7-oxo-DHEA enhances impaired M. tuberculosis-specific T cell responses during HIV-TB coinfection

Abstract

Background: Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), affecting approximately one third of the world's population. Development of an adequate immune response will determine disease progression or progress to chronic infection. Risk of developing TB among human immunodeficiency virus (HIV)-coinfected patients (HIV-TB) is 20-30 times higher than those without HIV infection, and a synergistic interplay between these two pathogens accelerates the decline in immunological functions. TB treatment in HIV-TB coinfected persons is challenging and it has a prolonged duration, mainly due to the immune system failure to provide an adequate support for the therapy. Therefore, we aimed to study the role of the hormone 7-oxo-dehydroepiandrosterone (7-OD) as a modulator of anti-tuberculosis immune responses in the context of HIV-TB coinfection. Methods: A cross-sectional study was conducted among HIV-TB patients and healthy donors (HD). We characterized the ex vivo phenotype of CD4 + T cells and also evaluated in vitro antigen-specific responses by Mtb stimulation of peripheral blood mononuclear cells (PBMCs) in the presence or absence of 7-OD. We assessed lymphoproliferative activity, cytokine production and master transcription factor profiles. Results:Our results show that HIV-TB patients were not able to generate successful anti-tubercular responses in vitro compared to HD, as reduced IFN-γ/IL-10 and IFN-γ/IL-17A ratios were observed. Interestingly, treatment with 7-OD enhanced Th1 responses by increasing Mtb-induced proliferation and the production of IFN-γ and TNF-α over IL-10 levels. Additionally, in vitro Mtb stimulation augmented the frequency of cells with a regulatory phenotype, while 7-OD reduced the proportion of these subsets and induced an increase in CD4 + T-bet+ (Th1) subpopulation, which is associated with clinical data linked to an improved disease outcome. Conclusions:We conclude that 7-OD modifies the cytokine balance and the phenotype of CD4 + T cells towards a more favorable profile for mycobacteria control. These results provide new data to delineate novel treatment approaches as co-adjuvant for the treatment of TB.

Therapeutic potential of 7-oxo-DHEA as an adjunctive host-directed therapy for pulmonary tuberculosis

“…Formerly, we described that 7-OD modulated CD4 + T cells Mtb-speci c responses, biasing phenotype and cytokine balance towards a more favorable pro le for mycobacteria control [22]. Therefore, the absolute levels (Supplementary Fig.…”

“…Previous research has shown that endogenous levels of 7-OD positively correlated with clinical parameters associated with a better outcome and the restriction of TB to the lungs in HIV-TB coinfected patients. Moreover, 7-OD enhanced Th1 responses of in vitro Mtb-stimulated peripheral blood mononuclear cells from HIV-TB coinfected patients by increasing proliferation, the production of IFN-γ and TNF-α, and the frequency of the CD4 + T-bet + subset [22]. Inasmuch as 7-OD modi ed the cytokine balance and the phenotype of CD4 + T cells towards a more favorable pro le for mycobacteria control in an in vitro model, the aim of this work was to study its role as a potential adjunctive treatment for TB.…”

Changes in the balance of Th17/Treg cells and oxidative stress markers in patients with HIV‑associated pulmonary tuberculosis who develop IRIS

“…with HIV is 20-30-fold higher than for those without HIV and the synergistic interplay of the two pathogens accelerates the decrease in immunological function (7). Pulmonary TB is the most common form of active TB in patients with HIV (8).…”

“…In 2019, 208,000 of ~1.4 million TB-related deaths were among HIV-positive people ( 6 ). The risk of developing TB for patients with HIV is 20-30-fold higher than for those without HIV and the synergistic interplay of the two pathogens accelerates the decrease in immunological function ( 7 ). Pulmonary TB is the most common form of active TB in patients with HIV ( 8 ).…”

The catalytic activity of mycelial fungi towards 7‐oxo‐DHEA – an endogenous derivative of steroidal hormone dehydroepiandrosterone

“…It was even recommended as a drug preventing Raynaud’s syndrome attacks (Kazihnitková et al ., 2007). 7‐Oxo‐DHEA may serve as natural antiglucocorticoid (Muller et al ., 2006), and it may be involved in the development of an effective immune response (Arsenou et al ., 2003; Vecchione et al ., 2020). It has been suggested that 7‐oxo‐DHEA as an antagonist of γ‐aminobutyric acid subtype A receptor (GABA A ) exerts a beneficial effect for memory retention in mice.…”