Altered frequencies of monocytes and dendritic cells among drug sensitive and resistant individuals infected with Mycobacterium tuberculosis
Background: The mechanism for Mycobacterium tuberculosis mediated exploitation of host immune defense, which confers different infection settings involving latency to drug resistance has not been fully resolved. Perturbation in the subsets of innate and adaptive immune cells and their cytokines during infection are pivotal in understanding the disease pathogenesis. We aimed to phenotypically characterize and analyze the monocyte and dendritic cell subsets from whole blood of the tuberculosis patients by immunophenotyping. Detailed studies of these monocyte subsets, will give us a better understanding of their functional roles and the relationship of each of the identified subsets to disease status and their utility as a biomarker.
Methods: Monocyte and dendritic cell subsets from healthy (HC=40), latently infected (LTB=38), drug sensitive TB (DS-TB=40) and single or multi-drug resistant TB (DR-TB=40) study participants are immuno-phenotypically studied through flow cytometry and we observed significant differences in the diseased groups. Functional parameters involving MLR/NLR ratios and monocyte related circulating cytokines were also analyzed. Kruskall Wallis statistical method was adopted to compare the data among all possible group combinations, specifically aimed at DS-TB vs DR-TB to define severity and resistance and among HC vs LTB to understand latency.
Results: Increase in the monocyte numbers, monocyte to lymphocyte ratio (MLR) and neutrophil to lymphocyte ratio (NLR) could be observed among DS-TB and DR-TB groups with AUC values (Range: 0.89-0.92) and found to be highly significant compared to HC and LTB groups. For immunophenotyping studies, when compared with HC and LTB groups, DS-TB group showed significant alterations with diminished frequencies of classical monocytes [81.04±1.57], plasmocytoid DCs [7.66±0.95] & cross-presenting myeloid DCs [0.04±0.00] and elevated frequencies of intermediate monocytes [7.62±0.69] & classical myeloid DCs [17.61±1.16]. However, in DR-TB, elevated frequencies of intermediate monocytes [5.58±0.49] and reduced frequencies of all DC subsets (cDC [9.71±0.94], cross-presenting mDC [0.07±0.01] and pDC [9.69±1.18]) have been observed. Elevated levels of IL-6 could be observed in both DS-TB and DR-TB groups whereas, levels of IL-10 were found to be reduced in DR-TB group in comparison with HC and LTB groups. The observed phenotypic differences were able to distinguish DS-TB and DR-TB from healthy and latent individuals but not between DR-TB and DS-TB groups.
Conclusions: Our study identified MLR/NLR ratios as a possible biomarker for differentiating the TB diseased (both sensitive and resistant) individuals from healthy and latent groups. From the altered subset composition during diseased condition, it can be concluded that monocytes exhibited the protective phenotype and dendritic cells attributed defective phenotype. Further studies on documenting their global transcriptomic profile and mapping their functional pathways will be helpful in identification of putative protective, severity as well as prognostic biomarkers of infection.
1. Department of Immunology, National Institute of Research in Tuberculosis (NIRT),
2. Department of Clinical Research, National Institute of Research in Tuberculosis (NIRT),
3. District TB Officer, Corporation of Chennai, India
4. Director In charge – ICMR- National Institute for Research in Tuberculosis, Chennai, India
5. Scientific Director, International Excellence of Research- national institute for health-National Institute for Research in Tuberculosis (ICER-NIH-NIRT)