Distinct Transcriptional and Anti-Mycobacterial Profiles of Peripheral Blood Monocytes Dependent on the Ratio of Monocytes: Lymphocytes

• A pathophysiological basis for involvement of the ML ratio in infectious, malignant and cardiovascular diseases is unclear.
• Monocytes from individuals with high ML ratio have impaired control of mycobacterial growth and a distinctive transcriptome.
• These monocytes are characterised by enhanced interferon signalling, and intermediate transcription factors.
• The ML-ratio associated transcript signature is enriched in TB and other diseases including atopy, IBD and SLE.
• Ontogeny-specific function of monocytes may be the possible mechanism for the prognostic value of the ML ratio.Enumeration of the absolute count of white blood cell subsets is one of the most frequently performed tests in clinical practice. Recently, elevation in the monocytes:lymphocytes (ML) ratio was linked to increased risk of tuberculosis and malaria disease, and poorer outcomes for many cancers and cardiovascular diseases. We sought to understand the mechanism of these disease associations. We found that the ML ratio reflects the functional capacity of monocytes and that genes that are differentially expressed in monocytes from donors with a high ML ratio are similar to those in other diseases such as HIV and inflammatory bowel disease. Because a specific type of blood-making stem cell regulates the ML ratio, it is plausible that the ratio reflects monocyte function because it is a clue to different monocyte origins. Our findings offer a mechanism for the predictive value of the ML ratio that may help improve its clinical utility.

The ratio of monocytes and lymphocytes (ML ratio) in peripheral blood is associated with tuberculosis and malaria disease risk and cancer and cardiovascular disease outcomes. We studied anti-mycobacterial function and the transcriptome of monocytes in relation to the ML ratio.Mycobacterial growth inhibition assays of whole or sorted blood were performed and mycobacteria were enumerated by liquid culture. Transcriptomes of unstimulated CD14 + monocytes isolated by magnetic bead sorting were characterised by microarray. Transcript expression was tested for association with ML ratio calculated from leucocyte differential counts by linear regression.The ML ratio was associated with mycobacterial growth in vitro (β = 2.23, SE 0.91, p = 0.02). Using sorted monocytes and lymphocytes, in vivo ML ratio (% variance explained R2 = 11%, p = 0.02) dominated over in vitro ratios (R2 = 5%, p = 0.10) in explaining mycobacterial growth. Expression of 906 genes was associated with the ML ratio and 53 with monocyte count alone. ML-ratio associated genes were enriched for type-I and -II interferon signalling (p = 1.2 × 10− 8), and for genes under transcriptional control of IRF1, IRF2, RUNX1, RELA and ESRRB. The ML-ratio-associated gene set was enriched in TB disease (3.11-fold, 95% CI: 2.28–4.19, p = 5.7 × 10− 12) and other inflammatory diseases including atopy, HIV, IBD and SLE.The ML ratio is associated with distinct transcriptional and anti-mycobacterial profiles of monocytes that may explain the disease associations of the ML ratio.