SUNScholar - Browsing by Author "Chegou, Novel N."

Browsing by Author "Chegou, Novel N."

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Africa-wide evaluation of host biomarkers in QuantiFERON supernatants for the diagnosis of pulmonary tuberculosis
(Nature Research, 2018-02-08) Chegou, Novel N.; Sutherland, Jayne S.; Namuganga, Anna-Ritah; Corstjens, Paul L. A. M.; Geluk, Annemieke; Gebremichael, Gebremedhin; Mendy, Joseph; Malherbe, Stephanus; Stanley, Kim; Van Der Spuy, Gian D.; Kriel, Magdalena; Loxton, Andre G.; Kriel, Belinda; Simukonda, Felanji; Bekele, Yonas; Sheehama, Jacob A.; Nelongo, Josefina; Van Der Vyver, Marieta; Gebrexabher, Atsbeha; Hailu, Habteyes; Esterhuyse, Maria M.; Rosenkrands, Ida; Aagard, Claus; Kidd, Martin; Kassa, Desta; Mihret, Adane; Howe, Rawleigh; Cliff, Jacqueline M.; Crampin, Amelia C.; Mayanja-Kizza, Harriet; Kaufmann, Stefan H. E.; Dockrell, Hazel M.; Ottenhoff, Tom H. M.; Walzl, Gerhard; AE-TBC consortium
We investigated host-derived biomarkers that were previously identified in QuantiFERON supernatants, in a large pan-African study. We recruited individuals presenting with symptoms of pulmonary TB at seven peripheral healthcare facilities in six African countries, prior to assessment for TB disease. We then evaluated the concentrations of 12 biomarkers in stored QuantiFERON supernatants using the Luminex platform. Based on laboratory, clinical and radiological findings and a pre-established algorithm, participants were classified as TB disease or other respiratory diseases(ORD). Of the 514 individuals included in the study, 179(34.8%) had TB disease, 274(51.5%) had ORD and 61(11.5%) had an uncertain diagnosis. A biosignature comprising unstimulated IFN-γ, MIP-1β, TGF-α and antigen-specific levels of TGF-α and VEGF, identified on a training sample set (n = 311), validated by diagnosing TB disease in the test set (n = 134) with an AUC of 0.81(95% CI, 0.76–0.86), corresponding to a sensitivity of 64.2%(95% CI, 49.7–76.5%) and specificity of 82.7%(95% CI, 72.4–89.9%). Host biomarkers detected in QuantiFERON supernatants can contribute to the diagnosis of active TB disease amongst people presenting with symptoms requiring investigation for TB disease, regardless of HIV status or ethnicity in Africa.
Analysis of host responses to secreted, latent and reactivation Mycobacterium tuberculosis antigens in a multi-site study of subjects with different TB and HIV infection states in sub-Saharan Africa
(Public Library of Science, 2013-09-10) Sutherland, Jayne S.; Lalor, Maeve K.; Black, Gillian F.; Ambrose, Lyn R.; Loxton, Andre G.; Chegou, Novel N.; Kassa, Desta; Mihret, Adane; Howe, Rawleigh; Mayanja-Kizza, Harriet; Gomez, Marie P.; Donkor, Simon; Franken, Kees; Boom, W. Henry; Thiel, Bonnie A.; Crampin, Amelia C.; Hanekom, Willem; Klein, Michel R.; Parida, Shreemanta K.; Ota, Martin; Walzl, Gerhard; Ottenhoff, Tom H. M.; Dockrell, Hazel M.; Kaufmann, Stefan H. E.
Background: Tuberculosis (TB) remains a global health threat with 9 million new cases and 1.4 million deaths per year. In order to develop a protective vaccine, we need to define the antigens expressed by Mycobacterium tuberculosis (Mtb), which are relevant to protective immunity in high-endemic areas. Methods: We analysed responses to 23 Mtb antigens in a total of 1247 subjects with different HIV and TB status across 5 geographically diverse sites in Africa (South Africa, The Gambia, Ethiopia, Malawi and Uganda). We used a 7-day whole blood assay followed by IFN-γ ELISA on the supernatants. Antigens included PPD, ESAT-6 and Ag85B (dominant antigens) together with novel resuscitation-promoting factors (rpf), reactivation proteins, latency (Mtb DosR regulon-encoded) antigens, starvation-induced antigens and secreted antigens. Results: There was variation between sites in responses to the antigens, presumably due to underlying genetic and environmental differences. When results from all sites were combined, HIV- subjects with active TB showed significantly lower responses compared to both TST- and TST+ contacts to latency antigens (Rv0569, Rv1733, Rv1735, Rv1737) and the rpf Rv0867; whilst responses to ESAT-6/CFP-10 fusion protein (EC), PPD, Rv2029, TB10.3, and TB10.4 were significantly higher in TST+ contacts (LTBI) compared to TB and TST- contacts fewer differences were seen in subjects with HIV co-infection, with responses to the mitogen PHA significantly lower in subjects with active TB compared to those with LTBI and no difference with any antigen. Conclusions: Our multi-site study design for testing novel Mtb antigens revealed promising antigens for future vaccine development. The IFN-γ ELISA is a cheap and useful tool for screening potential antigenicity in subjects with different ethnic backgrounds and across a spectrum of TB and HIV infection states. Analysis of cytokines other than IFN-γ is currently on-going to determine correlates of protection, which may be useful for vaccine efficacy trials.
Application of cerebrospinal fluid host protein biosignatures in the diagnosis of tuberculous meningitis in children from a high burden setting
(Hindawi, 2019-04) Manyelo, Charles M.; Solomons, Regan; Snyders, Candice I.; Manngo, Portia M.; Mutavhatsindi, Hygon; Kriel, Belinda; Stanley, Kim; Walzl, Gerhard; Chegou, Novel N.
Background. The diagnosis of tuberculous meningitis (TBM) especially in children is challenging. New tests are urgently needed for the diagnosis of the disease, especially in resource-limited settings. Methods. We collected cerebrospinal fluid (CSF) samples from children presenting with symptoms requiring investigation for meningitis at a tertiary hospital in Cape Town, South Africa. Children were later classified as TBM or no TBM using published case definitions. Using a multiplex platform, we investigated the concentrations of biomarkers comprising a previously established 3-marker biosignature (VEGF, IL-13, and LL-37) and other potentially useful host biomarkers as diagnostic candidates for TBM. Findings. Out of 47 children, age, 3 months to 13 years, 23 were diagnosed with TBM and six (16%) were HIV-infected. We validated the previously identified CSF biosignature (sensitivity of 95.7% (95% CI, 79.0-99.2%) and specificity of 37.5% (95% CI, 21.2-57.3%)). However, substitution of IL-13 and LL-37 with IFN-γ and MPO, respectively, resulted in improved accuracy (area under the ROC curve (AUC) = 0 97, 95% CI, 0.92-1.00, up to 91.3% (21/23) sensitivity and up to 100% (24/24) specificity). An alternative four-marker biosignature (sICAM-1, MPO, CXCL8, and IFN-γ) also showed potential, with an AUC of 0.97. Conclusion. We validated a previously identified CSF biosignature and showed that refinement of this biosignature by incorporation of other biomarkers diagnosed TBM with high accuracy. Incorporation of these biomarkers into a point-of-care or bedside diagnostic test platform may result in the improved management of TBM in children.
CCL1 and IL-2Ra differentiate Tuberculosis disease from latent infection Irrespective of HIV infection in low TB burden countries
(ElsevierLtd, 2021-10) Chendi, Bih H.; Tveiten, Hallgeir; Snyders, Candice I.; Tonby, Kristian; Jenum, Synne; Nielsen, Susanne Dam; Hove-Skovsgaard, Malene; Walzl, Gerhard; Chegou, Novel N.; Dyrhol-Riise, Anne M
Objectives: To evaluate the performance of selected host immunological biomarkers in differentiating tu- berculosis (TB) disease from latent TB infection (LTBI) in HIV uninfected and infected individuals enrolled in TB low-burden countries. Design: Participants with TB disease ( N = 85) and LTBI ( N = 150) were recruited from prospective co- horts at hospitals in Norway and Denmark. Plasma concentrations of 54 host markers were assessed by Luminex multiplex immunoassays. Using receiver operator characteristic curves and general discriminant analysis, we determined the abilities of individual and combined biomarkers to discriminate between TB disease and LTBI including when patients were stratified according to HIV infection status. Results: Regardless of the groups compared, CCL1 and IL-2Ra were the most accurate single biomarkers in differentiating TB disease from LTBI. Regardless of HIV status, a 4-marker signature (CCL1 + RANTES + CRP + MIP-1 α) derived from a training set ( n = 155) differentiated TB disease from LTBI in the test set ( n = 67) with a sensitivity of 56.0% (95% CI, 34.9–75.6) and a specificity of 85.7% (95% CI, 71.5–94.6). A 5-marker signature derived from the HIV uninfected group (CCL1 + RANTES + MIP- 1 α+ procalcitonin + IP-10) performed in HIV-infected individuals with a sensitivity of 75.0% and a speci- ficity of 96.7% after leave-one-out cross validation. A 2-marker signature (CCL1 + TNF- α) identified in HIV- infected persons performed in HIV-uninfected with a sensitivity and specificity of 66.7% and 100% respec- tively in the test set. Conclusions: Plasma CCL1 and IL-2Ra have potential as biomarkers for differentiating TB disease from LTBI in low TB burden settings unaffected by HIV infection. Combinations between these and other biomarkers in bio-signatures for global use warrant further exploration.
Changes in host immune–endocrine relationships during tuberculosis treatment in patients with cured and failed treatment outcomes
(Frontiers Media, 2017) Kleynhans, Leanie; Ruzive, Sheena; Ehlers, Lizaan; Thiart, Lani; Chegou, Novel N.; Conradie, Magda; Kriel, Magdalena; Kim Stanley; Van Der Spuy, Gian D.; Kidd, Martin; Van Helden; Walzl, Gerhard; Ronacher, Katharina
A bidirectional communication between the immune and endocrine systems exists and facilitates optimum responses in the host during infections. This is in part achieved through changes in secretion patterns of hypothalamic hormones induced by inflammatory cytokines. The aim of this study was to elucidate the immune–endocrine alterations during tuberculosis (TB) treatment in patients with cured and failed TB treatment outcomes. Blood samples were collected from 27 cured and 10 failed patients and hormone as well as cytokine concentrations quantified at baseline, week 4, and month 6 of TB treatment. Hormone profiles of the two treatment outcome groups were different from each other prior to as well as during TB treatment. Treatment response effects were observed for cortisol, estradiol, T3, T4 ghrelin, leptin, amylin, adiponectin, and dehydroepiandrosterone (DHEA). Trends suggest that T4, amylin, and DHEA concentrations were different between treatment outcomes, although these did not reach statistical significance. Relationships between endocrine and inflammatory markers and the biological pathways involved differed between cured and failed treatment patients. These results highlight the complex interaction between the endocrine and immune system during active TB disease and throughout treatment and suggest that endocrine markers in conjunction with inflammatory markers may be useful in predicting unfavorable treatment outcomes.
Chronic obstructive pulmonary disease (COPD) : neutrophils, macrophages and lymphocytes in patients with anterior tuberculosis compared to tobacco related COPD
(BioMed Central, 2018-03-27) Guiedem, Elise; Ikomey, George Mondinde; Nkenfou, Celine; Walter, Pefura-Yone Eric; Mesembe, Martha; Chegou, Novel N.; Jacobs, Graeme Brendon; Okomo Assoumou, Marie Claire
Objective: The inflammatory profile of chronic obstructive pulmonary disease (COPD) related to tobacco is known in certain studies while that of the post tuberculosis form is not yet known. This study aimed to evaluate the levels of neutrophils, macrophages and lymphocytes cells in sputum of COPD patients with history of smoking or anterior tuberculosis. Enumeration of cells in samples was analyzed using standard microscopy. Results: We enrolled 92 participants, 46 (50%) were COPD subjects comprising 22 (47.83%) smokers and 24 (52.17%) with anterior tuberculosis while 46 (50%) healthy persons constituted the control group. The levels of neutrophils, lymphocytes and monocytes were statistically higher in COPD patients compared to the control group with p-values of 0.0001 respectively. Neutrophils levels were higher in COPD patients with history of tobacco than in COPD patients with anterior tuberculosis with a mean rate of 4.72 × 106/ml and 2.48 × 106/ml respectively (p = 0.04). The monocytes and lymphocytes levels were not statistically different between the two sub-groups of COPD patients with p-value of 0.052 and 0.91 respectively. Neutrophils are the only inflammatory cells that were significantly higher in COPD patients with history of smoking as compared to COPD patients with anterior tuberculosis.
The combination of red palm oil and rooibos show anti-inflammatory effects in rats
(BioMed Central, 2014-12) Katengua-Thamahane, Emma; Marnewick, Jeanine L.; Ajuwon, Olawale R.; Chegou, Novel N.; Szucs, Gergo; Ferdinandy, Peter; Csont, Tamas; Csonka, Csaba; Van Rooyen, Jacques
Background Red palm oil (RPO) and rooibos have been shown to exhibit cardioprotective properties. RPO is rich in essential fatty acids and fat soluble antioxidants while rooibos contains polyphenolic compounds with a unique composition of flavonoids. They exert their biological effects in different cellular compartments. Therefore the combination of these two natural food compounds has the potential to enhance the spectrum of available dietary antioxidants in different cellular compartments, which could result in an enhanced protection against certain pathological conditions such as inflammation. Methods Male Wistar rats weighing 150-200 g were supplemented with RPO, rooibos or their combination for 28 days. The Langendorff system and the lipoposaccharide (LPS)-induced inflammatory model were used to establish if RPO and rooibos, when supplemented alone or in combination, will reverse the negative effects of LPS on cardiac function at baseline. The effect of dietary intervention was also investigated on modulation of pro-inflammatory and anti-inflammatory cytokines in plasma and myocardial tissue. Results and discussion The LPS resulted in induction of systemic inflammation as evidenced by increased levels of IL-1β in plasma of LPS-treated rats compared to their non-treated control counterparts. Dietary supplementation and LPS treatment did not have an effect on baseline cardiac functional parameters. However, the elevation of IL-1β levels in plasma of LPS-induced rats consuming either RPO or rooibos alone were paralleled with increased levels of the anti-inflammatory cytokine, IL-10. The combination of rooibos and RPO was associated with enhanced endogenous production of myocardial IL-10 in LPS-induced rats. Conclusion The results of this study indicate that RPO and rooibos when supplemented individually showed anti-inflammatory effect at systemic level while their combination exhibited an enhanced anti-inflammatory effect in the myocardial tissue. Therefore, the findings in the current study argue that the combination of these two natural food substances could be beneficial in clinically relevant conditions where inflammation plays a role.
Current use and acceptability of novel diagnostic tests for active tuberculosis : a worldwide survey
(Sociedade Brasileira de Pneumologia e Tisiologia, 2017-09-03) Amicosante, Massimo; D’Ambrosio, Lia; Munoz, Marcela; Mello, Fernanda Carvalho de Queiroz; Tebruegge, Marc; Chegou, Novel N.; Seghrouchni, Fouad; Centis, Rosella; Goletti, Delia; Bothamley, Graham; Migliori, Giovanni Battista; TB Diagnostic Survey Working Group
Objective: To determine the current use and potential acceptance (by tuberculosis experts worldwide) of novel rapid tests for the diagnosis of tuberculosis that are in line with World Health Organization target product profiles. Methods: A multilingual survey was disseminated online between July and November of 2016. Results: A total of 723 individuals from 114 countries responded to the survey. Smear microscopy was the most commonly used rapid tuberculosis test (available to 90.9% of the respondents), followed by molecular assays (available to 70.7%). Only a small proportion of the respondents in middle- and low-income countries had access to interferon-gamma-release assays. Serological and lateral flow immunoassays were used by more than a quarter (25.4%) of the respondents. Among the respondents who had access to molecular tests, 46.7% were using the Xpert assay overall, that proportion being higher in lower middle-income countries (55.6%) and low-income countries (76.6%). The data also suggest that there was some alignment of pricing for molecular assays. Respondents stated they would accept novel rapid tuberculosis tests if available, including molecular assays (acceptable to 86.0%) or biomarker-based serological assays (acceptable to 81.7%). Simple biomarker-based assays were more commonly deemed acceptable in middle- and lowincome countries. Conclusions: Second-generation molecular assays have become more widely available in high- and low-resource settings. However, the development of novel rapid tuberculosis tests continues to be considered important by tuberculosis experts. Our data also underscore the need for additional training and education of end users.
Detection of a combination of serum IgG and IgA antibodies against selected mycobacterial targets provides promising diagnostic signatures for active TB
(Impact Journals, 2017-03-24) Awoniyi, Dolapo O.; Baumann, Ralf; Chegou, Novel N.; Kriel, Belinda; Jacobs, Ruschca; Kidd, Martin; Loxton, Andre G.; Kaempfer, Susanne; Singh, Mahavir; Walzl, Gerhard
ENGLISH ABSTRACT: Immunoglobulin G (IgG) based tests for the diagnosis of active tuberculosis (TB) disease often show a lack of specificity in TB endemic regions, which is mainly due to a high background prevalence of LTBI. Here, we investigated the combined performance of the responses of different Ig classes to selected mycobacterial antigens in primary healthcare clinic attendees with signs and symptoms suggestive of TB. The sensitivity and specificity of IgA, IgG and/or IgM to LAM and 7 mycobacterial protein antigens (ESAT-6, Tpx, PstS1, AlaDH, MPT64, 16kDa and 19kDa) and 2 antigen combinations (TUB, TB-LTBI) in the plasma of 63 individuals who underwent diagnostic work-up for TB after presenting with symptoms and signs compatible with possible active TB were evaluated. Active TB was excluded in 42 individuals of whom 21 has LTBI whereas active TB was confirmed in 21 patients of whom 19 had a follow-up blood draw at the end of 6-month anti-TB treatment. The leading single serodiagnostic markers to differentiate between the presence or absence of active TB were anti-16 kDa IgA, anti-MPT64 IgA with sensitivity and specificity of 90%/90% and 95%/90%, respectively. The combined use of 3 or 4 antibodies further improved this performance to accuracies above 95%. After successful completion of anti-TB treatment at month 6, the levels of 16 kDa IgA and 16 kDa IgM dropped significantly whereas LAM IgG and TB-LTBI IgG increased. These results show the potential of extending investigation of anti-tuberculous IgG responses to include IgM and IgA responses against selected protein and non-protein antigens in differentiating active TB from other respiratory diseases in TB endemic settings.
Diagnostic potential of novel salivary host biomarkers as candidates for the immunological diagnosis of tuberculosis disease and monitoring of tuberculosis treatment response
(Public Library of Science, 2016-08-03) Jacobs, Ruschca; Maasdorp, Elizna; Malherbe, Stephanus; Loxton, Andre G.; Stanley, Kim; Van Der Spuy, Gian; Walzl, Gerhard; Chegou, Novel N.
Background: There is an urgent need for new tools for the early diagnosis of TB disease and monitoring of the response to treatment, especially in resource-constrained settings. We investigated the usefulness of host markers detected in saliva as candidate biomarkers for the immunological diagnosis of TB disease and monitoring of treatment response. Methods: We prospectively collected saliva samples from 51 individuals that presented with signs and symptoms suggestive of TB disease at a health centre in Cape Town, South Africa, prior to the establishment of a clinical diagnosis. Patients were later classified as having TB disease or other respiratory disease (ORD), using a combination of clinical, radiological and laboratory findings. We evaluated the concentrations of 69 host markers in saliva samples using a multiplex cytokine platform, and assessed the diagnostic potentials of these markers by receiver operator characteristics (ROC) curve analysis, and general discriminant analysis. Results: Out of the 51 study participants, 18 (35.4%) were diagnosed with TB disease and 12 (23.5%) were HIV infected. Only two of the 69 host markers that were evaluated (IL-16 and IL-23) diagnosed TB disease individually with area under the ROC curve ≥0.70. A five-marker biosignature comprising of IL-1β, IL-23, ECM-1, HCC1 and fibrinogen diagnosed TB disease with a sensitivity of 88.9% (95% CI,76.7–99.9%) and specificity of 89.7% (95% CI, 60.4–96.6%) after leave-one-out cross validation, regardless of HIV infection status. Eight-marker biosignatures performed with a sensitivity of 100% (95% CI, 83.2–100%) and specificity of 95% (95% CI, 68.1–99.9%) in the absence of HIV infection. Furthermore, the concentrations of 11 of the markers changed during treatment, indicating that they may be useful in monitoring of TB treatment response. Conclusion: We have identified novel salivary biosignatures which may be useful in the diagnosis of TB disease and monitoring of the response to TB treatment. Our findings require further validation in larger studies before these biosignatures could be considered for point-of-care screening test development.
Differential expression of host biomarkers in saliva and serum samples from individuals with suspected pulmonary tuberculosis
(Hindawi Publishing Corporation, 2013-09) Phalane, Khutso G.; Kriel, Magdalena; Loxton, Andre G.; Menezes, Angela; Stanley, Kim; Van der Spuy, Gian D.; Walzl, Gerhard; Chegou, Novel N.
The diagnosis of tuberculosis remains challenging in individuals with difficulty in providing good quality sputum samples such as children. Host biosignatures of inflammatory markers may be valuable in such cases, especially if they are based on more easily obtainable samples such as saliva. To explore the potential of saliva as an alternative sample in tuberculosis diagnostic/biomarker investigations, we evaluated the levels of 33 hostmarkers in saliva samples fromindividuals presenting with pulmonary tuberculosis symptoms and compared them to those obtained in serum. Of the 38 individuals included in the study, tuberculosis disease was confirmed in 11 (28.9%) by sputum culture. In both the tuberculosis cases and noncases, the levels of most markers were above the minimum detectable limit in both sample types, but there was no consistent pattern regarding the ratio ofmarkers in serum/saliva. Fractalkine, IL-17, IL-6, IL-9, MIP-1𝛽�, CRP, VEGF, and IL-5 levels in saliva and IL-6, IL-2, SAP, and SAA levels in serum were significantly higher in tuberculosis patients (𝑃� < 0.05). These preliminary data indicate that there are significant differences in the levels of host markers expressed in saliva in comparison to those expressed in serumand that inflammatory markers in both sample types are potential diagnostic candidates for tuberculosis disease.
Effects of Anchomanes difformis on inflammation, apoptosis, and organ toxicity in STZ-induced diabetic cardiomyopathy
(MDPI, 2020-02-08) Alabi, Toyin D.; Chegou, Novel N.; Brooks, Nicole L.; Oguntibeju, Oluwafemi O.
ENGLISH ABSTRACT: Persistent hyperglycemia is known to cause enhanced generation of reactive oxygen species in diabetes. Several inflammatory cytokines are induced by oxidative stress, and their release also leads to increased oxidative stress; this makes oxidative stress one of the important factors in the development of chronic inflammation and other immune responses. These have been implicated in the development of diabetic complications such as nephropathy and cardiomyopathy. Anchomanes difformis has been shown to possess antioxidant and anti-inflammatory potentials. The present study investigated the immunomodulatory potential and the antiapoptotic ability of Anchomanes difformis to ameliorate heart toxicity and injury in type II diabetes. Two weeks of fructose (10%) administration followed by single intraperitoneal injection of streptozotocin (40 mg/kg) were used to induce type II diabetes in male Wistar rats. Leaf extract (aqueous) of Anchomanes difformis (200 and 400 mg/kg) was administered orally for six weeks. Blood glucose concentrations and body weights before and after interventions were determined. Interleukin (IL)-1β, IL-6, IL-10, IL-18, monocyte chemoattractant protein 1 (MCP-1), and tumor necrosis factor alpha (TNFα) were measured in the heart homogenates. Catalase (CAT), superoxide dismutase (SOD), total protein, oxygen radical absorbance capacity (ORAC), ferric reducing antioxidant power (FRAP), thiobarbituric acid reactive substances (TBARS), and heart-type fatty acid-binding protein (H-FABP) levels were determined. Expressions of transcription factors (Nrf 2 and NFkB/p65) and apoptotic markers were also investigated in the heart. Anchomanes difformis administration reduced pro-inflammatory cytokines, increased anti-inflammatory markers, and enhanced antioxidant defense in the heart of diabetic treated animals. Anchomanes difformis is a new, promising therapeutic agent that can be explored for the treatment of pathological conditions associated with immune responses and will be a useful tool in the management of associated diabetic complications.
The functional response of B cells to antigenic stimulation : a preliminary report of latent tuberculosis
(Public Library of Science, 2016-04) Du Plessis, Willem J.; Kleynhans, Leanie; Du Plessis, Nelita; Stanley, Kim; Malherbe, Stephanus T.; Maasdorp, Elizna; Ronacher, Katharina; Chegou, Novel N.; Walzl, Gerhard; Loxton, Andre G.
Mycobacterium tuberculosis (M.tb) remains a successful pathogen, causing tuberculosis disease numbers to constantly increase. Although great progress has been made in delineating the disease, the host-pathogen interaction is incompletely described. B cells have shown to function as both effectors and regulators of immunity via non-humoral methods in both innate and adaptive immune settings. Here we assessed specific B cell functional interaction following stimulation with a broad range of antigens within the LTBI milieu. Our results indicate that B cells readily produce pro- and anti-inflammatory cytokines (including IL-1β, IL-10, IL-17, IL-21 and TNF-α) in response to stimulation. TLR4 and TLR9 based stimulations achieved the greatest secreted cytokine-production response and BCG stimulation displayed a clear preference for inducing IL-1β production. We also show that the cytokines produced by B cells are implicated strongly in cell-mediated communication and that plasma (memory) B cells (CD19+CD27+CD138+) is the subset with the greatest contribution to cytokine production. Collectively our data provides insight into B cell responses, where they are implicated in and quantifies responses from specific B cell phenotypes. These findings warrant further functional B cell research with a focus on specific B cell phenotypes under conditions of active TB disease to further our knowledge about the contribution of various cell subsets which could have implications for future vaccine development or refined B cell orientated treatment in the health setting.
Host cytokine responses induced after overnight stimulation with novel M. tuberculosis infection phase-dependent antigens show promise as diagnostic candidates for TB disease
(PLoS, 2014-07-15) Essone, Paulin N.; Chegou, Novel N.; Loxton, Andre G.; Stanley, Kim; Kriel, Magdalena; Van der Spuy, Gian; Franken, Kees L.; Ottenhoff, Tom H.; Walzl, Gerhard
Background: We previously identified Mycobacterium tuberculosis (M.tb) antigen-induced host markers that showed promise as TB diagnostic candidates in 7-day whole blood culture supernatants. The aim of the present study was to evaluate the utility of these markers further, and cross-compare results with short-term antigen stimulated and unstimulated culture supernatants. Methods: We recruited 15 culture confirmed TB cases and 15 non-TB cases from a high-TB endemic community in Cape Town, South Africa into a pilot case-control study from an on-going larger study. Blood samples collected from study participants were stimulated with 4 M.tb antigens that were previously identified as promising (ESAT6/CFP10 (early secreted), Rv2029c (latency), Rv2032 (latency) and Rv2389c (rpf)) in a 7-day or overnight culture assay. Supernatants were also collected form the standard QuantiFERON In Tube (QFT-IT) test. The levels of 26 host markers were evaluated in the three culture supernatants using the Luminex platform. Results: The unstimulated levels of CRP, Serum amyloid P (SAP) and serum amyloid A (SAA) and ESAT-6/CFP-10 specific IP-10 and SAA were amongst the best discriminatory markers in all 3 assays, ascertaining TB with AUC of 72–84%. Four-marker models accurately classified up to 92%, 100% and 100% of study participants in the overnight, 7-day and Quantiferon culture supernatants, respectively, after leave-one-out cross validation. Conclusion: Unstimulated and antigen-specific levels of CRP, SAA, IP-10, MMP-2 and sCD40L hold promise as diagnostic candidates for TB disease in short-term stimulation assays. Larger studies are required to validate these findings but the data suggest that antigen-specific cytokine production and in particular mutimarker biosignatures might contribute to future diagnostic strategies.
Host markers in Quantiferon supernatants differentiate active TB from latent TB infection : preliminary report
(BioMed Central, 2009-05) Chegou, Novel N.; Black, Gillian F.; Kidd, Martin; Van Helden, Paul D.; Walzl, Gerhard
Background: Interferon gamma release assays, including the QuantiFERON® TB Gold In Tube (QFT) have been shown to be accurate in diagnosing Mycobacterium tuberculosis infection. These assays however, do not discriminate between latent TB infection (LTBI) and active TB disease. Methods: We recruited twenty-three pulmonary TB patients and 34 household contacts from Cape Town, South Africa and performed the QFT test. To investigate the ability of new host markers to differentiate between LTBI and active TB, levels of 29 biomarkers in QFT supernatants were evaluated using a Luminex multiplex cytokine assay. Results: Eight out of 29 biomarkers distinguished active TB from LTBI in a pilot study. Baseline levels of epidermal growth factor (EGF) soluble CD40 ligand (sCD40L), antigen stimulated levels of EGF, and the background corrected antigen stimulated levels of EGF and macrophage inflammatory protein (MIP)-1β were the most informative single markers for differentiation between TB disease and LTBI, with AUCs of 0.88, 0.84, 0.87, 0.90 and 0.79 respectively. The combination of EGF and MIP-1β predicted 96% of active TB cases and 92% of LTBIs. Combinations between EGF, sCD40L, VEGF, TGF-α and IL-1α also showed potential to differentiate between TB infection states. EGF, VEGF, TGF-α and sCD40L levels were higher in TB patients. Conclusion: These preliminary data suggest that active TB may be accurately differentiated from LTBI utilizing adaptations of the commercial QFT test that includes measurement of EGF, sCD40L, MIP-1β, VEGF, TGF-α or IL-1α in supernatants from QFT assays. This approach holds promise for development as a rapid diagnostic test for active TB.
Identification of novel host biomarkers in plasma as candidates for the immunodiagnosis of tuberculosis disease and monitoring of tuberculosis treatment response
(Impact Journals, 2016-08-19) Jacobs, Ruschca; Malherbe, Stephanus; Loxton, Andre G.; Stanley, Kim; Van Der Spuy, Gian; Walzl, Gerhard; Chegou, Novel N.
ENGLISH ABSTRACT: There is an urgent need for new tools for the rapid diagnosis of tuberculosis disease. We evaluated the potentials of 74 host markers as biomarkers for the immunological diagnosis of tuberculosis and monitoring of treatment response. Fifty-five individuals that presented with signs and symptoms requiring investigation for tuberculosis disease were prospectively recruited prior to clinical diagnosis, at a health centre in Cape Town, South Africa. Patients were later classified as having tuberculosis disease or other respiratory diseases (ORD) using a combination of clinical, radiological and laboratory findings. Out of 74 host markers that were evaluated in plasma samples from study participants using a multiplex platform, 18 showed potential as tuberculosis diagnostic candidates with the most promising being NCAM, CRP, SAP, IP-10, ferritin, TPA, I-309, and MIG, which diagnosed tuberculosis disease individually, with area under the ROC curve ≥0.80. Six-marker biosignatures containing NCAM diagnosed tuberculosis disease with a sensitivity of 100% (95%CI, 86.3-100%) and specificity of 89.3% (95%CI, 67.6-97.3%) irrespective of HIV status, and 100% accuracy in the absence of HIV infection. Furthermore, the concentrations of 11 of these proteins changed with treatment, thereby indicating that they may be useful in monitoring of the response to tuberculosis treatment. Our findings have potential to be translated into a point-of-care screening test for tuberculosis, after future validation studies.
Kolaviron, a Garcinia biflavonoid complex ameliorates hyperglycemia-mediated hepatic injury in rats via suppression of inflammatory responses
(BioMed Central, 2013-12) Ayepola, Omolola R.; Chegou, Novel N.; Brooks, Nicole L.; Oguntibeju, Oluwafemi O.
Background: Chronic inflammation plays a crucial role in hyperglycemia-induced liver injury. Kolaviron (KV), a natural biflavonoid from Garcinia kola seeds have been shown to possess anti- inflammatory properties which has not been explored in diabetes. To our knowledge, this is the first study to investigate the effect of KV on pro-inflammatory proteins in the liver of diabetic rats. Methods: Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ) (50 mg/kg) in male Wistar rats. Kolaviron (100 mg/kg) was administered orally five times a week for six weeks. The concentrations of cytokines and chemokine were measured using Bio-plex Pro™ magnetic bead-based assays (Bio-Rad Laboratories, Hercules, USA). Plasma glucose and serum biomarkers of liver dysfunction were analyzed with diagnostic kits in an automated clinical chemistry analyzer. Insulin concentration was estimated by radioimmunoassay (RIA). Result: Kolaviron (100mg/kg) treatment significantly ameliorated hyperglycemia and liver dysfunction. Serum levels of hepatic marker enzymes were significantly reduced in kolaviron treated diabetic rats. Kolaviron prevented diabetes induced increase in the hepatic levels of proinflammatory cytokines; interleukin (IL)-1beta, IL-6, tumour necrosis factor (TNF-α) and monocyte chemotactic protein (MCP-1). Conclusion: The results of this study demonstrate that the hepatoprotective effects of kolaviron in diabetic rats may be partly associated with its modulating effect on inflammatory responses.
Long-term impact of neonatal intake of oleanolic acid on the expression of AMP-activated protein kinase, adiponectin and inflammatory cytokines in rats fed with a high fructose diet
(MDPI, 2019-01-22) Matumba, Mashudu Given; Ayeleso, Ademola Olabode; Nyakudya, Trevor; Erlwanger, Kennedy; Chegou, Novel N.; Mukwevho, Emmanuel
ENGLISH ABSTRACT: AMP-activated protein kinase (AMPK) is known to regulate both glucose and lipid metabolism, which play vital roles in the development of metabolic syndrome. One way of regulating AMPK is through hormonal activation using adiponectin. Patients diagnosed with type-2 diabetes (T2D) and obesity exhibit low adiponectin concentration levels in their blood. Moreover, studies have also shown that inflammatory processes play a significant role in the etiology of these metabolic diseases. In this study, the long-term effects of neonatal intake of oleanolic acid (OA) on the AMPK gene, genes associated with glucose transport and lipid metabolism, adiponectin levels, and inflammatory biomarkers in rats fed with a high fructose diet were investigated. Seven day old pups were randomly divided into five groups and treated as follows; 0.5% dimethylsulphoxide v/v in distilled water vehicle control (CON), oleanolic acid (OA, 60 mg/kg), high fructose diet (HF, 20% w/v), high fructose diet combined with oleanolic acid (HF+OA), and high fructose diet combined with metformin (HF+MET, 500 mg/kg). The treatments were administered once daily until day 14. The rats were then weaned at day 21 and fed standard rat chow and had ad libitum access to plain drinking water until day 112. The quantitative polymerase chain reaction (qPCR) was used to analyze the gene expressions of AMPK, Glut-4, Cpt-1, AdipoR1, AdipoR2, TNF-α, and IL-6 in the skeletal muscles. Bio-Plex Pro magnetic bead-based assay was used to measure plasma levels of inflammatory markers (TNF-α, IL-6, VEGF, and MCP-1) while ELISA kits were used to measure adiponectin concentration in blood plasma. The results obtained in this study showed that neonatal supplementation with OA significantly increased AMPK gene expression approximately ~4-fold in OA fed rats compared to those that were fed with HF alone. In addition, glut-4 gene expression was also significantly higher in the OA treatment group compared to all the other experimental groups except the CON group whereas Cpt-1 gene was more expressed when OA was administered alone. Together, these results indicated that OA can play a role in glucose and lipid metabolism gene regulation. Furthermore, the results showed that the OA group had ~1.5-fold increase in adiponectin concentration when comparedto the HF group. Moreover, HF increased levels of inflammatory cytokines, which was attenuated by neonatal administration of OA. Plasma concentration and gene expression in the skeletal muscle for TNF-α and IL-6 were significantly increased in rats that were treated with HF alone when compared to all the other groups. On the contrary, the high levels of TNF-α and IL-6 were reduced when OA was administered. These findings suggest that intake of oleanolic acid during the neonatal stage of development could be a potential strategic intervention for the long-term prevention of metabolic diseases such as T2D and obesity.
Modulation of inflammatory cytokines and islet morphology as therapeutic mechanisms of Basella alba in streptozotocin-induced diabetic rats
(Korean Society of Toxicology, 2018) Arokoyo, Dennis S.; Oyeyipo, Ibukun P.; Du Plessis, Stefan S.; Chegou, Novel N.; Aboua, Yapo G.
The mechanism of the previously reported antidiabetic effect of Basella alba is unknown. This study investigated the role of B. alba aqueous leaf extract in the modulation of inflammatory cytokines and islet morphology in streptozotocin-induced diabetic rats. Forty male Wistar rats, between 8 and 10 weeks old, were randomly divided into four groups (n = 10) and administered the following treatments: Healthy control (H-c) and Diabetic control (D-c) animals received normal saline 0.5 mL/100 g body weight daily, while Healthy Treatment (H-Ba) and Diabetic Treatment (D-Ba) rats received the plant extract 200 mg/kg body weight daily. All treatments were administered by oral gavage. Diabetes was induced in D-c and D-Ba rats by a single intraperitoneal injection of streptozotocin (55 mg/kg body). The body weight and fasting blood sugar (FBS) levels were recorded every week for 4 weeks, after which the rats were euthanized and samples collected for further analysis. After the experiment, FBS level was significantly reduced (p < 0.0001) in rats in the D-Ba group, but increased (p < 0.001) in rats in the D-c group. The absolute (H-c and H-Ba vs D-c, p < 0.05) and relative (D-Ba vs H-c, p < 0.05; D-Ba vs H-Ba, p < 0.005) weights of the pancreases were significantly higher after the experiment. The rats in the D-c group had significantly higher levels of serum interleukin-1β (p < 0.001 vs H-c; p < 0.05 vs H-Ba and D-Ba) and monocyte chemotactic protein-1 (p < 0.0001), but lower levels of interleukin-10 (p < 0.05) in comparison with the other groups. Histopathological examination revealed severe interstitial congestion, reduced islet area (p < 0.0001), and increased islet cell density in the D-c group compared with those in the D-Ba group. From these findings, it was concluded that the aqueous extract of B. alba stimulates the recovery of beta-islet morphology in streptozotocininduced diabetic rats by modulating the peripheral production of inflammatory cytokines.
Past and present approaches to diagnosis of active pulmonary tuberculosis
(Frontiers, 2021-09-23) Namuganga, Anna Ritah; Chegou, Novel N.; Mayanja-Kizza, Harriet
ENGLISH ABSTRACT: Tuberculosis disease continues to contribute to the mortality burden globally. Due to the several shortcomings of the available diagnostic methods, tuberculosis disease continues to spread. The difficulty to obtain sputum among the very ill patients and the children also affects the quick diagnosis of tuberculosis disease. These challenges warrant investigating different sample types that can provide results in a short time. Highlighted in this review are the approved pulmonary tuberculosis diagnostic methods and ongoing research to improve its diagnosis. We used the PRISMA guidelines for systematic reviews to search for studies that met the selection criteria for this review. In this review we found out that enormous biosignature research is ongoing to identify host biomarkers that can be used as predictors of active PTB disease. On top of this, more research was also being done to improve already existing diagnostic tests. Host markers required more optimization for use in different settings given their varying sensitivity and specificity in PTB endemic and non-endemic settings.

Browsing by Author "Chegou, Novel N."

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