Abstract
Existing understanding of molecular composition of sputum and its role in tuberculosis patients is variously limited to its diagnostic potential. We sought to identify infection induced sputum proteome alteration in active/non tuberculosis patients (A/NTB) and their role in altered lung patho-physiology. Out of the study population (n = 118), sputum proteins isolated from discovery set samples (n = 20) was used for an 8-plex isobaric tag for relative and absolute concentration analysis. A minimum set of protein with at least log2(ATB/NTB) >±1.0 in ATB was selected as biosignature and validated in 32 samples. Predictive accuracy was calculated from area under the receiver operating characteristic curve (AUC of ROC) using a confirmatory set (n = 50) by Western blot analysis. Mass spectrometry analysis identified a set of 192 sputum proteins, out of which a signature of β-integrin, vitamin D binding protein:DBP, uteroglobin, profilin and cathelicidin antimicrobial peptide was sufficient to differentiate ATB from NTB. AUC of ROC of the biosignature was calculated to 0.75. A shift in DBP-antimicrobial peptide (AMP) axis in the lungs of tuberculosis patients is observed. The identified sputum protein signature is a promising panel to differentiate ATB from NTB groups and suggest a deregulated DBP-AMP axis in lungs of tuberculosis patients.
Highlights
Pulmonary tuberculosis (TB) involves complex patho-physiological perturbations and present with heterogeneous complications[1]
For both GeneXpert and sputum microscopy, were grouped as active tuberculosis (ATB) and with double negative results as non tuberculosis (NTB) patients suffering from asthma, chronic obstructive pulmonary diseases (COPD), lung cancer or pneumonia (Fig. 1c)
Sputum pH was found to be significantly lower in ATB than NTB subjects (Supplementary Fig. S2)
Summary
Pulmonary tuberculosis (TB) involves complex patho-physiological perturbations and present with heterogeneous complications[1]. Sputum is a complex dilute aqueous solution of lipids, proteins and glycoconjugates. It contains inhaled air particles, exogenous as well as endogenous bacterial products, antibacterial secretions, cell and plasma-derived mediators and proteins[4]. Mycobacterium tuberculosis (Mtb), the causative organism of TB, resides in respiratory tract by embedding in mucous in the lumen, adhering to or internalized in respiratory epithelial cells, neutrophils and macrophages in the interstitium between cells and granuloma. Mtb has been reported to release molecules that compromise the host system to make it suitable for its survival[6]. We aim to capture the Mtb infection induced sputum proteome composition alteration in drug naïve TB patients. Information obtained may provide vital clues as to how Mycobacteria affect the host cells, organs and cause overall changes in constituents for its own benefit
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