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-?. 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-?, 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-?. Finally, lateral gene transfer, phenotypic screens and genome sequencing will be used to identify genomic polymorphisms that determine chlamydial IFN-? sensitivity in animals and humans. Public Health Relevance: Our study will identify genes that determine chlamydial pathogenic diversity and virulence and could lead to improved animal models for study of human chlamydial disease. The data could also inform attempts to construct effective anti-chlamydial vaccines.
Our study will identify genes that determine chlamydial pathogenic diversity and virulence and could lead to improved animal models for study of human chlamydial disease. The data could also inform attempts to construct effective anti-chlamydial vaccines.
|Gehre, Lena; Gorgette, Olivier; Perrinet, Stéphanie et al. (2016) Sequestration of host metabolism by an intracellular pathogen. Elife 5:e12552|
|Haldar, Arun K; Piro, Anthony S; Finethy, Ryan et al. (2016) Chlamydia trachomatis Is Resistant to Inclusion Ubiquitination and Associated Host Defense in Gamma Interferon-Primed Human Epithelial Cells. MBio 7:|
|Brothwell, Julie A; Muramatsu, Matthew K; Toh, Evelyn et al. (2016) Interrogating Genes That Mediate Chlamydia trachomatis Survival in Cell Culture Using Conditional Mutants and Recombination. J Bacteriol 198:2131-9|
|Muramatsu, Matthew K; Brothwell, Julie A; Stein, Barry D et al. (2016) Beyond Tryptophan Synthase: Identification of Genes That Contribute to Chlamydia trachomatis Survival during Gamma Interferon-Induced Persistence and Reactivation. Infect Immun 84:2791-801|
|Rajaram, Krithika; Nelson, David E (2015) Chlamydia muridarum infection of macrophages elicits bactericidal nitric oxide production via reactive oxygen species and cathepsin B. Infect Immun 83:3164-75|
|Rajaram, Krithika; Giebel, Amanda M; Toh, Evelyn et al. (2015) Mutational Analysis of the Chlamydia muridarum Plasticity Zone. Infect Immun 83:2870-81|
|Taylor, Lacey D; Nelson, David E (2014) Chlamydial MACPF protein CT153. Subcell Biochem 80:255-69|