Chlamydia trachomatis causes the most prevalent sexually transmitted bacterial infection in the US. It induces genital inflammation in female hosts that can lead to pelvic inflammatory disease and potentially life-threatening ectopic pregnancy. While the immune response acts protectively to destroy the bacteria, it also causes collateral damage to infected genital tissue, resulting in pathogenic scarring. This double-edged sword leaves the human host in an evolutionary dilemma: how can there be a robust immune response to protect against Chlamydia infection when that same immune response can cause fatal pathologic sequelae? Jörn Coers and Jacob Dockterman, authors of the review “Immunopathogenesis of genital Chlamydia infection: insights from mouse models” in Pathogens and Disease, present these controversial mechanisms in the #FEMSmicroBlog. #FascinatingMicrobes
A complex immune response
A genital Chlamydia infection induces a complex and multifaceted immune response. The cascade begins with cell-autonomous immunity in genital epithelial cells and continues with cytokine production to activate and recruit innate immune cells such as macrophages and neutrophils. It finally culminates in an adaptive immune response dominated by Th1 CD4+ T cells and cytotoxic CD8+ T cells. These branches of the immune system operate via different mechanisms, each with their own protective qualities and pathogenic potential.
Currently, there is no vaccine for Chlamydia, while antibiotic resistance rates continue to rise. Hence, the goal is to develop vaccines and host-directed therapies that effectively clear genital Chlamydia infection without inducing harmful immune responses. To reach this goal, it will be crucial to harnessing protective immune mechanisms while limiting the activity of pathogenic immune responses.
To clarify which immune mechanisms are protective and which are pathogenic, mouse models have been useful. While the genital anatomy and exact mechanisms of pathology differ between mouse and human hosts, human systems are affected by limited tractability.
To develop a vaccine against Chlamydia, it is crucial to harnessing protective immune mechanisms while limiting the activity of pathogenic immune responses.
The underlying mechanisms
In the review “Immunopathogenesis of genital Chlamydia infection: insights from mouse models” in Pathogens and Disease, we summarize what is known about the mouse immune response to genital Chlamydia infection. We give a step-by-step explanation of the various components of the immune system: when and how they are activated, whether they confer protective immunity, and whether they contribute to subsequent pathology.
Based on an extensive review of the literature, we discuss that the protective immune response converges on cytokine interferon-γ (IFNγ) and its signalling pathway. Early in infection, genital tissue-resident innate immune lymphoid cells produce IFNγ while Chlamydia-specific Th1 CD4+ T cells produce the cytokine later in infection. IFNγ activates epithelial cells and macrophages to initiate a potent antimicrobial defense program. It is also known that sustained genital IFNγ production over 4-8 weeks is sufficient to clear Chlamydia infection.
A host immune response leading to tissue damage
We further describe what is known about the immune mechanisms that cause direct tissue damage and lead to pathologic scarring. Pathogenic immune mechanisms include neutrophils, which produce destructive proteases and reactive oxygen and nitrogen species, as well as CD8+ T cells, which produce the pathogenic cytokine tumor necrosis factor α (TNFα).
Studies in humans have found that increased production of IFNγ correlates with protection from chlamydial disease. Additionally, high concentrations of neutrophils, CD8+ T cells, and TNFα correlate with pelvic inflammation and scarring. These findings validate the use of mouse models to characterize the two-faced nature of immune responses to genital Chlamydia infection.
For researchers or clinicians interested in Chlamydia infection, our review provides a convenient summary of described phenotypes from mouse studies and an effective guide for understanding genital immunity.
- Read the paper “Immunopathogenesis of genital Chlamydia infection: insights from mouse models” by Dockterman and Coers (2021) in Pathogens and Disease.
Jörn Coers is an Associate Professor of Molecular Genetics and Microbiology and the Director of the Center for Host-Microbial Interactions at Duke University Medical School in Durham, North Carolina (USA). He obtained his PhD from the University of Basel (Switzerland) followed by postdoctoral training at Harvard Medical School in Boston (USA). The Coers lab investigates innate immune and inflammatory responses to bacterial pathogens such as Chlamydia trachomatis as well as the mechanisms by which Chlamydia and other human pathogens subvert our immune defenses.
Jake Dockterman is a seventh-year student in the Duke University Medical Scientist Training Program. He completed his undergraduate education at Harvard University, and he currently conducts research in Jörn Coers’ lab at Duke focusing on cell-autonomous immunity to intracellular pathogens as well as genital inflammation in mouse models of Chlamydia infection. After obtaining his PhD in the Duke Immunology Department, he will return to medical school to complete his MD and plans to begin his residency in internal medicine.
About this blog section
The section #FascinatingMicrobes for the #FEMSmicroBlog explains the science behind a paper and highlights the significance and broader context of a recent finding. One of the main goals is to share the fascinating spectrum of microbes across all fields of microbiology.
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