RESUMO
Not all women infected with chlamydiae develop upper genital tract disease, but the reason(s) for this remains undefined. Host genetics and hormonal changes associated with the menstrual cycle are possible explanations for variable infection outcomes. It is also possible that disease severity depends on the virulence of the chlamydial inoculum. It is likely that the inoculum contains multiple genetic variants, differing in virulence. If the virulent variants dominate, then the individual is more likely to develop severe disease. Based on our previous studies, we hypothesized that the relative degree of virulence of a chlamydial population dictates the microRNA (miRNA) expression profile of the host, which, in turn, through regulation of the host inflammatory response, determines disease severity. Thus, we infected C57BL/6 mice with two populations of Chlamydia muridarum, each comprised of multiple genetic variants and differing in virulence: an attenuated strain (NiggA) and a virulent strain (NiggV). NiggA and NiggV elicited upper tract pathology in 54% and 91% of mice, respectively. miRNA expression analysis in NiggV-infected mice showed significant downregulation of miRNAs involved in dampening fibrosis (miR-200b, miR-200b-5p, and 200b-3p miR-200a-3p) and in transcriptional regulation of cytokine responses (miR-148a-3p, miR-152-3p, miR-132, and miR-212) and upregulation of profibrotic miRNAs (miR-142, and miR-147). Downregulated miRNAs were associated with increased expression of interleukin 8 (IL-8), CXCL2, IL-1ß, tumor necrosis factor alpha (TNF-α), and IL-6. Infection with NiggV but not NiggA led to decreased expression of Dicer and Ago 2, suggesting that NiggV interaction with host cells inhibits expression of the miRNA biogenesis machinery, leading to increased cytokine expression and pathology.
Assuntos
Infecções por Chlamydia/genética , Infecções por Chlamydia/microbiologia , Chlamydia muridarum/patogenicidade , MicroRNAs/genética , Virulência/genética , Animais , Linhagem Celular Tumoral , Citocinas/genética , Regulação para Baixo/genética , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Variação Genética/genética , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Transcrição Gênica/genética , Ativação Transcricional/genética , Regulação para Cima/genéticaRESUMO
Prostate cancer frequently progresses despite early diagnosis and appropriate treatment with radical prostatectomy and/or radiotherapy. The clinical utility of SELDI-TOF MS to identify serum biomarker patterns associated with prostate cancer progression was examined by analysis of the serum proteome of advanced prostate cancer patients receiving standard androgen deprivation therapy. Serum from advanced-stage patients receiving androgen deprivation therapy was profiled by SELDI-TOF MS. Group 1 patients (n=15) had stable prostate specific antigen (PSA) responses to treatment; Group 2 (n=16) had rising PSA levels. Spectra were subjected to peak identification following total ion current (TIC) normalization. Peak intensities with m/z between 2,000 and 20,000 were tested for group differences via Kruskal-Wallis tests, and assessed individually for PSA-independent associations with overall survival via covariate-adjusted Cox regressions. TIC normalization yielded 53 useable spectra; 119 peaks with m/z between 2,000 and 20,000 were identified. Seven peaks showed statistically significant (p<0.05) differences between PSA groups, and several other peaks showed significant associations with overall survival independent of PSA status. In summary, SELDI-TOF MS captured a specific biomarker profile associated with biochemical relapse and provided additional prognostic information regarding long-term survival, independent of clinical PSA status.
