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

Abstract

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.

Update on tuberculosis biomarkers: From correlates of risk, to correlates of active disease and of cure from disease

“…It has been postulated that this may be related to enhanced myelopoiesis in response to IFN-γ produced by other cells, which is released in the circulation during TB infection and inflammation. [69][70][71] This has been confirmed in active TB. 72…”

“…The cumulative findings of these older and more recent studies is that elevated levels of circulating monocytes are an independent CoR for developing active TB in patients’ contacts. It has been postulated that this may be related to enhanced myelopoiesis in response to IFN‐γ produced by other cells, which is released in the circulation during TB infection and inflammation . This has been confirmed in active TB …”

“…Combined analysis of Mtb‐specific CD4 and CD8 T‐cell responses was a powerful diagnostic tool for diagnosing TB . Additional immune profiling studies focused on a TB CoD already identified long ago, namely the ratio of myeloid over lymphoid cells in the blood of patients . The cumulative findings of these older and more recent studies is that elevated levels of circulating monocytes are an independent CoR for developing active TB in patients’ contacts.…”

“…68 Additional immune profiling studies focused on a TB CoD already identified long ago, namely the ratio of myeloid over lymphoid cells in the blood of patients. [69][70][71] The cumulative findings of these older and more recent studies is that elevated levels of circulating monocytes are an independent CoR for developing active TB in patients' contacts. It has been postulated that this may be related to enhanced myelopoiesis in response to IFN-γ produced by other cells, which is released in the circulation during TB infection and inflammation.…”

Blood tolerogenic monocytes and low proportions of dendritic cell subpopulations are hallmarks of human tuberculosis

“…CD16 + monocytes are also more prone to produce TNF‐α, and to undergo cell death in response to Mtb infection . Results obtained in different prospective cohort studies indicated that an increased monocytes/lymphocytes ratio is associated with the risk of subsequent TB disease, possibly due to a monocyte dysfunction as these changes were associated with an enrichment of interferon‐associated transcripts in monocytes …”