Application of multiplexed ion mobility spectrometry towards the identification of host protein signatures of treatment effect in pulmonary tuberculosis

Kedia, Komal; Wendler, Jason P.; Baker, Erin; Jarsberg, Leah G.; Stratton, Kelly G.; Wright, Aaron; Piehowski, Paul; Gritsenko, Marina; Lewinsohn, David; Sigal, George B.; Weiner, Marc; Smith, Richard; Jacobs, Jon; Nahid, Payam

doi:10.1016/j.tube.2018.07.005

Cited by 17 publications

(26 citation statements)

References 61 publications

(71 reference statements)

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“…SAA1 has been reported to be upregulated in lung parenchyma and bronchi of patients with COPD compared with smoking controls (Lopez-Campos et al, 2013). During TB treatment, SAA1 expression is reduced, and the reduction is greater for patients who culture-converted at later time points (Sigal et al, 2017;Kedia et al, 2018). In our study, this gene was found to be downregulated in OM cholesteatoma and COPD large airway brushings, but upregulated in CRS.…”

Section: Discussionsupporting

confidence: 50%

Identification of Novel Genes and Biological Pathways That Overlap in Infectious and Nonallergic Diseases of the Upper and Lower Airways Using Network Analyses

et al. 2020

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Previous genetic studies on susceptibility to otitis media and airway infections have focused on immune pathways acting within the local mucosal epithelium, and outside of allergic rhinitis and asthma, limited studies exist on the overlaps at the gene, pathway or network level between the upper and lower airways. In this report, we compared [1] pathways identified from network analysis using genes derived from published genomewide family-based and association studies for otitis media, sinusitis, and lung phenotypes, to [2] pathways identified using differentially expressed genes from RNA-sequence data from lower airway, sinus, and middle ear tissues, in particular cholesteatoma tissue compared to middle ear mucosa. For otitis media, a large number of genes (n = 1,806) were identified as differentially expressed between cholesteatoma and middle ear mucosa, which in turn led to the identification of 68 pathways that are enriched in cholesteatoma. Two differentially expressed genes CR1 and SAA1 overlap in middle ear, sinus, and lower airway samples and are potentially novel genes for otitis media susceptibility. In addition, 56 genes were differentially expressed in both tissues from the middle ear and either sinus or lower airways. Pathways that are common in upper and lower airway diseases, whether from published DNA studies or from our RNA-sequencing analyses, include chromatin organization/remodeling, endocytosis, immune system process, protein folding, and viral process. Taken together, our findings from genetic susceptibility and differential tissue expression studies support the hypothesis that the unified airway theory wherein the upper and lower respiratory tracts act as an integrated unit also applies to infectious and nonallergic airway epithelial disease. Our results may be

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Section: Discussionsupporting

confidence: 50%

Identification of Novel Genes and Biological Pathways That Overlap in Infectious and Nonallergic Diseases of the Upper and Lower Airways Using Network Analyses

et al. 2020

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“…bovis-infected cattle. In human TB, the SAA level was significantly higher in TB patients than in healthy controls, and it was also significantly increased in TB patients with lung lesions and tended to decline in patients undergoing TB treatment (29–31). The AGP level was found to be increased in active TB patients and may be a possible marker of a slow response to anti-TB treatment (32).…”

Section: Discussionmentioning

confidence: 99%

Interleukin 8 and Pentaxin (C-Reactive Protein) as Potential New Biomarkers of Bovine Tuberculosis

Gao

Guo

et al. 2019

J Clin Microbiol

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Bovine tuberculosis (bTB) is caused by Mycobacterium bovis. During the early stage of infection, greater than 15% of M. bovis-infected cattle shed mycobacteria through nasal secretions, which can be detected by nested PCR. To compare the differences in the protein profiles of M. bovis-infected cattle that were nested PCR positive (bTBPCR-P) and M. bovis-infected cattle that were nested PCR negative (bTBPCR-N) and to screen for biomarkers that will facilitate the early and accurate detection of bTB, we investigated the protein expression profiles of serum and bovine purified protein derivative (PPD-B)-stimulated plasma among bTBPCR-P (n = 20), bTBPCR-N (n = 20), and uninfected cattle (NC; n = 20) by iTRAQ labeling coupled with two-dimensional liquid chromatography-tandem mass spectrometry (iTRAQ-2D LC-MS/MS). After comprehensive analysis, we selected 15 putative differentially expressed serum proteins and 15 plasma proteins for validation by parallel reaction monitoring (PRM) with the same cohort used in the iTRAQ analysis. Four serum and five PPD-B-stimulated proteins were confirmed in follow-up enzyme-linked immunosorbent assays. PPD-B-stimulated interleukin 8 (IL-8) displayed the potential to differentiate M. bovis-infected cattle from NC, with an area under the curve (AUC) value of 0.9662, while PPD-B-stimulated C-reactive protein (CRP) displayed the potential to differentiate bTBPCR-P from bTBPCR-N, with an AUC value of 1.00. Finally, double-blind testing with 244 cattle indicated that the PPD-B-stimulated IL-8 test exhibited good agreement with traditional tests (κ > 0.877) with a >90% relative sensitivity and a >98% relative specificity; the PPD-B-stimulated CRP test displayed good agreement with nested PCR (κ = 0.9117), with an observed 94% relative sensitivity and 97% relative specificity. Therefore, the PPD-B-stimulated IL-8 and CRP tests could be used to detect bTB and to differentiate bTBPCR-P from bTBPCR-N.

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“…If these observations can be extended, emphasis should be placed on replacing the invasive BALF procedure with a more easily obtained sample. Analysis of serum samples by multiplexed ion mobility spectrometry similarly shows a similar decrease of acute phase proteins in response to antibiotic treatment and culture status (Kedia et al, 2018 ). This supports the clinical translatability of identified BALF markers being applied for blood-based testing.…”

Section: Discussionmentioning

confidence: 90%

Investigating Non-sterilizing Cure in TB Patients at the End of Successful Anti-TB Therapy

Beltran

Heunis

Gallant

et al. 2020

Front. Cell. Infect. Microbiol.

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Mycobacterium tuberculosis (Mtb) is extremely recalcitrant to antimicrobial chemotherapy requiring 6 months to treat drug-sensitive tuberculosis (TB). Despite this, 4–10% of cured patients will develop recurrent disease within 12 months after completing therapy. Reasons for relapse in cured TB patients remains speculative, attributed to both pathogen and host factors. Populations of dormant bacilli are hypothesized to cause relapse in initially cured TB patients however, development of tests to convincingly demonstrate their presence at the end of anti-TB treatment has been challenging. Previous studies have indicated the utility of culture filtrate supplemented media (CFSM) to detect differentially culturable tubercle bacilli (DCTB). Here, we show that 3/22 of clinically cured patients retained DCTB in induced sputum and bronchoalveolar lavage fluid (BALF), with one DCTB positive patient relapsing within the first year of completing therapy. We also show a correlation of DCTB status with “unresolved” end of treatment FDG PET-CT imaging. Additionally, 19 end of treatment induced sputum samples from patients not undergoing bronchoscopy were assessed for DCTB, identifying a further relapse case with DCTB. We further show that induced sputum is a less reliable source for the DCTB assay at the end of treatment, limiting the utility of this assay in a clinical setting. We next investigated the host proteome at the site of disease (BALF) using multiplexed proteomic analysis and compared these to active TB cases to identify host-specific factors indicative of cure. Distinct signatures stratified active from cured TB patients into distinct groups, with a DCTB positive, subsequently relapsing, end of treatment patient showing a proteomic signature closer to active TB disease than cure. This exploratory study offers evidence of live Mtb, undetectable with conventional culture methods, at the end of clinically successful treatment and putative host protein biomarkers of active disease and cure. These findings have implications for the assessment of true sterilizing cure in TB patients and opens new avenues for targeted approaches to monitor treatment response.

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Application of multiplexed ion mobility spectrometry towards the identification of host protein signatures of treatment effect in pulmonary tuberculosis

Cited by 17 publications

References 61 publications

Identification of Novel Genes and Biological Pathways That Overlap in Infectious and Nonallergic Diseases of the Upper and Lower Airways Using Network Analyses

Identification of Novel Genes and Biological Pathways That Overlap in Infectious and Nonallergic Diseases of the Upper and Lower Airways Using Network Analyses

Interleukin 8 and Pentaxin (C-Reactive Protein) as Potential New Biomarkers of Bovine Tuberculosis

Investigating Non-sterilizing Cure in TB Patients at the End of Successful Anti-TB Therapy

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