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Forward Genetic Approaches in Chlamydia trachomatis
Published on: October 23, 2013
The Chromosome-Encoded Hypothetical Protein TC0668 Is an Upper Genital Tract Pathogenicity Factor of Chlamydia
Turner Allen Conrad1, Siqi Gong1, Zhangsheng Yang1
1Department of Microbiology and Immunology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
Abstract:
We previously associated a missense mutation of the tc0668 gene of serial in vitro-passaged Chlamydia muridarum, a murine model of human urogenital C. trachomatis, with severely attenuated disease development in the upper genital tract of female mice. Since these mutants also contained a TC0237 Q117E missense mutation that enhances their in vitro infectivity, an effort was made here to isolate and characterize a tc0668 single mutant to determine its individual contribution to urogenital pathogenicity. Detailed genetic analysis of C. muridarum passages revealed a truncated variant with a G216* nonsense mutation of the 408-amino-acid TC0668 protein that does not produce a detectable product. Intracellular growth and infectivity of C. muridarum in vitro remain unaffected in the absence of TC0668. Intravaginal inoculation of the TC0668 null mutant into C3H/HeJ mice results in a typical course of lower genital tract infection but, unlike a pathogenic isogenic control, is unable to elicit significant chronic inflammation of the oviduct and fails to induce hydrosalpinx. Thus, TC0668 is demonstrated as an important chromosome-encoded urogenital pathogenicity factor of C. muridarum and the first with these characteristics to be discovered for a Chlamydia pathogen.
Insights
The TC0668 gene is crucial for Chlamydia muridarum pathogenicity, causing upper genital tract infections and hydrosalpinx in mice. Its absence leads to milder infections, highlighting its role in chlamydial disease.
Area of Science:
- Microbiology
- Immunology
- Genetics
Background:
- Chlamydia muridarum is a murine model for human Chlamydia trachomatis infections.
- Previous studies linked a tc0668 gene mutation to reduced disease severity.
- A co-occurring mutation (TC0237 Q117E) enhanced in vitro infectivity, necessitating investigation of tc0668 alone.
Purpose of the Study:
- To isolate and characterize a single tc0668 mutant of Chlamydia muridarum.
- To determine the specific contribution of the TC0668 gene to urogenital pathogenicity.
- To identify novel pathogenicity factors in Chlamydia.
Main Methods:
- Genetic analysis of C. muridarum passages to identify mutations.
- Creation and characterization of a TC0668 null mutant.
- In vitro assessment of intracellular growth and infectivity.
- Intravaginal inoculation of mice (C3H/HeJ) to evaluate urogenital pathogenicity.
Main Results:
- A TC0668 null mutant was successfully generated, lacking detectable protein product due to a nonsense mutation.
- The absence of TC0668 did not affect C. muridarum's in vitro intracellular growth or infectivity.
- Mice infected with the TC0668 null mutant showed lower genital tract infection but lacked upper tract inflammation and hydrosalpinx.
Conclusions:
- TC0668 is a critical, chromosome-encoded virulence factor for Chlamydia muridarum in the urogenital tract.
- TC0668 is essential for inducing oviduct inflammation and hydrosalpinx, key indicators of severe chlamydial disease.
- This discovery identifies the first Chlamydia pathogenicity factor with these specific characteristics.
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