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Identification of Host Pathways Targeted by Bacterial Effector Proteins using Yeast Toxicity and Suppressor Screens
Published on: October 25, 2019
The Chlamydia trachomatis-secreted effector protein CT181 binds to Mcl-1 and prolongs neutrophil survival
Robert Faris1, Rebecca Koch2, Paige McCaslin1
1Department of Microbiology and Immunology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
Insights
Chlamydia trachomatis uses a novel effector, CT181, to bind Mcl-1, prolonging neutrophil survival. This mechanism helps the bacteria evade immune responses and persist during infection, contributing to disease.
Area of Science:
- Microbiology
- Immunology
- Pathogenesis
Background:
- Chlamydia trachomatis evades host immunity, leading to persistent and often asymptomatic infections.
- Bacterial effector proteins are crucial for immune subversion, but their mechanisms are not fully understood.
Purpose of the Study:
- To identify novel Chlamydia trachomatis effector proteins involved in immune evasion.
- To investigate the function of the identified effector CT181 in host-pathogen interactions.
Main Methods:
- Identification of CT181 as a novel Chlamydia trachomatis effector.
- Analysis of CT181's interaction with host protein Mcl-1.
- Assessment of CT181's role in bacterial survival in neutrophils and a murine infection model.
Main Results:
- CT181 binds to Mcl-1, a key regulator of neutrophil survival.
- A CT181 mutant showed reduced Chlamydia trachomatis survival in neutrophils.
- CT181 contributes to bacterial colonization and inflammatory cytokine production in vivo.
Conclusions:
- CT181 is the first identified bacterial effector that binds Mcl-1.
- CT181 promotes Chlamydia trachomatis persistence by prolonging neutrophil survival and modulating immune responses.
- This reveals a novel strategy for immune dysregulation by Chlamydia trachomatis.
Abstract:
Chlamydia trachomatis (C.t.) infections can lead to severe complications due to the pathogen's ability to evade the host immune response, often resulting in asymptomatic infections. The mechanisms underlying this immune subversion remain incompletely understood, but likely involve specific bacterial effector proteins. Here, we identify CT181 as a novel effector that binds to Mcl-1, a key regulator of neutrophil survival. While a C.t. CT181 mutant exhibited only modest defects in epithelial cell replication and inclusion development, it was required for C.t. survival in neutrophils, which correlated with elevated Mcl-1 levels in cells infected with wild-type C.t. Using a murine infection model, we demonstrate that CT181 contributes to C.t. colonization and inflammatory cytokine production in vivo. Our findings establish CT181 as the first bacterial effector protein known to bind Mcl-1 and show that it is associated with prolonged neutrophil survival, revealing a novel strategy by which C.t. promotes immune dysregulation, facilitating bacterial persistence while driving C.t. pathogenesis.IMPORTANCEChlamydia trachomatis is an obligate intracellular pathogen that must evade early immune defenses to establish infection. This study identifies CT181 as a previously undescribed secreted effector that associates with the host pro-survival protein Mcl-1 and is linked to prolonged neutrophil survival during infection. Neutrophils, which normally undergo rapid apoptosis, persist longer when infected with wild-type C. trachomatis, whereas loss of CT181 reduces bacterial survival in these cells. In a mouse model of infection, the CT181 mutant exhibits reduced bacterial burden and diminished inflammatory responses, including neutrophil recruitment and cytokine production. Together, these findings highlight CT181 as a bacterial factor that contributes to host cell survival and immune modulation during C. trachomatis infection, underscoring the complex strategies used by intracellular pathogens to persist within the host.
