Kevin Mason, PhD

Studies in my laboratory focus on understanding the complex molecular mechanisms that underlie bacterial pathogenesis and the host response. Nontypeable Haemophilus influenzae (NTHi) is a common member of the host normal flora (a commensal) and yet predominates in both chronic otitis media with effusion, acute otitis media and in other localized respiratory diseases such as acute sinusitis, community-acquired pneumonia and has important consequences in patients with chronic obstructive pulmonary disease and cystic fibrosis (opportunistic pathogen). We hypothesized that NTHi differentially expresses a number of genes as the microbe transitions to an opportunistic disease state. Our investigations provided one of the earliest description and understanding of Haemophilus pathogenesis in vivo. Importantly, NTHI adaptation to the diverse host environment resulted in the up-regulation of sap (sensitivity to antimicrobial peptides) operon gene expression, previously shown in other microorganisms to mediate resistance to killing by antimicrobial peptides (APs), key components of the host innate immune response. These genes encode the Sap transporter, a member of an ABC transporter family that mediates recognition of small peptides, cations, or iron-containing proteins, which are then targeted for transport across the inner membrane into the bacterial cytoplasm. We hypothesized that the pathogenic potential of NTHI is dictated by its ability to resist immune-mediated clearance mechanisms and specifically, killing by host APs. Using genetic tools and biophotonic imaging of NTHi-infected chinchillas, we demonstrated that the sap genes are expressed in vivo early in infection and mutants defective in sap gene expression are sensitive to killing by host APs, and thus, are rapidly cleared in vivo. Our work showed that APs directly bind the Sap transporter binding protein, supporting a model of AP transport to the bacterial cytoplasm and subsequent proteolysis or destruction, and initiation of a regulatory cascade that activates other resistance determinants. We further demonstrated that components of the Sap transporter are also required for potassium uptake in NTHi, a function which counters rapid potassium efflux from the bacterium, a hallmark of AP lethality. Current work in my laboratory continues to define how NTHI senses and transports APs, and define a role for Sap proteins in ATP-dependence on potassium transport, thus supporting a dual molecular mechanism that promotes bacterial survival and establishment of disease. Further, we are interested in the role Sap gene products play in NTHi survival on epithelial cells since mutations in the Sap transporter alter NTHi biofilm formation, adherence properties and alter host cell responses. Since Sap system homologues are conserved among bacterial species, our long-range goal is to better define a global resistance mechanism which, if targeted, could have far-reaching implications and therapeutic value. 

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Kevin Mason, PhD, is an Assistant Professor of Pediatrics at The Ohio State University School of Medicine in the Center for Microbial Pathogenesis, The Research Institute at Nationwide Children’s Hospital.

The Mason laboratory studies pathogenic mechanisms that equip survival of nontypeable Haemophilus influenzae (NTHi) during transition from a commensal microorganism of the nasopharynx to pathogen of the upper and lower airways. Of critical importance is the ability of NTHI to adapt to host microenvironments, specifically the limitation of nutrients and host immune pressures. The lab has identified mechanisms of innate immune resistance and nutrient uptake that are essential for NTHI pathogenesis. The lab's work is focused on three main areas of investigation: 1) how host nutritional immunity influences NTHI biofilm architecture via morphological changes in bacteria, invasion of host epithelial cells and modulation of inflammatory responses that contributes to persistence and disease severity; 2) Sap-transporter mediated uptake of nutrients and host derived antimicrobial peptides as a mechanism of survival; 3) biochemical analysis of Sap ABC transporter assembly and function in response to host nutritional and innate immune pressures. Elucidation of mechanisms of pathogenesis will allow the lab to develop and apply novel strategies to target NTHI virulence mechanisms.