DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medical and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Division of Medical Virology, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
Front Immunol. 2022 Jul 22;13:883886. doi: 10.3389/fimmu.2022.883886. eCollection 2022.
Successful TB treatment is hampered by increasing resistance to the two most effective first-line anti-TB drugs, namely isoniazid and rifampicin, thus innovative therapies focused on host processes, termed host-directed therapies (HDTs), are promising novel approaches for increasing treatment efficacy without inducing drug resistance. We assessed the ability of Sildenafil, a type-5 phosphodiesterase inhibitor, as a repurposed compound, to serve as HDT target, by counteracting the suppressive effects of myeloid-derived suppressor cells (MDSC) obtained from active TB cases on T-cell responsiveness. We confirm that MDSC suppress non-specific T-cell activation. We also show that Sildenafil treatment fails to reverse the MDSC-mediated suppression of T-cell functions measured here, namely activation and proliferation. The impact of Sildenafil treatment on improved immunity, using the concentration tested here, is likely to be minimal, but further identification and development of MDSC-targeting TB host-directed therapies are warranted.
成功的结核病治疗受到两种最有效的一线抗结核药物（即异烟肼和利福平）耐药性增加的阻碍，因此，针对宿主过程的创新疗法，称为宿主定向治疗（HDT），是提高治疗效果而不诱导耐药性的有前途的新方法。我们评估了 Sildenafil（一种 5 型磷酸二酯酶抑制剂）作为一种再利用化合物的能力，通过抵消从活动性结核病病例中获得的髓样来源的抑制细胞（MDSC）对 T 细胞反应性的抑制作用，作为 HDT 靶点。我们证实 MDSC 抑制非特异性 T 细胞活化。我们还表明，Sildenafil 治疗未能逆转 MDSC 介导的在此处测量的 T 细胞功能的抑制，即激活和增殖。使用此处测试的浓度，Sildenafil 治疗对改善免疫的影响可能很小，但需要进一步鉴定和开发针对 MDSC 的结核病宿主定向治疗方法。
