PONE-D-20-02309

Impact and Prognosis of the Expression of IFN-α Among Tuberculosis Patients

PLOS ONE

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Reviewer #1: Taneja et al describe a study of interferon gene expression in Tuberculosis patients. The study is of interest and relevant as many questions still remain related to the role of type I interferons in TB. My main concern relates to the main findings presented and how the data is analyzed and interpreted.

The authors measure different IFNs by quantifying gene expression by RT-PCR and normalizing to B-actin and expressing relative values as 2-ddCT. High expression was defined as mRNA expression of IFN >1 fold, however the results plotted show median values of less than 1 (Figure 1 & 2). There may be difference between the patient and controls for these values, but what does that mean if the fold expression is less than 1 ?

In parallel from the in vitro challenge model the fold expression is indeed much greater than 1, between 100-1000 fold. This makes the ex vivo data very challenging to interpret.

Related how was the house-keeping gene selected ? Where there any differences in its expression between the different groups examined ? Have the authors tested whether these modest gene expression differences reflect differences in circulating immune cell proportions?

Also how do the authors reconcile their findings with the literature where although ISG signatures have been identified in TB disease by many groups, elevated IFN gene expression (Berry et al, Nature 2010) or more recently elevated protein levels (Llibre et al, Front Cell Infect Microbiol. 2019) have not been reported.

Minor

- How were patients defined to have TB disease ?

- Which IFNa subtype is detected with this assay ?

- Figures 1 & 2 should be plotted with a log scale as the break in the axis is confusing.

- Fig 4 should be plotted on log scale as many points are too close to the threshold, and the correlation plot should be included

- How do the authors explain that blocked IFNa alone inhibits bacterial growth, but not when given with anti-IFNB and anti-IFNg ? Do THP1 cells express IFNGR and IFNAR ? To equal levels ?

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Reviewer #1: No

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Impact and Prognosis of the Expression of IFN-α Among Tuberculosis Patients

PONE-D-20-02309R1

Dear Dr. Hanumanthappa,

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