Adjunctive steroid therapy for managing pulmonary tuberculosis

Critchley, Julia; Orton, Lois; Pearson, Fiona

doi:10.1002/14651858.cd011370

Cited by 22 publications

(17 citation statements)

References 94 publications

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“…Future studies in animal models and clinical trials should investigate the effectiveness of imatinib in combination with glucocorticoids in the host-directed treatment of mycobacterial infections. This may be particularly useful in the management of inflammatory reactions (54–58), including immune reconstitution inflammatory syndrome, which occurs in HIV/TB-coinfected individuals at the initiation of chemotherapy and which is treated with glucocorticoids (59). …”

Section: Discussionmentioning

confidence: 99%

Imatinib Triggers Phagolysosome Acidification and Antimicrobial Activity againstMycobacterium bovisBacille Calmette–Guérin in Glucocorticoid-Treated Human Macrophages

Steiger

Stephan

Inkeles

et al. 2016

The Journal of Immunology

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Glucocorticoids are extensively used to treat inflammatory diseases; however, their chronic intake increases the risk for mycobacterial infections. Meanwhile, the effects of glucocorticoids on innate host responses are incompletely understood. In this study, we investigated the direct effects of glucocorticoids on antimycobacterial host defense in primary human macrophages. We found that glucocorticoids triggered the expression of cathelicidin, an antimicrobial critical for antimycobacterial responses, independent of the intracellular vitamin D metabolism. Despite upregulating cathelicidin, glucocorticoids failed to promote macrophage antimycobacterial activity. Gene expression profiles of human macrophages treated with glucocorticoids and/or IFN-γ, which promotes induction of cathelicidin, as well as antimycobacterial activity, were investigated. Using weighted gene coexpression network analysis, we identified a module of highly connected genes that was strongly inversely correlated with glucocorticoid treatment and associated with IFN-γ stimulation. This module was linked to the biological functions autophagy, phagosome maturation, and lytic vacuole/lysosome, and contained the vacuolar H+-ATPase subunit a3, alias TCIRG1, a known antimycobacterial host defense gene, as a top hub gene. We next found that glucocorticoids, in contrast with IFN-γ, failed to trigger expression and phagolysosome recruitment of TCIRG1, as well as to promote lysosome acidification. Finally, we demonstrated that the tyrosine kinase inhibitor imatinib induces lysosome acidification and antimicrobial activity in glucocorticoid-treated macrophages without reversing the anti-inflammatory effects of glucocorticoids. Taken together, we provide evidence that the induction of cathelicidin by glucocorticoids is not sufficient for macrophage antimicrobial activity, and identify the vacuolar H+-ATPase as a potential target for host-directed therapy in the context of glucocorticoid therapy.

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Section: Discussionmentioning

confidence: 99%

Imatinib Triggers Phagolysosome Acidification and Antimicrobial Activity againstMycobacterium bovisBacille Calmette–Guérin in Glucocorticoid-Treated Human Macrophages

Steiger

Stephan

Inkeles

et al. 2016

The Journal of Immunology

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“…Several studies have tried to improve the outcome of pulmonary TB by lowering the inflammatory response using high doses of corticosteroids in combination with antibiotics. While it was found that this therapy leads to faster resolution of symptoms and lesions in radiographic examinations and a more rapid discharge from hospitals, a statistically significant survival benefit could not be shown (Table 1) [70][71][72]. In addition, high dose corticosteroids may result in serious side effects such as diabetes and psychiatric symptoms.…”

Section: The Role Of Corticosteroids In Tb Treatmentmentioning

confidence: 99%

Host-Directed Therapies and Anti-Virulence Compounds to Address Anti-Microbial Resistant Tuberculosis Infection

2020

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Despite global efforts to contain tuberculosis (TB), the disease remains a leading cause of morbidity and mortality worldwide, further exacerbated by the increased resistance to antibiotics displayed by the tubercle bacillus Mycobacterium tuberculosis. In order to treat drug-resistant TB, alternative or complementary approaches to standard anti-TB regimens are being explored. An area of active research is represented by host-directed therapies which aim to modulate the host immune response by mitigating inflammation and by promoting the antimicrobial activity of immune cells. Additionally, compounds that reduce the virulence of M. tuberculosis, for instance by targeting the major virulence factor ESX-1, are being given increased attention by the TB research community. This review article summarizes the current state of the art in the development of these emerging therapies against TB.

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“…Corticosteroids (prednisolone and dexamethasone) are a class of HDT candidates which are already given to patients experiencing severe inflammation during anti-TB treatment. The drugs themselves do not have targeted effects but rather a general dampening of the host immune response to extend survival in the short-term (Critchley et al, 2016). However, emerging evidence from clinical studies involving patients with MDR-TB may help identify more targeted HDT strategies which could be standardised for some patient groups i.e.…”

Section: Standardised Therapy For Mdr-tbmentioning

confidence: 99%

Improving treatment outcomes for MDR-TB — Novel host-directed therapies and personalised medicine of the future

Rao

Ippolito

Mfinanga

et al. 2019

International Journal of Infectious Diseases

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A B S T R A C TMultidrug-resistant TB (MDR-TB) is a major threat to global health security. In 2017, only 50% of patients with MDR-TB who received WHO-recommended treatment were cured. Most MDR-TB patients who recover continue to suffer from functional disability due to long-term lung damage. Whilst new MDR-TB treatment regimens are becoming available, conventional drug therapies need to be complemented with host-directed therapies (HDTs) to reduce tissue damage and improve functional treatment outcomes. This viewpoint highlights recent data on biomarkers, immune cells, circulating effector molecules and genetics which could be utilised for developing personalised HDTs. Novel technologies currently used for cancer therapy which could facilitate in-depth understanding of host genetics and the microbiome in patients with MDR-TB are discussed. Against this background, personalised cell-based HDTs for adjunct MDR-TB treatment to improve clinical outcomes are proposed as a possibility for complementing standard therapy and other HDT agents. Insights into the molecular biology of the mechanisms of action of cellular HDTs may also aid to devise non-cell-based therapies targeting defined inflammatory pathway (s) in Mtb-driven immunopathology.

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Adjunctive steroid therapy for managing pulmonary tuberculosis

Cited by 22 publications

References 94 publications

Imatinib Triggers Phagolysosome Acidification and Antimicrobial Activity againstMycobacterium bovisBacille Calmette–Guérin in Glucocorticoid-Treated Human Macrophages

Imatinib Triggers Phagolysosome Acidification and Antimicrobial Activity againstMycobacterium bovisBacille Calmette–Guérin in Glucocorticoid-Treated Human Macrophages

Host-Directed Therapies and Anti-Virulence Compounds to Address Anti-Microbial Resistant Tuberculosis Infection

Improving treatment outcomes for MDR-TB — Novel host-directed therapies and personalised medicine of the future

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