Monique Bennett

Nutrient acquisition is necessary for the survival of microorganisms. Nutrient metals, including iron, play key roles in cellular metabolism, respiration, and redox catalysis. One particularly important nutrient acquisition system is the iron-regulated surface determinant (Isd) system that scavenges heme iron from the human host and enables the acquisition of iron in iron-deplete conditions. Staphylococcus aureus uses the cell surface receptors IsdB and IsdH to bind hemoproteins and transfer heme to IsdA, ultimately leading to the transfer of heme across the cell surface for use as an iron source. IsdA is the final surface protein before heme-iron is transported through the peptidoglycan, which presents a unique bottleneck for disruption of heme uptake and establishes IsdA as a promising and unexplored therapeutic target. To define the human B cell response to IsdA, panels of cross-reactive human monoclonal antibodies (mAbs) specific to the surface proteins of the staphylococcal Isd system were isolated and investigated to determine if their function was solely the blocking of heme iron uptake. Two of the identified IsdA-specific mAbs worked cooperatively in a murine septic model of infection to reduce bacterial burden during staphylococcal infection. The protection depended largely on Fc-mediated antibody effector functions, with additional protection imparted from partial heme blocking. This study suggests that IsdA is a potential target for therapeutic human monoclonal antibodies that mediate anti-staphylococcal effects using diverse functions. 

Cohort: 2014
Principal Investigator: James E. Crowe, Jr., M.D.
Internship Company: Merck
Internship Year: 2017
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