Host inflammatory response and development of complications of Chlamydia trachomatis genital infection in CCR5-deficient mice and subfertile women with the CCR5delta32 gene deletion

Erika L. Barr¹, Sander Ouburg², Joseph U. Igietseme^3,4, Servaas A. Morr², Edith Okwandu¹, Francis O. Eko⁴, Godwin Ifere⁴, Tesfaye Belay¹, Qing He^3,4, Deborah Lyn⁴, Gift Nwankwo¹, James Lillard⁴, Carolyn M. Black³, Godwin A. Ananaba^1
1Clark Atlanta University, Atlanta, GA, USA; ²Department of Pathology, Laboratory of Immunogenetics, Section Immunogenetics of Infectious Diseases, VU University Medical Center, Amsterdam, The Netherlands; ³Center for Disease Control and Prevention, Atlanta, GA; and 4Morehouse School of Medicine, Atlanta, GA, USA

Received: March 11, 2005 Revised: May 3, 2005 Accepted: May 19, 2005

Corresponding author: Dr. Joseph U. Igietseme, NCID/SRP/CDC, Mailstop C17, 1600 Clifton Road, Atlanta, GA 30333, USA. E-mail:

T cell immunity protects against diseases caused by the obligate intracellular bacterium Chlamydia trachomatis. Incidentally, host inflammatory response that includes T cells appears to also contribute to the pathogenesis of chlamydial diseases such as trachoma and tubal factor infertility (TFI). Therefore, designing effective prevention strategies requires a delineation of immune processes responsible for pathology and those mediating immunity, and identification of the immunogenetic factors predisposing to complication development. The chemokine receptor CCR5 is crucial for T cell activation and function since its deficiency causes suppression of T cell response. We investigated the hypothesis that the clearance of genital chlamydial infection in CCR5-deficient mice could be delayed in the short term; however, a beneficial effect could include protection against inflammation-related complications such as TFI. In a translational study in humans, we investigated the effect of a functional 32 bp deletion in the CCR5 gene on the risk of developing tubal pathology in Dutch Caucasian women with immunologic evidence [i.e., immunoglobulin G (IgG) responses] of chlamydial infection. When genitally-infected wild-type (WT) and CCR5 knockout (CCR5KO) mice were evaluated for microbiologic shedding of chlamydiae, there was a greater intensity of infection and delayed resolution in the knockout mice. However, compared to WT mice, the fertility of infected CCR5KO mice (measured by pregnancy rate) was only mildly affected in the short term and unaffected in the long term (70% vs 30% reduction in the short term, and 50 vs 0% in the long term, respectively). Immunobiologic analysis revealed that the diminished capacity of CCR5KO to control acute chlamydial infection correlated with the relatively low chemokine [interferon-inducible protein 10 (IP-10) and regulated upon activation normal cell expressed and secreted (RANTES)] and cytokine (mainly interferon-gamma and tumor necrosis factor-alpha) expression corresponding to a poor early T-helper I response. However, the reduced incidence of complications in the CCR5KO mice appears to correlate with the low activity of long term inflammatory mediators. Besides, the translational studies in humans revealed that among patients with positive anti-chlamydial IgG responses, tubal pathology correlated with a low incidence of CCR5delta32 deletion (7%), while women without tubal pathology had higher incidence of the CCR5delta32 deletion (31%) as compared to controls (19%). Thus, in mice and humans the inflammation associated with CCR5 function may predispose to development of complications of chlamydial infection, such as TFI.

Key words: Chemokine receptors, chlamydia, gene deletion, genetic predisposition to disease, immunogenetics

J Microbiol Immunol Infect 2005;38:244-254.