Identification of Serum Cytokine Biomarkers Associated with Multidrug Resistant Tuberculosis (MDR-TB)

Abstract

Existing tools (including GeneXpert) for diagnosis of multidrug resistant TB (MDR-TB) have limited utility when sputum samples for microbiological analyses cannot be obtained. There is the need for immunological biomarkers which could serve as putative diagnostic markers of MDR-TB. We measured and compared the serum cytokine levels of inflammatory cytokines (IFN-γ, TNF-α, IL12p70, IL-17A, granzyme B) and anti-inflammatory cytokines (IL-10, IL-6, IL-4) among MDR-TB, drug-susceptible (DS)-TB and healthy controls (no-TB) using the Human Magnetic Luminex Multiplex Immunoassay. Levels of IFN-γ and IL-4 were respectively 1.5 log lower and 1.9 log higher in MDR-TB compared to DS-TB cases. Moreover, IFN-γ, TNF-α, IL-10, IL-6, and IL-4 levels were significantly higher in individuals with MDR-TB and DS-TB cases compared to healthy controls. Pairs of cytokines, IL-4 and IFN-γ (p = 0.019), IL-4 and TNF (p = 0.019), and Granzyme B and TNF-α (p = 0.019), showed significant positive correlation in MDR-TB. Serum cytokine profiles can be exploited for immunodiagnostics, as made evident by the Interferon Gamma Release Assays (IGRAs) for TB infection. Using area under the curve values, no single or multiple cytokine combinations could discriminate between DS- and MDR-TB in this study. Studies with a larger sample size and more cytokines could better address the issue.

Differential Frequencies of Intermediate Monocyte Subsets Among Individuals Infected With Drug-Sensitive or Drug-Resistant Mycobacterium tuberculosis

“…The expression of other pro-inflammatory cytokines (TNF-a and IL-2) are different from the existing studies (36)(37)(38)(39). The reduced IL-10 levels in TB groups are quite contrary to the reported studies (40)(41)(42) and were associated with greater pathogen clearance; however, loss of immunity was observed during reinfection. This observation clearly explains reduced IL-10 levels are a key factor in preserving the effector memory populations through an unknown mechanism (43).…”

Cytokine upsurge among drug-resistant tuberculosis endorse the signatures of hyper inflammation and disease severity

“…Similar to our findings, DR-TB groups were previously suggested with increased TNF, IFN-γ and IL-10 26 , 27 associated with marked necrosis and resistance to drugs. Mensah et al stated no differences between the DS-TB and DR-TB with smaller sample size 25 . Though the studies for DR-TB is minimal and with varying cytokine levels, the obtained differences from the current study offer a classical view of better separation of DR-TB from DS-TB, LTB, and HC.…”

“…Considering this, we attempted to estimate an array of cytokines (14 plex) during latency, drug-sensitive and drug-resistant conditions compared to normal healthy condition. The inclusion of all the stages of TB disease spectrum aids an advantage over previous studies that either lack LTB 25 , 26 or DR-TB 8 , 22 in revealing the serial increase of cytokines from LTB to DS-TB and DR-TB. This trend marks the hyper immune responses and severity of DR-TB by the accumulation of multiple cytokines (IL-12p70, TNF-α, INF-γ, IL-2, IL-17, IL-6, and IL-10) at higher concentration.…”

Advancing personalized medicine for tuberculosis through the application of immune profiling

“…These results substantiated previous observations that the reduction of plasma IP-10 is associated with successful TB treatment (Azzurri et al, 2005;Djoba Siawaya et al, 2009); hence IP-10 could be utilized as a valuable indicator of clinical response and treatment success. Furthermore, an investigation was recently conducted that quantified serum inflammatory and anti-inflammatory cytokine concentrations and compared MDR-TB, DS-TB, and HC (Mensah et al, 2021). The results identified a low concentration of serum IFN-g and a high level of IL-4 related to MDR-TB compared to DS-TB individuals.…”

“…Recently, immune profile biomarkers have been of interest to quantify treatment efficacy in relation to treatment response due to the length of time needed for bacterial culture and the difficulty of sputum production (Thorsted et al, 2020;Mensah et al, 2021). During TB infection, the immune response is triggered by Mtb, producing several immune biomarkers.…”