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1.
PLoS One ; 7(1): e30747, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22292031

RESUMO

Loss of the conserved "cryptic" plasmid from C. trachomatis and C. muridarum is pleiotropic, resulting in reduced innate inflammatory activation via TLR2, glycogen accumulation and infectivity. The more genetically distant C. caviae GPIC is a natural pathogen of guinea pigs and induces upper genital tract pathology when inoculated intravaginally, modeling human disease. To examine the contribution of pCpGP1 to C. caviae pathogenesis, a cured derivative of GPIC, strain CC13, was derived and evaluated in vitro and in vivo. Transcriptional profiling of CC13 revealed only partial conservation of previously identified plasmid-responsive chromosomal loci (PRCL) in C. caviae. However, 2-deoxyglucose (2DG) treatment of GPIC and CC13 resulted in reduced transcription of all identified PRCL, including glgA, indicating the presence of a plasmid-independent glucose response in this species. In contrast to plasmid-cured C. muridarum and C. trachomatis, plasmid-cured C. caviae strain CC13 signaled via TLR2 in vitro and elicited cytokine production in vivo similar to wild-type C. caviae. Furthermore, inflammatory pathology induced by infection of guinea pigs with CC13 was similar to that induced by GPIC, although we observed more rapid resolution of CC13 infection in estrogen-treated guinea pigs. These data indicate that either the plasmid is not involved in expression or regulation of virulence in C. caviae or that redundant effectors prevent these phenotypic changes from being observed in C. caviae plasmid-cured strains.


Assuntos
Infecções por Chlamydia/microbiologia , Chlamydia/genética , Chlamydia/fisiologia , Chlamydia/patogenicidade , Plasmídeos/genética , Infecções do Sistema Genital/microbiologia , Receptor 2 Toll-Like/fisiologia , Virulência/genética , Animais , Células Cultivadas , Chlamydia/imunologia , Infecções por Chlamydia/imunologia , Infecções por Chlamydia/patologia , Modelos Animais de Doenças , Evolução Molecular , Feminino , Deleção de Genes , Cobaias , Células HEK293 , Humanos , Ativação Linfocitária/genética , Plasmídeos/fisiologia , Infecções do Sistema Genital/imunologia , Infecções do Sistema Genital/patologia , Transdução de Sinais/imunologia , Receptor 2 Toll-Like/imunologia , Receptor 2 Toll-Like/metabolismo
2.
Infect Immun ; 79(3): 1349-62, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21149587

RESUMO

Interleukin 17 (IL-17) contributes to development of Th1 immunity and neutrophil influx during Chlamydia muridarum pulmonary infection, but its role during C. muridarum genital tract infection has not been described. We detected similar numbers of Chlamydia-specific Th17 and Th1 cells in iliac nodes of wild-type mice early during genital C. muridarum infection, while Th1 cells predominated later. il17ra(-/-) mice exhibited a reduced chlamydia-specific Th1 response in draining iliac nodes and decreased local IFN-γ production. Neutrophil influx into the genital tract was also decreased. However, il17ra(-/-) mice resolved infection normally, and no difference in pathology was observed compared to the wild type. Macrophage influx and tumor necrosis factor alpha (TNF-α) production were increased in il17ra(-/-) mice, providing a compensatory mechanism to effectively control chlamydial genital tract infection despite a reduced Th1 response. In ifnγ(-/-) mice, a marked increase in cellular infiltrates and chronic pathology was associated with an increased Th17 response. Although neutralization of IL-17 in ifnγ(-/-) mice decreased neutrophil influx, macrophage infiltration remained intact and the bacterial burden was not increased. Collectively, these results indicate that IL-17 contributes to the generation of Th1 immunity and neutrophil recruitment but is not required for macrophage influx or normal resolution of C. muridarum genital infection. These data highlight the redundant immune mechanisms operative at this mucosal site and the importance of examining site-specific responses to mucosal pathogens.


Assuntos
Infecções por Chlamydia/imunologia , Interleucina-17/imunologia , Macrófagos/imunologia , Infiltração de Neutrófilos/imunologia , Células Th1/imunologia , Células Th17/imunologia , Animais , Colo do Útero/imunologia , Colo do Útero/microbiologia , Colo do Útero/patologia , Infecções por Chlamydia/patologia , Chlamydia muridarum/imunologia , Feminino , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oviductos/imunologia , Oviductos/microbiologia , Oviductos/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Subpopulações de Linfócitos T/imunologia
3.
Infect Immun ; 79(1): 486-98, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21078858

RESUMO

We have previously shown that MyD88 knockout (KO) mice exhibit delayed clearance of Chlamydia muridarum genital infection compared to wild-type (WT) mice. A blunted Th1 response and ineffective suppression of the Th2 response were also observed in MyD88 KO mice. The goal of the present study was to investigate specific mechanisms whereby absence of MyD88 leads to these effects and address the compensatory mechanisms in the genital tract that ultimately clear infection in the absence of MyD88. It was observed that NK cells recruited to the genital tract in MyD88 KO mice failed to produce gamma interferon (IFN-γ) mRNA and protein. This defect was associated with decreased local production of interleukin-17 (IL-17), IL-18, and tumor necrosis factor alpha (TNF-α) but normal levels of IL-12p70. Additionally, recruitment of CD4 T cells to the genital tract was reduced in MyD88 KO mice compared to that in WT mice. Although chronic infection in MyD88 KO mice resulted in oviduct pathology comparable to that of WT mice, increased histiocytic inflammation was observed in the uterine horns. This was associated with increased CCL2 levels and recruitment of macrophages as a potential compensatory mechanism. Further deletion of TLR4-TRIF signaling in MyD88 KO mice, using TLR4/MyD88 double-KO mice, did not further compromise host defense against chlamydiae, suggesting that compensatory mechanisms are Toll-like receptor (TLR) independent. Despite some polarization toward a Th2 response, a Th1 response remained predominant in the absence of MyD88, and it provided equivalent protection against a secondary infection as observed in WT mice.


Assuntos
Chlamydia muridarum , Interferon gama/metabolismo , Células Matadoras Naturais/metabolismo , Monócitos/fisiologia , Fator 88 de Diferenciação Mieloide/metabolismo , Células Th1/fisiologia , Animais , Infecções por Chlamydia/imunologia , Infecções por Chlamydia/microbiologia , Infecções por Chlamydia/patologia , Tubas Uterinas/patologia , Feminino , Regulação da Expressão Gênica , Inflamação/patologia , Interferon gama/genética , Interleucinas/genética , Interleucinas/metabolismo , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Linfócitos T/fisiologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Útero/patologia , Vaginite/microbiologia
4.
Infect Immun ; 77(12): 5334-46, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19805535

RESUMO

Recent findings have implicated interleukin-1beta (IL-1beta) as an important mediator of the inflammatory response in the female genital tract during chlamydial infection. But how IL-1beta is produced and its specific role in infection and pathology are unclear. Therefore, our goal was to determine the functional consequences and cellular sources of IL-1beta expression during a chlamydial genital infection. In the present study, IL-1beta(-/-) mice exhibited delayed chlamydial clearance and decreased frequency of hydrosalpinx compared to wild-type (WT) mice, implying an important role for IL-1beta both in the clearance of infection and in the mediation of oviduct pathology. At the peak of IL-1beta secretion in WT mice, the major producers of IL-1beta in vivo are F4/80(+) macrophages and GR-1(+) neutrophils, but not CD45(-) epithelial cells. Although elicited mouse macrophages infected with Chlamydia muridarum in vitro secrete minimal IL-1beta, in vitro prestimulation of macrophages by Toll-like receptor (TLR) ligands such as lipopolysaccharide (LPS) purified from Escherichia coli or C. trachomatis L2 prior to infection greatly enhanced secretion of IL-1beta from these cells. By using LPS-primed macrophages as a model system, it was determined that IL-1beta secretion was dependent on caspase-1, potassium efflux, and the activity of serine proteases. Significantly, chlamydia-induced IL-1beta secretion in macrophages required bacterial viability but not growth. Our findings demonstrate that IL-1beta secreted by macrophages and neutrophils has important effects in vivo during chlamydial infection. Additionally, prestimulation of macrophages by chlamydial TLR ligands may account for the elevated levels of pro-IL-1beta mRNA observed in vivo in this cell type.


Assuntos
Infecções por Chlamydia/imunologia , Chlamydia muridarum/imunologia , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Macrófagos/imunologia , Macrófagos/microbiologia , Animais , Infecções por Chlamydia/microbiologia , Contagem de Colônia Microbiana , Tubas Uterinas/patologia , Feminino , Células HeLa , Humanos , Interleucina-1beta/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia
5.
J Immunol ; 179(6): 3707-14, 2007 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-17785807

RESUMO

Ligation of the purinergic receptor, P2X7R, with its agonist ATP has been previously shown to inhibit intracellular infection by chlamydiae and mycobacteria in macrophages. The effect of P2X7R on chlamydial infection had never been investigated in the preferred target cells of chlamydiae, cervical epithelial cells, nor in vaginally infected mice. In this study, we show that treatment of epithelial cells with P2X7R agonists inhibits partially Chlamydia infection in epithelial cells. Chelation of ATP with magnesium or pretreatment with a P2X7R antagonist blocks the inhibitory effects of ATP. Similarly to previous results obtained with macrophages, ATP-mediated inhibition of infection in epithelial cells requires activation of host-cell phospholipase D. Vaginal infection was also more efficient in P2X7R-deficient mice, which also displayed a higher level of acute inflammation in the endocervix, oviduct, and mesosalpingeal tissues than in infected wild-type mice. However, secretion of IL-1beta, which requires P2X7R ligation during infection by other pathogens, was decreased mildly and only at short times of infection. Taken together, these results suggest that P2X7R affects Chlamydia infection by directly inhibiting infection in epithelial cells, rather than through the ability of P2X7R to modulate IL-1beta secretion.


Assuntos
Colo do Útero/metabolismo , Infecções por Chlamydia/patologia , Infecções por Chlamydia/prevenção & controle , Doenças dos Genitais Femininos/prevenção & controle , Receptores Purinérgicos P2/fisiologia , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/fisiologia , Animais , Linhagem Celular Tumoral , Colo do Útero/imunologia , Colo do Útero/microbiologia , Infecções por Chlamydia/genética , Infecções por Chlamydia/imunologia , Chlamydia muridarum/crescimento & desenvolvimento , Chlamydia muridarum/imunologia , Doença Crônica , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Tubas Uterinas/metabolismo , Tubas Uterinas/patologia , Feminino , Doenças dos Genitais Femininos/imunologia , Doenças dos Genitais Femininos/metabolismo , Doenças dos Genitais Femininos/microbiologia , Doenças dos Genitais Femininos/patologia , Células HeLa , Humanos , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Agonistas do Receptor Purinérgico P2 , RNA Mensageiro/biossíntese , Receptores Purinérgicos P2/deficiência , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X7
6.
Am J Surg Pathol ; 29(11): 1472-81, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16224214

RESUMO

Patients with ulcerative colitis (UC) may develop inflammation in the distal ileum thought to be due to "backwash" of cecal contents ("backwash ileitis"). However, a systematic analysis of ileal changes in UC has never been performed, and the prevalence and criteria for "backwash" ileitis have not been defined. The aim of this study was to evaluate the prevalence and spectrum of inflammatory changes in the ileum in patients with UC and to correlate ileal changes with outcome after total proctocolectomy and ileal pouch-anal anastomosis. Routinely processed ileocolonic resection specimens from 200 consecutive patients with clinically and pathologically confirmed UC were evaluated for a wide variety of pathologic features in the ileum and colon. The ileal data were correlated with both the clinical features and the pathologic findings in the colon. Follow-up data were obtained to confirm absence of Crohn's disease and to evaluate outcome of ileo-anal pouches. Overall, 34 of 200 (17%) UC patients had inflammatory changes in the ileum (male/female ratio, 16/18; mean age, 42 years); 32 of 34 (94%) had pancolitis, which was significantly higher than the rate of pancolitis (39%) in patients without ileal disease (N = 166) (P < 0.001), but there were no other differences between patients with or without ileal pathology. In the colon, 22 of 34 (65%) patients had severe activity. Ileal changes included villous atrophy and crypt regeneration without increased inflammation (N = 3), increased neutrophilic and mononuclear inflammation in the lamina propria (N = 6), patchy cryptitis and crypt abscesses (N = 21) and focal superficial surface erosions (N = 4), some with pyloric metaplasia (N = 2 of 4). In general, the severity of ileal changes paralleled the severity of colonic activity. However, 2 of 4 (50%) patients with superficial erosions in the ileum had subtotal or left-sided colitis only, and had only mild colonic activity. Other cases showed only mild to moderate colonic activity and patchy or discontinuous involvement of the distal ileum. Upon follow-up of patients with erosions (mean, 48.5 months; range, 26-102 months), none developed manifestations of Crohn's disease anywhere in the gastrointestinal tract. The presence of inflammatory changes in the ileum had no effect on the prevalence of pouch complications or on the occurrence of dysplasia or cancer. Ileal changes in UC are not uncommon (prevalence, 17%), are generally mild in nature (villous atrophy, increased inflammation, scattered crypt abscesses), and are not associated with an increased rate of ileo-anal pouch complications, dysplasia, or carcinoma. In some cases, our findings are consistent with a backwash etiology. However, rarely, ileal erosions may occur in patients without cecal involvement, which may indicate that other pathogenetic mechanisms should be considered in the etiology of ileitis in UC patients.


Assuntos
Colite Ulcerativa/patologia , Bolsas Cólicas/patologia , Ileíte/patologia , Proctocolectomia Restauradora/métodos , Adulto , Idoso , Estudos de Coortes , Colite Ulcerativa/complicações , Colite Ulcerativa/cirurgia , Feminino , Humanos , Ileíte/epidemiologia , Ileíte/etiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos
10.
J Immunol ; 171(11): 6187-97, 2003 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-14634135

RESUMO

The roles of Toll-like receptor (TLR) 2 and TLR4 in the host inflammatory response to infection caused by Chlamydia trachomatis have not been elucidated. We examined production of TNF-alpha and IL-6 in wild-type TLR2 knockout (KO), and TLR4 KO murine peritoneal macrophages infected with the mouse pneumonitis strain of C. trachomatis. Furthermore, we compared the outcomes of genital tract infection in control, TLR2 KO, and TLR4 KO mice. Macrophages lacking TLR2 produced significantly less TNF-alpha and IL6 in response to active infection. In contrast, macrophages from TLR4 KO mice consistently produced higher TNF-alpha and IL-6 responses than those from normal mice on in vitro infection. Infected TLR2-deficient fibroblasts had less mRNA for IL-1, IL-6, and macrophage-inflammatory protein-2, but TLR4-deficient cells had increased mRNA levels for these cytokines compared with controls, suggesting that ligation of TLR4 by whole chlamydiae may down-modulate signaling by other TLRs. In TLR2 KO mice, although the course of genital tract infection was not different from that of controls, significantly lower levels of TNF-alpha and macrophage-inflammatory protein-2 were detected in genital tract secretions during the first week of infection, and there was a significant reduction in oviduct and mesosalpinx pathology at late time points. TLR4 KO mice responded to in vivo infection similarly to wild-type controls and developed similar pathology. TLR2 is an important mediator in the innate immune response to C. trachomatis infection and appears to play a role in both early production of inflammatory mediators and development of chronic inflammatory pathology.


Assuntos
Infecções por Chlamydia/imunologia , Chlamydia trachomatis , Tubas Uterinas/patologia , Doenças dos Genitais Femininos/imunologia , Glicoproteínas de Membrana/fisiologia , Receptores de Superfície Celular/fisiologia , Animais , Anticorpos Antibacterianos/sangue , Células Cultivadas , Quimiocina CXCL2 , Quimiocinas/genética , Quimiocinas/metabolismo , Infecções por Chlamydia/genética , Infecções por Chlamydia/patologia , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Tubas Uterinas/imunologia , Feminino , Fibroblastos/imunologia , Fibroblastos/microbiologia , Fibroblastos/patologia , Doenças dos Genitais Femininos/genética , Doenças dos Genitais Femininos/patologia , Imunoglobulina G/sangue , Interleucina-1/genética , Interleucina-1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia/genética , Pneumonia/imunologia , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/metabolismo , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/genética , Receptor 2 Toll-Like , Receptor 4 Toll-Like , Receptores Toll-Like , Fator de Necrose Tumoral alfa/metabolismo
11.
J Biol Chem ; 278(11): 9496-502, 2003 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-12509420

RESUMO

The BCL-2 family member BAX plays a critical role in regulating apoptosis. Surprisingly, bax-deficient mice display limited phenotypic abnormalities. Here we investigate the effect of BAX on infection by the sexually transmitted pathogen, Chlamydia muridarum (the mouse pneumonitis strain of Chlamydia trachomatis). Bax(-/-) cells are relatively resistant to Chlamydia-induced apoptosis, and fewer bacteria are recovered after two infection cycles from Bax(-/-) cells than from wild-type cells. These results suggest that BAX-dependent apoptosis may be used to initiate a new round of infection, most likely by releasing Chlamydia-containing apoptotic bodies from infected cells that could be internalized by neighboring uninfected cells. Nonetheless, infected Bax(-/-) cells die through necrosis, which is normally associated with inflammation, more often than infected wild-type cells. These studies were confirmed in mice infected intravaginally with C. muridarum; since the infection disappears more quickly from Bax(-/-) mice than from wild-type mice, secretion of proinflammatory cytokines is increased in Bax(-/-) mice, and large granulomas are present in the genital tract of Bax(-/-) mice. Taken together, these data suggest that chlamydia-induced apoptosis via BAX contributes to bacterial propagation and decreases inflammation. Bax deficiency results in lower infection and an increased inflammatory cytokine response associated with more severe pathology.


Assuntos
Apoptose , Chlamydia muridarum/metabolismo , Inflamação , Proteínas Proto-Oncogênicas c-bcl-2 , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/fisiologia , Animais , Infecções por Chlamydia/patologia , Feminino , Granuloma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Necrose , Proteínas Proto-Oncogênicas/metabolismo , Fatores de Tempo , Proteína X Associada a bcl-2
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