P. Scott Hefty

Chlamydia (klah-MID-e-a) are obligate intracellular bacteria that comprise a unique phylum that is distantly related from many other model bacterial systems. Included in this phylum are species associated with human diseases, including Chlamydia trachomatis and Chlamydia pneumoniae. These species have an immense impact on public health in the US and globally. Chlamydia trachomatis causes both genital tract and ocular diseases. According to the CDC, C. trachomatis has the highest incidence of infection among all reportable infectious diseases in the US.C. trachomatis also is the leading cause of preventable blindness (trachoma) worldwide. C. pneumoniae infections are a common cause of community acquired pneumonia and is also associated with atherosclerosis and Alzheimer’s disease. There are no vaccines available for these infections and the limited antibiotics treatments have negative effects on human microbiomes. Moreover, we still have a poor appreciation for how these bacteria cause disease.

Functional Genomics to Discover and Characterize Virulence Factors

Our laboratory developed a suite of genetic tools for Chlamydia, including transposon mutagenesis and inter-species lateral gene transfer. These genomic manipulation systems have enabled the unbiased discovery of genes and complex trait loci that encode factors that critical for mammalian infection and disease (i.e., virulence factor). A mouse model of Chlamydia infection is utilized to discover gene products that are critical to establishing infection in the lower genital tract, ascension to the upper genital tract, and development of chronic inflammatory disease. As these virulence factors are discovered, we characterize the molecular function and specific role of gene products in Chlamydia-host interactions.

Developmental Cycle Regulatory Mechanism

Chlamydia is propagated and maintained through a phylum defining bi-phasic developmental cycle. Our laboratory focuses on the molecular mechanisms that regulate this developmental cycle. We are attempting to understand what chemical signals and molecular mechanisms that trigger conversion between the infectious and replicative forms of Chlamydia as well as the processes that are key to the conversion process. We also focus on the components that are essential for maintaining the intracellular environment and countering the many intrinsic cellular responses. We apply a variety of genetic, biochemical, and cell biologic approaches to address these fundamental questions.

Structural Proteomics for Functional Insights

Approximately 35% of the Chlamydia genome encodes proteins that lack sufficient sequence similarity to enable functional annotation. To provide a better understanding of these gene products, we have applied the paradigm that two proteins that share limited sequence similarity can adopt very similar three-dimensional structure. As the three-dimensional structure of a protein can define the function, this can be leveraged to overcome sequence limited functional assignments. Through experimental and computational tools (e.g., AlphaFold), we have determined the structure of Chlamydia proteins and used this to predict biologic or molecular function. These predictions have been used as the basis for hypotheses to experimentally validate within the context of Chlamydia.

Chemical Biology and Vaccine Development

Small compounds that specifically inhibit a given protein can be used to analyze the function and biological role. These compounds can potentially be developed into effective pathogen specific antibiotics and used for therapeutic purposes. Our structural proteomics and virulence determinant analyses provide key information for rational design of small molecule inhibitors. To complement this approach, we also perform random screens for small molecules that inhibit growth of Chlamydia. Our screens have consisted of natural products and unique chemically diverse libraries. Moreover, we have use structure-guided approaches to discover small molecules that bind to various protein targets. Moreover, our efforts in discovering virulence determinants have also enabled novel vaccine development and challenge studies using a mouse model.

Center for Chemical Biology of Infectious Disease (CoBRE)

I serve as PI and Director of this NIH funded research center which supports and enables a diverse scientific community that applies chemical biology for a better understanding and possible treatments of infectious diseases. This center focuses on building and supporting scientific community through programmatic aspects such as symposium, workshops, and seminar series. The center provides resources for recruiting new faculty as well as research project funding and mentoring for junior investigators. The center also supports four research core facilities that includes infectious disease assay development, synthetic chemical biology, computational chemical biology, and flow cytometry.