidence for surface exposure was provided by whole-cell ELISA and flow cytometry (Murphy et al 2017 ). This raises questions regarding the role of AfeA in mediating metal ion transport.…”