斯科特Grieshaber

My laboratory studies the pathogenesis of the obligate intracellular bacterial pathogen Chlamydia. In my lab we pursue two main areas of interest: 1) understanding the cytological effects of chlamydial infection on the host cell, and 2) understanding and dissecting the mechanisms of chlamydial differentiation with an eye to developing novel genetic tools in this difficult to manipulate pathogen.

Intracellular bacterial pathogens are a diverse group of bacteria with an acutely adapted life cycle. These bacteria enter and exploit the intracellular environment of a eukaryotic host cell for replication and survival. The study of this class of pathogens is uniquely challenging as these organisms are dependent on the host cell for many aspects of their life cycle. Gaining access to and utilizing the resources of the host cell depends on a complex interaction between the host and pathogen. Throughout my career my research interests have focused on the intimate interaction between host cells and these pathogens. Although I have contributed to the understanding of pathogenesis in both Coxiella burnetii and Rickettsia species, 我目前的工作重点是衣原体的发病机制.

Chlamydiaceae are obligate intracellular bacterial pathogens 哪一个, 取决于物种, 在人类和动物中引起广泛的疾病. Members of the this group are the leading cause of bacterial sexually transmitted disease in humans, the leading cause of infectious preventable blindness in developing countries and a major source of community acquired pneumonia, 支气管炎和鼻窦炎. Related Chlamydia pathogens are responsible for similar diseases in ruminants, 猫, 鸟类和啮齿动物. 在女性, untreated Chlamydia genital infections can result in devastating consequences such as pelvic inflammatory disease, 异位妊娠, 和不孕症. Chlamydia trachomatis infections are also strongly epidemiologically linked to increased rates in cervical cancer, 全球第二大女性常见癌症.

Chlamydia undergo a tightly regulated developmental cycle 哪一个 begins with the infection of the host cell by the metabolically inert, 芽孢样初生体. 在感染, the EB differentiates to the non-infectious metabolically active reticulate body (RB) 哪一个 divides repeatedly by binary fission within a pathogen modified endocytic vacuole. After multiple rounds of binary fission a subset of RBs differentiate back to the EB 哪一个 in turn infect neighboring cells upon release by cell lysis or inclusion extrusion.

我的实验室主要研究两个领域:

1. understand the cytological effects of infection on the host cell, and
2. understand and dissect the mechanisms of chlamydial differentiation with an eye to developing novel genetic tools in this difficult to manipulate pathogen.

• Determine the mechanism by 哪一个 CPAF causes both centrosome amplification and early mitotic exit. My lab’s studies revealed that the chlamydial protease CPAF is a necessary factor causing DNA segregation errors in infected cells through its induction of centrosome amplification and early mitotic exit. We are now in the process of describing the exact mechanism through 哪一个 CPAF acts to cause these disparate phenotypes.
• Determine the chlamydial proteins involved in minus end microtubule trafficking. In an effort to identify the secreted chlamydial effector responsible for centrosome association as well as those effectors responsible for inclusion migration, we are undertaking a high content screening approach utilizing a Chlamydia mutant library to identify mutants that differ in this process.
• Determine chlamydial chromatin structure during development in host cells and effect of EB energy metabolism on initial chromatin decondensation. A key element in the transition between the infectious and vegetative chlamydial cell type is the structure of the chlamydial nucleoid. The EB nucleoid is formed by two chlamydial histone related proteins, HctA和HctB, 哪一个, 感染后立即, 从染色质中释放并缓慢降解. New histones are expressed late in the chlamydial cycle concomitant with re-compaction of the chromatin, 基因表达下调和RB向EB分化. This critical pattern of repression and derepression places the chlamydial histones at the apex of the regulatory circuits that regulate the developmental cycle. We are currently investigating HctA和HctB chromatin binding dynamics as well as the role that histones play in gene expression during development using a combination of in vitro and in vivo assays combined with DNase-seq and ChIP-seq strategies.