Abstract
BackgroundTo facilitate better discrimination between patients with active tuberculosis (TB) and latent TB infection (LTBI), whole blood transcriptomic studies have been performed to identify novel candidate host biomarkers. SERPING1, which encodes C1-inhibitor (C1-INH), the natural inhibitor of the C1-complex has emerged as candidate biomarker. Here we collated and analysed SERPING1 expression data and subsequently determined C1-INH protein levels in four cohorts of patients with TB. MethodsSERPING1 expression data were extracted from online deposited datasets. C1-INH protein levels were determined by ELISA in sera from individuals with active TB, LTBI as well as other disease controls in geographically diverse cohorts. FindingsSERPING1 expression was increased in patients with active TB compared to healthy controls (8/11 cohorts), LTBI (13/14 cohorts) and patients with other (non-TB) lung-diseases (7/7 cohorts). Serum levels of C1-INH were significantly increased in The Gambia and Italy in patients with active TB relative to the endemic controls but not in South Africa or Korea. In the largest cohort (n = 50), with samples collected longitudinally, normalization of C1-INH levels following successful TB treatment was observed. This cohort, also showed the most abundant increase in C1-INH, and a positive correlation between C1q and C1-INH levels. Combined presence of increased levels of both C1q and C1-INH had high specificity for active TB (96 %) but only very modest sensitivity 38 % compared to the endemic controls. InterpretationSERPING1 transcript expression is increased in TB patients, while serum protein levels of C1-INH were increased in half of the cohorts analysed.
Highlights
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb)
Available microarray data were retrieved from Gene Expression Omnibus (GEO) from thirteen studies (Anderson et al, 2014; Berry et al, 2010; Blankley et al, 2016; Bloom et al, 2013; Esterhuyse et al, 2015; Kaforou et al, 2013; Lee et al, 2016; Maertzdorf et al, 2016, 2011a; Maertzdorf et al, 2011b, 2012; Ottenhoff et al, 2012; Walter et al, 2016), from different populations across the world, and all data were ranked according to differential expression between TB patient and Healthy Controls (HC), latent TB infection (LTBI) or other lung-diseases
The number of studies that reported on differential gene expression between patients with TB and HC (Fig. 1A), LTBI (Fig. 1B) or other lung-diseases (Fig. 1C) was plotted for complement system inhibitors: SERPING1, CFH, C4BPA, CD46, CD55 and CD59
Summary
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb). We reported that increased levels of C1q can be used a host serum biomarker that can discriminate active TB disease from LTBI and non-TB pulmonary infections or sarcoidosis (Lubbers et al, 2018). We collated and analysed SERPING1 expression data and subsequently determined C1-INH protein levels in four cohorts of patients with TB. C1-INH protein levels were determined by ELISA in sera from individuals with active TB, LTBI as well as other disease controls in geographically diverse cohorts. In the largest cohort (n = 50), with samples collected longitudinally, normalization of C1-INH levels following successful TB treatment was observed. Interpretation: SERPING1 transcript expression is increased in TB patients, while serum protein levels of C1-INH were increased in half of the cohorts analysed
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