Description of Research
General areas: Type I Diabetes, Probiotics, Antimicrobials, Citrus greening disease.
1.Host-microbe interactions in prevention of Diabetes type I:Commensal bacteria regulate a myriad of host processes and provide several nutrients to their host and their symbionts within the microbial community. In healthy individuals these relationships are thought to occur in equilibrium. However, disruption of this equilibrium may contribute to a variety of conditions including inflammatory bowel disease and atopy. This connection is gaining credibility as associations between gut microbiota and either the risk for or presence of a variety of specific human diseases is demonstrated. Genetics undoubtedly plays a major role in the development of Type 1 Diabetes (T1D), however numerous environmental factors have been suggested that could trigger genetic susceptibility. Interactions between the intestinal environment, barrier function, and immune system have been shown to have a major impact in the rate of T1D development. Using rodent models we performed microbiota analyses and determined that the presence of Lactobacillusand Bifidobacteriumspecies were correlated with a healthy status in diabetes prone rats (BBDP) (Roesch et al., 2009). Furthermore, we found that the administration of L. johnsoniiN6.2 to BBDP rats reduced the incidence of type 1 diabetes. The feeding of this microorganism post-weaning was followed by changes in the native microbiota, host mucosal proteins, and oxidative stress response. We hypothesized that the decrease in the pro-inflammatory cytokines IFNγ and TNFα observed was the result of a decrease in the host oxidative stress response (Valladares et al., 2010, 2013; Kingma et al., 2011). Since the food supplied to the BBDP rats has high phenolic content and L. johnsoniistrain express several esterases capable of modifying phytophenols, we hypothesized that the interplay between L. johnsoniiand dietary phytophenols resulted in the reduced inflammatory environment. Translating this work toward the prevention of T1D in humans required a pilot study in healthy individuals. We performed a human trial to evaluate the safety, tolerability, and general response to consumption of this microorganism in healthy individuals. The results obtained from this pilot study will provide a solid foundation for the approval of an investigation into prevention of T1D onset by L. johnsoniiN6.2 consumption in an at-risk human population.
2.Identification of small molecules that modulate the activity of transcription factors: I’m very interested in the elucidation of molecular events in transcription factors that follow the binding small molecules. These small molecules can be natural ligands for the proteins under study or can have a chemical scaffold that is very similar the native regulatory molecule. I have used small molecule screens as an unbiased approach to identified chemicals with this function. As a proof of concept, we used IclR from Escherichia coliand identified glyoxylate and pyruvate as antagonistic effector molecules (Lorca et al., 2008). Using this approach it was possible to identify novobiocin as the specific ligand for a MarR transcription factor (Pagliai et al., 2010), kaempferol as ligand for a LysR transcription factor (Pande et al., under review), ascorbate as inhibitor of the main acid phosphatase (AcpA) of Francisella tularensis(McRae et al., 2010) as well as quinacrine and inorganic polyphosphate as modulators of SspA/MglA interactions in F. tularensis(Wrench et al., 2013). We used a similar approach to discover that benzbromarone as an avid binder of LdtR, a transcriptional activator on the unculturable citrus pathogen, CandidatusLiberibacter asiaticus (Pagliai et al., 2014). Currently, we are testing the efficacy of this and several other compounds on active citrus groves.
- Teaching Interests
- MCB 4422 – Probiotics
- MCB 6424 - Probiotics
- MCB 6318 - Comparative Microbial Genomics