Genetic analysis of mechanisms of chlamydial immune evasion

描述（由申请人提供）：沙眼衣原体性传播感染率稳定或上升，这些感染的后果每年造成数十亿美元的医疗费用。我们需要针对这些病原体的疫苗，但我们对衣原体如何逃避免疫系统的了解有限，阻碍了实现这一目标的进展。衣原体基因组很小且高度保守。这些病原体是如何绕过免疫系统，瞄准它们喜欢的组织并引起疾病的，目前尚不清楚。我们的知识存在空白的一个主要原因是，这些病原体无法在基因上进行操纵。许多决定不同衣原体感染的组织和宿主类型的基因可能位于一个称为可塑性区（PZ）的可变基因组区域。怀疑这些PZ基因抵消了由细胞因子控制的宿主细胞防御

DESCRIPTION (provided by applicant): Rates of Chlamydia trachomatis sexually transmitted infection are stable or increasing and consequences of these infections incur billions in medical costs annually. Vaccines for these pathogens are needed but our limited understanding of how chlamydiae evade the immune system has inhibited progress towards this goal. Chlamydial genomes are small and highly conserved. How these pathogens circumvent immunity, target their preferred tissues and cause disease is unknown. A major reason for gaps in our knowledge was that these pathogens could not be genetically manipulated. Many genes that determine the types of tissues and hosts that different Chlamydia spp. infect may reside in a variable genomic region called the plasticity zone (PZ). It is suspected these PZ genes counteract host cell defenses controlled by the cytokine IFN-γ. Other results indicate polymorphisms in core genes of C. trachomatis clinical isolates also contribute to immune evasion and disease severity. We recently developed genetic tools that now make it possible to test these hypotheses. In our first aim, we will use a reverse genetic approach to inactivate PZ genes and test if the mutants are sensitive to IFN-γ, or have other alterations in pathogenicity in vitro and in vivo using a tractable mouse model. In aim two we will use unbiased mutagenesis and forward genetic screens to identify chlamydial genes that contribute to evasion of IFN-γ. Finally, lateral gene transfer, phenotypic screens and genome sequencing will be used to identify genomic polymorphisms that determine chlamydial IFN-γ sensitivity in animals and humans.