RESUMEN
The hallmark of chlamydial infection is the development of upper genital pathology in the form of hydrosalpinx and oviduct and/or tubal dilatation. Although molecular events leading to genital tissue presentation and cellular architectural remodelling are unclear, early-stage host immune responses are believed to contribute to these long-term sequelae. Recently, we reported the contribution of selected infection-associated microRNAs (miRs) in the generation of host immunity at early-stage infection (day 6 after intravaginal Chlamydia muridarum challenge in C57BL/6 mice). In this report, we describe the contribution of an infection-associated microRNA, i.e. miR-214, to host immunity. Chlamydia muridarum infection in the C57BL/6 mouse genital tract significantly down-regulated miR-214 while up-regulating intracellular adhesion molecule 1 (ICAM1) gene expression. These in vivo observations were confirmed by establishing direct regulation of ICAM-1 by miR-214 in ex vivo genital cell cultures in the presence of miR-214 mimic and inhibitor. Because, ICAM-1 contributes to recruitment of neutrophils following infection, we also demonstrated that alteration of ICAM1 by miR-214 in interleukin-17A-deficient (IL-17A(-/-) ) mice correlated with reduction of neutrophils infiltrating genital tissue at day 6 after challenge. Additionally, these early-stage events resulted in significantly decreased genital pathology in IL-17A(-/-) mice compared with C57BL/6 mice. This report provides evidence for early-stage regulation of ICAM1 by microRNAs, resulting in reduction of genital pathology associated with chlamydial infection.
Asunto(s)
Infecciones por Chlamydia/inmunología , Chlamydia muridarum/inmunología , Regulación hacia Abajo/inmunología , Molécula 1 de Adhesión Intercelular/inmunología , MicroARNs/inmunología , Infecciones del Sistema Genital/inmunología , Regulación hacia Arriba/inmunología , Animales , Infecciones por Chlamydia/genética , Infecciones por Chlamydia/patología , Chlamydia muridarum/genética , Interleucina-17/genética , Interleucina-17/inmunología , Masculino , Ratones , Ratones Noqueados , MicroARNs/genética , Infiltración Neutrófila/genética , Infiltración Neutrófila/inmunología , Neutrófilos/inmunología , Neutrófilos/patología , Infecciones del Sistema Genital/genética , Infecciones del Sistema Genital/patologíaRESUMEN
Our laboratory has investigated the role of an evolutionarily conserved RNA species called microRNAs (miRs) in regulation of anti-chlamydial protective immunity. MiRs including miR-155 expressed in specific immune effector cells are critical for antigen specific protective immunity and IFN-γ production. Using miR-155 deficient mice, and a murine pulmonary model for chlamydial infection, we report here 1) the effect of host miR-155 on bacterial burden, and 2) identify probable immune genes regulated by miR-155.
Asunto(s)
Infecciones por Chlamydia/microbiología , Chlamydia muridarum/fisiología , Pulmón/inmunología , MicroARNs/inmunología , Animales , Carga Bacteriana , Infecciones por Chlamydia/genética , Infecciones por Chlamydia/inmunología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Regulación de la Expresión Génica/inmunología , Interferón gamma/metabolismo , Pulmón/microbiología , Ratones , MicroARNs/genéticaRESUMEN
We have previously determined the protective efficacy of intranasal vaccination with chlamydial protease-like activity factor (CPAF) against genital chlamydial infection. Since T-helper 1 (Th1) responses are important for anti-chlamydial immunity, we examined the contribution of CD4(+) T cells in CPAF mediated immunity against intravaginal (i.vag.) Chlamydia muridarum infection in C57BL/6 mice. CPAF+IL-12 vaccination induced antigen-specific CD4(+) T cells that secreted elevated levels of IFN-gamma, and generated strong humoral responses. The protective effects of CPAF vaccination against genital chlamydial challenge were abrogated by anti-CD4 neutralizing antibody treatment. Moreover, anti-chlamydial immunity could be adoptively transferred to naïve recipients using CPAF-specific CD4(+) T cells. Therefore, CPAF mediated anti-chlamydial immunity is highly dependent upon antigen-specific CD4(+) T cells.