Our research focuses on the cell signaling events that drive the propagation of the parasite Toxoplasma gondii. A great part of the pathogenesis associated with toxoplasmosis is due to the repeating cycles of cell invasion, replication and egress that drive its propagation through an infected individual. Our lab is interested in the signaling pathways that regulate various aspects of this lytic cycle. Given that events such as invasion and egress are essential for parasite survival and that Toxoplasma uses some unique signaling molecules our studies aim at discovering novel targets for the development of much needed anti-parasitic drugs. Visit our laboratory web site for more information.
The Derbigny Lab conducts studies to define the precise regulation of the specific cell signaling pathways that are activated during Chlamydia infection. To better understand the molecular cascade of events that ensues upon infection with C. trachomatis, a non-transformed murine oviduct epithelial cell line was developed using cells lining the oviduct epithelium of B6 mice. Our early work showed that the oviduct epithelial cell lines expressed mRNA for TLR1,-2, -3, -5, and -6, but failed to express any mRNA for TLR4, -7, -8, and -9. Additionally, we showed that these cells expressed mRNA for other pattern recognition receptors (PRRs) including Nod1 and Nod2. Experiments utilizing si-RNA and dominant-negative proteins showed that secretion of the acute inflammatory cytokines IL-6 and GM-CSF by Chlamydia-infected oviduct epithelial cells was dependent on TLR2 and MyD88. We plan to further investigate the role of TLR3 and to define the exact component of the Chlamydia structure that serves as an agonist for IFN-β production during infection of oviduct epithelial cells. A second major component of our research interests will focus on the effect(s) that IFN-β has on the regulation of IL-12p70, and other chemokines including Rantes, IP-10 (CXCL10), CXCL16, and MIG (CXCL9) theorized to preferentially recruit Th1 lymphocytes to the upper genital tract during Chlamydia infection.
The Gilk Lab studies how cholesterol and other lipids contribute to host cell colonization by Coxiella burnetii. We have made the surprising discovery that, unlike other bacterial pathogens, Coxiella is uniquely sensitive to host cell cholesterol and grows best in the absence of cholesterol. These exciting findings suggest treatment of Coxiella infection might be achieved by targeting host cholesterol metabolism, a strategy that would lessen the possibility of antibiotic resistance. Our current research is focused on determining why cholesterol is toxic to Coxiella, and how the bacteria manipulates host cholesterol metabolism. We are also characterizing the role of cholesterol in interactions between the Coxiella vacuole and the endoplasmic reticulum.
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Dr. John’s lab investigates malaria immunoepidemiology, the pathogenesis of severe malaria, and interactions between malaria and other disease states like iron deficiency and sickle cell disease.
The John Lab focuses on six major research questions:
1. Which host and pathogen factors contribute to development of severe malaria?
2. How does the immune response contribute to neurodevelopmental impairment in children with severe malaria?
3. How can iron deficiency be safely treated in malaria endemic areas?
4. What contributes to the increased risk of death from malaria in children with sickle cell disease?
5. How do changing transmission conditions affect development of immunity in malaria?
6. What causes malaria to persist in low transmission settings, and how might it be eliminated?
The Johnson laboratory currently has three major research projects.
1) Exploiting the GroEL/ES chaperonin system as a mechanistically novel antimicrobial target.
The GroEL/ES chaperonin system is a remarkable example of a diverse class of specialized proteins, called molecular chaperones, which help other proteins fold to their native states. As GroEL/ES is ubiquitous, essential, and highly conserved across bacteria, targeting of this chaperonin system represents an exciting strategy for developing mechanistically unique antibacterials. We are also investigating the applicability of this strategy for targeting pathogens other than bacteria and have found that Trypanosoma brucei parasites are susceptible to many of these inhibitors.
2) Modulation of molecular chaperones and protein homeostasis for the development of oncology therapeutics.
It is reasonable to believe that subsets of the recently identified GroEL/ES inhibitors might also have modulatory effects on the human homologue, HSP60/10. This poses an exciting possibility for developing chemical probes to study the function of the mammalian chaperonin system in a variety of cancers where the abnormally propagating cells have hijacked HSP60/10 regulation to help circumvent apoptosis (e.g. breast, cervical, ovarian, colon, and prostate).
3) Development of Mycobacteria tuberculosis protein tyrosine phosphatase B inhibitors.
The Nelson lab is an integrated group of basic scientists and physicians that studies the molecular mechanisms of chlamydial pathogenesis as well as the clinical risk factors that determine C. trachomatis susceptibility and disease expression. A long-term focus of our group has been development of tools for genetic manipulation of Chlamydia spp. Another focus is investigation of the mechanisms chlamydiae employ to circumvent innate and adaptive immunity including persistence. A third area of active investigation is development of attenuated anti-chlamydial vaccine strains. Most recently, we initiated a large clinical study to investigate the relationship between the urogenital microbiome and incident C. trachomatis infection, factors that influence chlamydial disease expression and the efficacy of front-line antibiotic regimens in elimination of these pathogens from a newly recognized reservoir.
The Sullivan Lab studies gene expression regulation in the protozoan parasite Toxoplasma gondii at various levels, as interference with these processes are likely to provide new opportunities for drug development that treat both the replicative and latent (encysted) forms of the parasite. We are currently investigating novel plant-like transcription factors and enzymes that control epigenetic features of gene regulation. We also study cellular signaling mediated by lysine acetylation and how phosphorylation of eIF2 modulates translational control in the parasite. We are also interested in host-pathogen interactions, specifically how the parasite may induce changes in the acetylation of host cell proteins.
Please visit our laboratory web site for more information.
The Tran Lab is focused on defining mechanisms of host immunity to malaria in endemic settings. By investigating naturally acquired immunity to malaria, we can gain a better understanding as to why malaria vaccines that perform well in naïve donors have performed less effectively in the field. To this end, we apply systems biology approaches such as transcriptomics, multi-parameter immunological analyses, and proteomics to elucidate the complex immune responses to P. falciparum during both asymptomatic and symptomatic infections. To conduct these studies, we collaborate with investigators in Mali and Kenya to collect clinical data and biospecimens from well-characterized cohorts of children and adults living in areas highly endemic for malaria. Working with leading malaria-vaccine researchers, we also employ transcriptomic approaches to determine the immunological predictors of protection in individuals who have been immunized with malaria vaccine candidates. This unbiased, systems biology approach allows us to generate new hypotheses related to immunity to human malaria, which we further validate and test at both the population and mechanistic level.