Cold-Induced Stress May Promote Chlamydia Genital Infection

Cold-Induced Stress Chlamydia Genital Infection
Cold-Induced Stress – Chlamydia Genital Infection

Update at BrainImmuneA study by Tesfaye Belay and Anthony Woart from the School of Arts and Sciences, Bluefield State College, Bluefield, West Virginia, published in Journal of Microbiology, Immunology and Infection is perhaps the first to document a link between cold (weather) stress and the course of Chlamydia trachomatis infection.

Chlamydia trachomatis (Ct) is the causative agent of a highly prevalent sexually transmitted bacterial disease and the genital infection by Chlamydia trachomatis (CT) is the most common bacterial sexually transmitted disease worldwide.

The World Health Organization estimates 131 million new cases of C. trachomatis genital infection occur annually. Globally, infection is most prevalent in young women and men (14-25 years), likely driven by asymptomatic infection, inadequate partner treatment and delayed development of protective immunity.

In women, genital tract Ct causes severe complications including pelvic inflammatory disease which is a leading cause of infertility, ectopic pregnancy and chronic pelvic pain. It is an obligate intracellular bacterium comprising of three biovars which in humans exhibit an array of pathological conditions.

The cell‐mediated immunity is the predominant component of protective immune responses to Chlamydia. It is the Th1 subpopulation of CD4 cells that is responsible for resolving chlamydial genital infection via an effector cytokine response, although other components such as CD8+ T cells also play a role. The protective CMI response is strongly associated with the production of IFN-γ either by CD4+ or by CD8+ T cells.

Stress is known to contribute to the development of many infections. Thus, stress is associated in a dose-response manner with an increased risk of acute infectious respiratory illness or common cold, the reactivation of latent herpes simplex virus, the Helicobacter pylori infections and peptic ulcers, etc. However, the role of stress in the pathogenesis of Chlamydial genital disease and the influence on immune response against Chlamydia remain poorly understood.

The focus of the Journal of Microbiology, Immunology and Infection study was to use a cold-stress mouse model to investigate the role of stress in the susceptibility and intensity of genital Chlamydial infection. Stress was applied by placing mice in a packet filled with 2 cm of cold water (1–4°C) for 5 minutes daily for 24 days.

The authors of this study, Tesfaye Belay and Anthony Woart demonstrate that stress increased the intensity of a primary genital CT infection, and the plasma or tissue noradrenaline and adrenaline levels in stressed compared to non-stressed animals. Moreover, stressed mice that suffered greater intensity and prolonged Chlamydia infection had decreased levels of interferon-gamma (IFN-γ), RANTES, MIP-1a, and IP-10. But the level of the immunosuppressive cytokine IL-10 was elevated in the stressed mice.

Thus, in experimental animals and conditions, the authors demonstrate that increased levels of catecholamines, the neurohormonal mediators released during cold-induced stress, are associated with greater susceptibility and intensity of Chlamydia genital infection. In addition, , IFN-γ and and MIP-1 alpha, driving Th1 responses and known to be crucial for clearance were down regulated in stressed mice, while a key immunosuppressive cytokine, IL-10 was up regulated.

It is known that stress regulates immunity via the neuroendocrine-immune axis, involving the two major stress hormones such as glucocorticoids and catecholamines. The sympathetic nervous system and the adrenal medulla are activated during exposure to cold.  Cold stress increases mostly plasma norepinephrine (noradrenaline). Norepinephrine levels, and thereby overall sympathetic nervous “activity” appears to play a key role in cold exposure.

Thus, the authors speculate that catecholamines may play a role in the immunosuppression observed in cold stress in this study. As we discussed here cold stress is linked to immunosuppression and increased tumor growth in experimental animals and catecholamine-induced suppression of cellular immunity and Th1 cells, and upregulation of immunosuppressive IL-10 may contribute to the pathogenesis of certain tumors.

Therefore, a similar mechanism, operating during cold-induced stress conditions may play a critical role in the modulation of the immune system leading to increased susceptibility and greater intensity of Chlamydia genital infection, as described in this study.

Source: Journal of Microbiology, Immunology and Infection, Volume 46, Issue 5, October 2013, Pages 330-337
Read More: Journal of Microbiology, Immunology and Infection


In a 2017 study, the same research group used the cold-induced stress model but applying Chlamydia muridarum infection. Chlamydia muridarum is an intracellular bacterial species that at one time belonged to Chlamydia trachomatis. However, C. trachomatis naturally only infects humans and C. muridarum naturally infects only members of the family Muridae (includes both mice and hamsters).

The new study demonstrates elevated levels of norepinephrine (NE) and epinephrine in stressed mice; upregulated IL-1β, TNF-α, IL-6 and nitric oxide production in macrophage-rich peritoneal cells; and new evidence that NE, in vitro, exerts an immunosuppressive effect on splenic T-cell production of cytokines.

The experiments with C. muridarum infection in stressed β1Adr/β2Adr receptor KO mice showed that the norepinephrine receptor-deficient mice developed low burden of C. muridarum compared to the stressed wild type, indicating that the receptors are associated with suppressing the immune response against C. muridarum infection.

Importantly, exposure of mice to cold water-induced stress was related to elevated shedding of chlamydia, indicating suppression of the immune system and subsequently leading to infection that is more progressive. And, of note, cold water-induced stress enhanced Chlamydia muridarum genital infection-induced infertility in mice.

Thus, overall, the results from the above-discussed studies may indicate that cold-water induced stress increases the intensity of chlamydia genital infection in mice. Importantly, the second study suggest that stress increases disease progression, contributing to pathology and increased chlamydia-induced infertility in experimental conditions.

A 2020 PLOS One study demonstrates an increase in expression of GATA-3, as determined by elevated section of IL-4, and decreased expression of T-bet, IL-12, and secretions of IFN-γ in CD4+ T cells of cold-stressed mice. And, an increased production of IL-4, IL-10, IL-17, and IL-23, in culture supernatants of co-culture of CD4+ T cells and BMDCs suggesting that stimulation of β2-AR receptor leads to the increased production of Th2 cytokines and decreased production of Th1cytokines in cold-stressed mice.

Thus, this is the 3rd study indicating that cold-water induced stress increases the intensity of experimental chlamydia genital infection in mice.