Katharina Ronacher

Publications (15) View all

• Source

  Available from: Léanie Kleynhans

  Article: THE CONTRACEPTIVE DEPO MEDROXYPROGESTERONE ACETATE IMPAIRS MYCOBACTERIAL CONTROL AND INHIBITS CYTOKINE SECRETION IN MICE INFECTED WITH M. TUBERCULOSIS.

  Léanie Kleynhans, Nelita Du Plessis, Nasiema Allie, Muazzam Jacobs, Martin Kidd, Paul D van Helden, Gerhard Walzl, Katharina Ronacher
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  ABSTRACT: The contraceptive depo medroxyprogesterone acetate (DMPA), with progestin as single active compound, possesses selective glucocorticoid activity and can alter the expression of glucocorticoid receptor regulated genes. We therefore propose that pharmacological doses of DMPA used for endocrine therapy could have significant immune modulatory effects and impact on susceptibility to, as well as clinical manifestation and outcome of infectious diseases. We investigated the effect of contraceptive doses of DMPA in two different murine Mycobacterium tuberculosis models. Multiplex bead array analysis revealed that DMPA altered serum cytokine levels of TNFα, G-CSF and6 IL-10 in C57BL/6 mice and IFNγ in BALB/c mice. DMPA also suppressed antigen specific production of TNFα, G-CSF, IL-10 and IL-6 and induced the production of IP-10 in C57BL/6 mice. In BALB/c mice, DMPA altered the antigen specific secretion of IFNγ, IL-17, GM-CSF, IL-6 and MCP-1. Furthermore we show that C57BL/6 mice treated with doses of DMPA, which result in serum concentrations similar to that observed in contraceptive users, have a significantly higher bacterial load in their lungs. Our data shows for the first time that DMPA impacts TB disease severity in a mouse model and that the effects of this contraceptive are not confined to infections of the genital tract. This could have major implications for the contraceptive policies not only in developing countries like South Africa, but worldwide.
  Infection and immunity 02/2013; · 4.21 Impact Factor
• Article: Distinct Phases of Blood Gene Expression Pattern Through Tuberculosis Treatment Reflect Modulation of the Humoral Immune Response.

  Jacqueline M Cliff, Ji-Sook Lee, Nicholas Constantinou, Jang-Eun Cho, Taane G Clark, Katharina Ronacher, Elizabeth C King, Pauline T Lukey, Ken Duncan, Paul D Van Helden, Gerhard Walzl, Hazel M Dockrell
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  ABSTRACT: Background. Accurate assessment of treatment efficacy would facilitate clinical trials of new antituberculosis drugs. We hypothesized that early alterations in peripheral immunity could be measured by gene expression profiling in tuberculosis patients undergoing successful conventional combination treatment.Methods. Ex vivo blood samples from 27 pulmonary tuberculosis patients were assayed at diagnosis and during treatment. RNA was processed and hybridized to Affymetrix GeneChips, to determine expression of over 47 000 transcripts.Results. There were significant ≥2-fold changes in expression of >4000 genes during treatment. Rapid, large-scale changes were detected, with down-regulated expression of 1261 genes within the first week, including inflammatory markers such as complement components C1q and C2. This was followed by slower changes in expression of different networks of genes, including a later increase in expression of B-cell markers, transcription factors, and signaling molecules.Conclusions. The fast initial down-regulation of expression of inflammatory mediators coincided with rapid killing of actively dividing bacilli, whereas slower delayed changes occurred as drugs acted on dormant bacilli and coincided with lung pathology resolution. Measurement of biosignatures during clinical trials of new drugs could be useful predictors of rapid bactericidal or sterilizing drug activity, and would expedite the licensing of new treatment regimens.
  The Journal of Infectious Diseases 08/2012; · 6.41 Impact Factor
• Source

  Available from: Francois van Loggerenberg

  Article: Symptomatic vaginal discharge is a poor predictor of sexually transmitted infections and genital tract inflammation in high-risk women in South Africa.

  Koleka Mlisana, Nivashnee Naicker, Lise Werner, Lindi Roberts, Francois van Loggerenberg, Cheryl Baxter, Jo-Ann S Passmore, Anneke C Grobler, A Willem Sturm, Carolyn Williamson, Katharina Ronacher, Gerhard Walzl, Salim S Abdool Karim
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  ABSTRACT: Diagnosis and treatment of sexually transmitted infections (STIs) is a public health priority, particularly in regions where the incidence of human immunodeficiency virus (HIV) infection is high. In most developing countries, STIs are managed syndromically. We assessed the adequacy of syndromic diagnosis of STIs, compared with laboratory diagnosis of STIs, and evaluated the association between STI diagnosis and the risk of HIV acquisition in a cohort of high-risk women. HIV-uninfected high-risk women (n = 242) were followed for 24 months. Symptoms of STIs were recorded, and laboratory diagnosis of common STI pathogens was conducted every 6 months. Forty-two cytokines were measured by Luminex in cervicovaginal lavage specimens at enrollment. Human immunodeficiency virus type 1 (HIV-1) infection was evaluated monthly. Only 12.3% of women (25 of 204) who had a laboratory-diagnosed, discharge-causing STI had clinically evident discharge. Vaginal discharge was thus a poor predictor of laboratory-diagnosed STIs (sensitivity, 12.3%; specificity, 93.8%). Cervicovaginal cytokine concentrations did not differ between women with asymptomatic STIs and those with symptomatic STIs and were elevated in women with asymptomatic STIs, compared with women with no STIs or bacterial vaginosis. Although laboratory-diagnosed STIs were associated with increased risk of HIV infection (hazard ratio, 3.3 [95% confidence interval, 1.5-7.2)], clinical symptoms were not. Syndromic STI diagnosis dependent on vaginal discharge was poorly predictive of laboratory-diagnosed STI. Laboratory-diagnosed STIs were associated with increased susceptibility to HIV acquisition, while vaginal discharge was not.
  The Journal of Infectious Diseases 04/2012; 206(1):6-14. · 6.41 Impact Factor
• Source

  Available from: Gerhard Walzl

  Article: Effect of standard tuberculosis treatment on plasma cytokine levels in patients with active pulmonary tuberculosis.

  Catherine Riou, Blas Perez Peixoto, Lindi Roberts, Katharina Ronacher, Gerhard Walzl, Claudia Manca, Roxana Rustomjee, Thuli Mthiyane, Dorothy Fallows, Clive M Gray, Gilla Kaplan
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  ABSTRACT: Sputum Mycobacterium tuberculosis (Mtb) culture is commonly used to assess response to antibiotic treatment in individuals with pulmonary tuberculosis (TB). Such techniques are constrained by the slow growth rate of Mtb, and more sensitive methods to monitor Mtb clearance are needed. The goal of this study was to evaluate changes in plasma cytokines in patients undergoing treatment for TB as a means of identifying candidate host markers associated with microbiologic response to therapy. Twenty-four plasma cytokines/chemokines were measured in 42 individuals diagnosed with active pulmonary TB, 52% were HIV co-infected. Individuals, undergoing a 26-week standard TB treatment, were followed longitudinally over 18 months and measurements were associated with HIV status and rates of sputum culture conversion. Plasma concentrations of interferon-inducible protein-10 (IP-10) and vascular endothelial growth factor (VEGF) were significantly reduced upon TB treatment, regardless of HIV status. By the end of treatment, IP-10 concentrations were significantly lower in HIV negative individuals when compared to HIV-positive individuals (p = 0.02). Moreover, in HIV negative patients, plasma VEGF concentrations, measured as early as 2-weeks post TB treatment initiation, positively correlated with the time of sputum conversion (p = 0.0017). No significant changes were observed in other studied immune mediators. These data suggest that VEGF plasma concentration, measured during early TB treatment, could represent a surrogate marker to monitor sputum culture conversion in HIV uninfected individuals.
  PLoS ONE 01/2012; 7(5):e36886. · 4.09 Impact Factor
• Article: Molecular bacterial load assay, a culture-free biomarker for rapid and accurate quantification of sputum Mycobacterium tuberculosis bacillary load during treatment.

  Isobella Honeyborne, Timothy D McHugh, Patrick P J Phillips, Selina Bannoo, Anna Bateson, Nora Carroll, Felicity M Perrin, Katharina Ronacher, Laura Wright, Paul D van Helden, Gerhard Walzl, Stephen H Gillespie
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  ABSTRACT: A molecular assay to quantify Mycobacterium tuberculosis is described. In vitro, 98% (n = 96) of sputum samples with a known number of bacilli (10(7) to 10(2) bacilli) could be enumerated within 0.5 log(10). In comparison to culture, the molecular bacterial load (MBL) assay is unaffected by other microorganisms present in the sample, results are obtained more quickly (within 24 h) and are seldom inhibited (0.7% samples), and the MBL assay critically shows the same biphasic decline as observed longitudinally during treatment. As a biomarker of treatment response, the MBL assay responds rapidly, with a mean decline in bacterial load for 111 subjects of 0.99 log(10) (95% confidence interval [95% CI], 0.81 to 1.17) after 3 days of chemotherapy. There was a significant association between the rate of bacterial decline during the same 3 days and bacilli ml(-1) sputum at day 0 (linear regression, P = 0.0003) and a 3.62 increased odds ratio of relapse for every 1 log(10) increase in pretreatment bacterial load (95% CI, 1.53 to 8.59).
  Journal of clinical microbiology 09/2011; 49(11):3905-11. · 4.16 Impact Factor