Research

     One major focus of our lab is the Gram-positive pathogen Streptococcus pneumoniae, responsible for 25% of all preventable deaths in children under the age of 5, and the leading cause in the US of community acquired pneumonia-related deaths. Although S. pneumoniae is responsible for a considerable disease burden on society, it first resides as a commensal in the nasopharynx, before disseminating into the host to cause a variety of infections usually under situations where one’s immune system is compromised. A key component of the success of the pneumococcus is its ability to avoid innate immunity via its polysaccharide capsule, which is its major virulence factor and defines the > 90 capsule-specific serotypes. As the current vaccine is composed only of a subset of these serotypes, it would be beneficial to identify new therapeutics for targeting all pneumococcal serotypes rather than a few. One of our research goals is to understand conserved molecular events that trigger the pneumococcal deadly switch from commensalism to pathogenesis.

 

     Through this research we have discovered a novel pathway responsible for controlling capsule activation during lung infection, and importantly lung to blood transition through the multidomain transcription factor SpxR. The Ulijasz lab is currently exploring how SpxR regulates these pneumococcal transitions thought SpxR regulation which are critical to its success as a pathogen. This project is currently funded by NIAID (NIH).

     Advanced glycan end products (AGEs) are a dark side to the seemingly benign and ancient metabolic process of glycolysis. AGEs result from biomolecules undergoing chemical reactions with Reactive Electrophilic Species (RES) such as dicarbonyls, of which glyoxal and methylglyoxal (“glyoxals”) are the major contributors. Glyoxals are produced ubiquitously in nature and stem from metabolic imbalances, predominantly from glycolysis. Recently glyoxals and their removal systems have gained increasing prominence in the literature as they are now implicated in virtually every major human disease, including: cancer, diabetes, nervous system disorders, hypertension, atherosclerosis and aging. Unfortunately, although AGEs are now deemed of equal importance to human disease as that of the more well-studied oxidative stress pathways, the signaling pathways involved in remediation of glyoxal-related stress responses are largely unmapped.

 

     Using a screening method devised in the Ulijasz lab (Met-Seq; see below) we have discovered a novel family of proteins, Bacterial ABM Dicarbonyl/Glyoxal Response proteins (BADGRs) we believe sense and respond to glyoxal. The Ulijasz lab is currently working on understanding the targets and mechanism(s) of these proteins both in bacteria and humans, focusing on one in Pseudomonas aeruginosa (BADGR1) and a family of others in humans. This project is currently funded by NIGMS (NIH).

     

 

     Phytochromes are classically unique red/far-red light receptors used by plants and bacteria to respond to light in the Near Infra-red (NIR). A number of years ago we and others created fluorescent versions of these proteins that could significantly impact the field of imaging, as Phytochrome-Based Fluorophores (PBFs) emit at NIR wavelengths that are within the ideal optical window for deep tissue imaging.

 

     As PBFs use the heme breakdown product of biliverdin (BV) to enable their unique fluorescence, we have also exploited these unique fluorescent proteins as heme biosensors in pathogenic bacteria, such as the Cystic Fibrosis pathogen Pseudomonas aeruginosa. Using PBFs in this Gram-negative pathogen as a biosensor, and coupling this technology with transposon sequencing (Tn-Seq) and Fluorescent Activated Cell Sorting (FACS) protocols, we devised the a novel method we call Metabolic-coupled Tn-sequencing (Met-Seq) to identify new heme-related proteins P. aeruginosa. These studies have paved the way for using this biosensor to identify iron/heme components in any biological system, including both prokaryotic and eukaryotic organisms. In addition, we are excited to use the Met-Seq methods with new biosensors to identify novel pathways in both Pseudomonads and other microbial pathogens.