Evaluation of cytokine responses against novel Mtb antigens as diagnostic markers for TB disease

Awoniyi, Dolapo Olaitan; Teuchert, Andrea; Sutherland, Jayne S.; Mayanja‐Kizza, Harriet; Howe, Rawleigh; Mihret, Adane; Loxton, André G.; Kassa, Desta; Crampin, Amelia C.; Dockrell, Hazel M.; Kidd, Martin; Rosenkrands, Ida; Geluk, Annemieke; Ottenhoff, Tom H. M.; Chegou, Novel N.; Walzl, Gerhard; Kriel, Magdalena; Spuy, Gian D. van der; Stanley, Kim; Malherbe, Stephanus T.; McAnda, Shirley; Kriel, Belinda; Phalane, Khutso G.; Essone, Paulin N.; Owolabi, Olumuyiwa; Sillah, Abdou K; Mendy, Joseph; Gindeh, Awa; Donkor, Simon; Togun, Toyin; Ota, Martin O. C.; Simukonda, Felanji; Amberbir, Alemayehu; Chilongo, Femia; Houben, Rein M. G. J.; Gebrezgeabher, Atsbeha; Mesfin, Getnet; Belay, Yohannes; Gebremichael, Gebremedhin; Alemayehu, Yodit; Vyver, Marieta van der; Amutenya, Faustina N.; Nelongo, Josefina N.; Monye, Lidia; Sheehama, Jacob; Iipinge, Scholastica; Namuganga, Anna Ritah; Muzanye, Grace; Nsereko, Mary; Peters, Pierre; Bekele, Yonas; Tessema, Bamlak; Lawrence, Yaacov Richard; Franken, Kees L. M. C.; Corstjens, Paul L. A. M.; Fat, Elisa M. Tjon Kon; Dood, Claudia J. de; Schip, Jolien J. van der Ploeg-van; Aagaard, Claus; Kaufmann, Stefan H. E.; Esterhuyse, Maria M.; Cliff, Jacqueline M.

doi:10.1016/j.jinf.2016.04.036

Cited by 25 publications

(12 citation statements)

References 45 publications

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“…However, the highest discriminative biomarker set was a complex co-expression of serum IL-18BP and IL-37 and IP-10 and IFN-γ, which may be useful in the rapid differentiation between ATB patients and LTBI individuals. Our data are consistent with the opinion that a complex biomarker panel is more robust than single markers for TB screening [5–7,26]. The set of seven serum biosignatures, comprised of apolipoprotein-A1, CRP, complement factor H, IFN-γ, IP-10, serum amyloid A and transthyretin, and a panel of five other serum biomarkers, including IFN-γ, IL-6, IL-18, CRP and MIG, showed potential in screening for TB in African countries endemic for HIV infection [8,27].…”

Section: Discussionsupporting

confidence: 91%

IL-18/IL-37/IP-10 signalling complex as a potential biomarker for discriminating active and latent TB

et al. 2019

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BackgroundCurrently, there are serious limitations in the direct diagnosis of active tuberculosis (ATB). We evaluated the levels of the IL-18/IL-37/IP-10 signalling complex proteins in Mycobacterium tuberculosis (M.tb)-specific antigen-stimulated QuantiFERON® Gold In-Tube (QFT) cultures and in serum samples from ATB patients, healthy individuals with latent M.tb infection (LTBI) and healthy controls (HC) to examine whether combined analyses of these proteins were useful in the differentiation of M.tb states.MethodsThe concentrations of IL-18, IL-18BP, IFN-γ, IL-37 and IP-10 in the serum and QFT supernatants were measured using specific enzyme-linked immunosorbent assay (ELISA) kits. Free IL-18 levels were calculated using the law of mass action.ResultsIncreased concentrations of total and free IL-18, IL-18BP, IFN-γ and IP-10 in the sera of ATB patients were detected. These increases were not counterbalanced by the overproduction of IL-37. Complex co-expression of serum IL-18BP and IL-37, IP-10 and IFN-γ was identified as the highest discriminative biomarker set for the diagnosis of ATB.ConclusionsOur results suggest that the IL-18 signalling complex might be exploited by M. tuberculosis to expand the clinical manifestations of pulmonary TB. Therefore, direct analysis of the serum components of the IL-18/IL-37 signalling complex and IP-10 may be applicable in designing novel diagnostic tests for ATB.

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Section: Discussionsupporting

confidence: 91%

IL-18/IL-37/IP-10 signalling complex as a potential biomarker for discriminating active and latent TB

et al. 2019

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“…CD107a was added to each well (to a final concentration of 0.2%) and the plate incubated for 15–16 h at 37°C, 5% CO 2 . The concentrations of PPD and EC, as well as the duration of stimulation, have been previously validated in our laboratory and by other groups ( 47 – 53 ). Subsequently, 1X protein transport inhibitor (eBioscience, UK) was added and incubation continued for a further 3 hrs.…”

Section: Methodsmentioning

confidence: 94%

Functional and Phenotypic Changes of Natural Killer Cells in Whole Blood during Mycobacterium tuberculosis Infection and Disease

et al. 2018

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Tuberculosis (TB) is still a global health concern, especially in resource-poor countries such as The Gambia. Defining protective immunity to TB is challenging: its pathogenesis is complex and involves several cellular components of the immune system. Recent works in vaccine development suggest important roles of the innate immunity in natural protection to TB, including natural killer (NK) cells. NK cells mediate cellular cytotoxicity and cytokine signaling in response to Mycobacterium tuberculosis (Mtb). NK cells can display specific memory-type markers to previous antigen exposure; thus, bridging innate and adaptive immunity. However, major knowledge gaps exist on the contribution of NK cells in protection against Mtb infection or TB. We performed a cross-sectional assessment of NK cells phenotype and function in four distinct groups of individuals: TB cases pre-treatment (n = 20) and post-treatment (n = 19), and household contacts with positive (n = 9) or negative (n = 18) tuberculin skin test (TST). While NK cells frequencies were similar between all groups, significant decreases in interferon-γ expression and degranulation were observed in NK cells from TB cases pre-treatment compared to post-treatment. Conversely, CD57 expression, a marker of advanced NK cells differentiation, was significantly lower in cases post-treatment compared to pre-treatment. Finally, NKG2C, an activation and imprinted-NK memory marker, was significantly increased in TST+ (latently infected) compared to TB cases pre-treatment and TST− (uninfected) individuals. The results of this study provide valuable insights into the role of NK cells in Mtb infection and TB disease, demonstrating potential markers for distinguishing between infection states and monitoring of TB treatment response.

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“…In addition to conforming the data previously published for a Chinese population (Cai et al) in 4 different TB cohorts, we also showed the specificity for TB disease in comparison to clinically important differential diagnoses, such as sarcoidosis and pneumonia. As C1q is produced by cells of monocytic origin, it reflects another component of the immune space compared to most currently applied TB biomarkers, such as C-reactive protein and IP-10 ( 44 – 47 ). In addition, C1q levels are technically easy to measure and the C1q protein is not sensitive to degradation.…”

Section: Discussionmentioning

confidence: 99%

Complement Component C1q as Serum Biomarker to Detect Active Tuberculosis

Lubbers

Sutherland

Goletti³

et al. 2018

Front. Immunol.

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Background: Tuberculosis (TB) remains a major threat to global health. Currently, diagnosis of active TB is hampered by the lack of specific biomarkers that discriminate active TB disease from other (lung) diseases or latent TB infection (LTBI). Integrated human gene expression results have shown that genes encoding complement components, in particular different C1q chains, were expressed at higher levels in active TB compared to LTBI.Methods: C1q protein levels were determined using ELISA in sera from patients, from geographically distinct populations, with active TB, LTBI as well as disease controls.Results: Serum levels of C1q were increased in active TB compared to LTBI in four independent cohorts with an AUC of 0.77 [0.70; 0.83]. After 6 months of TB treatment, levels of C1q were similar to those of endemic controls, indicating an association with disease rather than individual genetic predisposition. Importantly, C1q levels in sera of TB patients were significantly higher as compared to patients with sarcoidosis or pneumonia, clinically important differential diagnoses. Moreover, exposure to other mycobacteria, such as Mycobacterium leprae (leprosy patients) or BCG (vaccinees) did not result in elevated levels of serum C1q. In agreement with the human data, in non-human primates challenged with Mycobacterium tuberculosis, increased serum C1q levels were detected in animals that developed progressive disease, not in those that controlled the infection.Conclusions: In summary, C1q levels are elevated in patients with active TB compared to LTBI in four independent cohorts. Furthermore, C1q levels from patients with TB were also elevated compared to patients with sarcoidosis, leprosy and pneumonia. Additionally, also in NHP we observed increased C1q levels in animals with active progressive TB, both in serum and in broncho-alveolar lavage. Therefore, we propose that the addition of C1q to current biomarker panels may provide added value in the diagnosis of active TB.

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Evaluation of cytokine responses against novel Mtb antigens as diagnostic markers for TB disease

Abstract: A biosignature of 6 cytokines obtained after stimulation with four Mtb antigens has moderate potential as a diagnostic tool for pulmonary TB disease individuals and stimulated marker expression had no added value to unstimulated marker performance.

Cited by 25 publications

References 45 publications

IL-18/IL-37/IP-10 signalling complex as a potential biomarker for discriminating active and latent TB

IL-18/IL-37/IP-10 signalling complex as a potential biomarker for discriminating active and latent TB

Functional and Phenotypic Changes of Natural Killer Cells in Whole Blood during Mycobacterium tuberculosis Infection and Disease

Complement Component C1q as Serum Biomarker to Detect Active Tuberculosis

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