title: Host inflammatory response and development of complications of Chlamydia trachomatis genital infection in CCR5-deficient mice and subfertile women with the CCR5delta32 gene deletion.
abstract: 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.
authors.affiliation: Clark Atlanta University, Atlanta, GA 30333, USA.
authors.forename: Erika L
authors.initials: EL
authors.lastname: Barr
authors.forename: Sander
authors.initials: S
authors.lastname: Ouburg
authors.forename: Joseph U
authors.initials: JU
authors.lastname: Igietseme
authors.forename: Servaas A
authors.initials: SA
authors.lastname: Morré
authors.forename: Edith
authors.initials: E
authors.lastname: Okwandu
authors.forename: Francis O
authors.initials: FO
authors.lastname: Eko
authors.forename: Godwin
authors.initials: G
authors.lastname: Ifere
authors.forename: Tesfaye
authors.initials: T
authors.lastname: Belay
authors.forename: Qing
authors.initials: Q
authors.lastname: He
authors.forename: Deborah
authors.initials: D
authors.lastname: Lyn
authors.forename: Gift
authors.initials: G
authors.lastname: Nwankwo
authors.forename: James W
authors.initials: JW
authors.lastname: Lillard
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Black
authors.forename: Godwin A
authors.initials: GA
authors.lastname: Ananaba
mesh_terms: D000818:Animals; D002690:Chlamydia Infections / Q000150:complications / Q000276:immunology* / Q000473:pathology; D002692:Chlamydia trachomatis; D005187:Fallopian Tubes / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D005831:Genital Diseases, Female / Q000276:immunology*; D006801:Humans; D007247:Infertility, Female / Q000235:genetics* / Q000276:immunology*; D007249:Inflammation / Q000209:etiology*; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019713:Receptors, CCR5 / Q000235:genetics / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology; D051193:Toll-Like Receptors
chemical_list: D008562:Membrane Glycoproteins; D019713:Receptors, CCR5; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors