Burkholderia pseudomallei (Bp), a facultative intracellular pathogen, is a tier 1 select agent due to its potential use as a bioweapon and the often fatal disease it causes, melioidosis. Melioidosis has a wide variety of symptoms that affects essentially every tissue of the body. The varieties in clinical manifestations is due to th fact that Bp is genetically diverse among species and has a wide array of virulence mechanisms used to establish disease In order to develop effective vaccines and treatment strategies, the molecular pathogenesis of Bp must be elucidated. To date, only a handful of pathogenesis mechanisms have been described, for a bacterium with a very large and diverse genome of >7 mega base pairs. Through our innovative approach of transcriptionally profiling single Bp cells at different stages of infection, we have identified four hypothetical regulators essential for complete Bp pathogenesis in vivo. To study the pathogenic processes and the genes controlled by these regulators we propose Aim 1, which will identify the regulation networks and characterize their roles in pathogenesis. This will shed light on the regulation of either known virulence pathways and/or novel virulence pathways adding to the complete understanding of the Bp intracellular lifecycle.
Aim 2 proposes the mechanistic characterization of these novel transcriptional regulators by determining DNA-regulator interactions across the entire genome. This analysis will allow for identification of binding motifs for each regulator and validate their function. Taken together, the proposed aims will greatly enrich the understanding of Bp infection within the host that can lead to the development of novel vaccine and therapeutic strategies. The overall methodology used in this proposal has broad applicability to study other medically significant facultative intracellular pathogens.
Burkholderia pseudomallei (Bp) is endemic to tropical regions of the globe and its prevalence is increasing with improved diagnostic techniques and rising awareness Bp is a potential threat to homeland security and public health due the bacterium's ability to be aerosolized, high morbidity and mortality rates in endemic regions and the historic use of B. mallei (a clonal derivative of Bp) as bioweapon during the US Civil War, World War I and World War II. Although some mechanisms of pathogenesis have been described in detail, there is still no vaccine available and therapeutic treatment can be difficult due to Bp's intrinsi resistance to broad groups of antibiotics. To alleviate these challenges in treatment and prevention, our research proposes to investigate novel mechanisms of virulence regulation that will help complete the understanding of Bp pathogenesis and eventually aid in the development of novel vaccine and therapeutic strategies.
| Heacock-Kang, Yun; Zarzycki-Siek, Jan; Sun, Zhenxin et al. (2018) Novel dual regulators of Pseudomonas aeruginosa essential for productive biofilms and virulence. Mol Microbiol 109:401-414 |
| Heacock-Kang, Yun; McMillan, Ian A; Zarzycki-Siek, Jan et al. (2018) The heritable natural competency trait of Burkholderia pseudomallei in other Burkholderia species through comE and crp. Sci Rep 8:12422 |
| Norris, Michael H; Heacock-Kang, Yun; Zarzycki-Siek, Jan et al. (2017) Burkholderia pseudomallei natural competency and DNA catabolism: Identification and characterization of relevant genes from a constructed fosmid library. PLoS One 12:e0189018 |
