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Dr. Heinzen’s research program addresses the wide gaps in knowledge of Coxiella burnetti genetics, pathogenesis and cellular microbiology. This intracellular bacterium is a recognized category B biothreat that causes a disabling flu-like illness called Q fever. The organism invades mononuclear phagocytes where it directs biogenesis of a lysosome-like parasitophorous vacuole (PV) in which to replicate. Our overarching goals are to understand PV biogenesis, elucidate the pathogenic relevance of Coxiella morphological differentiation, define protective immune mechanisms, and identify protective and diagnostic antigens. Moreover, he and his laboratory aim to develop robust genetic methods to dissect the virulence of this refractory pathogen and to understand the extent and pathogenic relevance of Coxiella genetic diversity. These aims are in keeping with programmatic objectives of NIAID’s biodefense initiative in enabling development of new countermeasures against Q fever, such as rationally designed subunit vaccines and diagnostic reagents.
Dr. Heinzen’s efforts have defined novel aspects of Coxiella PV formation and biochemistry, revealed pathogen directed host cell survival responses, and identified a battery of type IV secreted Coxiella proteins that are presumably critical for successful parasitism and virulence. Moreover, he has revealed replicative and antigenic properties of Coxiella developmental forms and discovered a unique function of Coxiella lipopolysaccharide in shielding the organism from innate immune recognition. Through genome sequencing, we have provided insight into Coxiella genetic diversity and accompanying pathogenic potential, defined genetic lesions associated with Coxiella phase II lipopolysaccharide production and avirulence, and used whole proteome microarrays to reveal candidate diagnostic and vaccine antigens. We are the first research group to transposon mutagenize Coxiella and to grow the organism in cell-free media, which are major breakthroughs in the study of this refractory organism. We believe the final two achievements will result in a paradigm shift in how Coxiella is viewed and studied, i.e., a tractable facultative intracellular parasite amenable to genetic manipulation.