Towards host-directed therapies for tuberculosis

Zumla, Alimuddin; Chakaya, Jeremiah; Höelscher, Michael; Ntoumi, Francine; Rustomjee, Roxana; Vilaplana, Cristina; Yeboah-Manu, Dorothy; Rasolofo, Voahangy; Munderi, Paula; Singh, Nidhi; Aklillu, Eleni; Padayatchi, Nesri; Macete, Eusébio; Kapata, Nathan; Mulenga, Modest; Kibiki, Gibson; Mfinanga, Sayoki; Nyirenda, Thomas; Maboko, Leonard; García‐Basteiro, Alberto L.; Rakotosamimanana, Niaina; Bates, Matthew; Mwaba, Peter; Reither, Klaus; Gagneux, Sébastien; Edwards, Sarah; Mfinanga, Elirehema; Abdulla, Salim; Cardona, Père-Joan; Russell, James; Gant, Vanya; Noursadeghi, Mahdad; Elkington, Paul; Bonnet, Maryline; Menéndez, C Gissel García; Dieye, Tandakha N.; Diarra, Bassirou; Maïga, Almoustapha Issiaka; Aseffa, Abraham; Parida, Shreemanta K.; Wejse, Christian; Petersen, Eskild; Kaleebu, Pontiano; Oliver, Matt; Craig, Gill; Corrah, Tumena; Tientcheu, Leopold D.; Antonio, Martín; Rao, Martin; McHugh, Timothy D.; Sheikh, Aziz; Ippolito, Giuseppe; Ramjee, Gita; Kaufmann, Stefan H. E.; Churchyard, Gavin J.; Steyn, Adrie J. C.; Grobusch, Martin P.; Sanne, Ian; Martinson, Neil; Madansein, Rajhmun; Wilkinson, Robert J.; Mayosi, Bongani M.; Schito, Marco; Wallis, Robert S.; Maeurer, Markus

doi:10.1038/nrd4696

Cited by 107 publications

(84 citation statements)

References 5 publications

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“…ost-directed therapy (HDT) may offer expanded therapeutic options for improving tuberculosis (TB) treatment (1)(2)(3)(4)(5). Metformin (MetF), an AMP-activated protein kinase (AMPK)-activating drug for type 2 diabetes (DM), was reported to inhibit intracellular growth of mycobacteria by inducing reactive oxygen species and to enhance the efficacy of conventional anti-TB drugs in mouse models of acute and chronic TB; its use was associated with decreased TB severity and improved clinical outcomes in a retrospective analysis of 220 patients with DM and TB (6).…”

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confidence: 99%

Metformin Adjunctive Therapy Does Not Improve the Sterilizing Activity of the First-Line Antitubercular Regimen in Mice

Dutta

Pinn

Karakousis

2017

Antimicrob Agents Chemother

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Preliminary preclinical and observational studies suggest the potential utility of metformin as an adjunctive, host-directed agent for treatment of tuberculosis (TB). In this study, we sought to investigate the bactericidal and sterilizing activities of human-like exposures of metformin when given in combination with the firstline regimen against chronic tuberculosis in BALB/c mice. Mice receiving metformin adjunctive therapy had similar lung bacillary burdens with control mice during treatment, and the proportion of mice with microbiological relapse was similar between the two groups.KEYWORDS Mycobacterium tuberculosis, metformin, standard first-line regimen, BALB/c, bactericidal, sterilizing, host-directed therapy, relapse, cure, Denver regimen H ost-directed therapy (HDT) may offer expanded therapeutic options for improving tuberculosis (TB) treatment (1-5). Metformin (MetF), an AMP-activated protein kinase (AMPK)-activating drug for type 2 diabetes (DM), was reported to inhibit intracellular growth of mycobacteria by inducing reactive oxygen species and to enhance the efficacy of conventional anti-TB drugs in mouse models of acute and chronic TB; its use was associated with decreased TB severity and improved clinical outcomes in a retrospective analysis of 220 patients with DM and TB (6). In another retrospective study, Srujitha et al. showed that MetF use was associated with a 3.9-fold reduction in TB incidence among patients with DM (7). Based on these findings, we hypothesized that MetF adjunctive therapy would enhance the bactericidal and sterilizing activities of the standard first-line treatment (8, 9) against chronic TB infection in mice and shorten the duration of curative treatment as assessed by microbiological relapse.All animal-related procedures were approved by the Johns Hopkins University (JHU) School of Medicine Animal Care and Use Committee. A total of 170 female BALB/c mice aged 4 to 6 weeks (Charles River Labs, Wilmington, MA) were aerosol infected with Mycobacterium tuberculosis H37Rv (JHU) using the inhalation exposure system (GlasCol, Terre Haute, IN) calibrated to deliver ϳ10 2 CFU per mouse lung in two consecutive runs. After aerosol infection, the mice were randomized into the two treatment groups. Six weeks postinfection, the mice were treated daily (5 days/week) via esophageal cannulation with human-equivalent doses of rifampin (10 mg/kg), isoniazid (10 mg/kg), pyrazinamide (150 mg/kg), and ethambutol (100 mg/kg) (RHZE) with or without MetF (250 mg/kg) for up to 6 months (2, 10, 11). For the first 2 months of treatment, the mice received RHZE and, for the remaining 4 months, only rifampin and isoniazid (RH) to mirror the first-line regimen in humans. The rifampin dose preceded that of the other drugs by at least 1 h to prevent pharmacokinetic antagonism (12, 13). The dose of MetF (6) and is estimated (14) to be equivalent to 25 mg/kg in humans (15), which is well tolerated (15, 16). Groups of 5 mice were sacrificed on the day after infection, on the day of treatment initi...

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confidence: 99%

Metformin Adjunctive Therapy Does Not Improve the Sterilizing Activity of the First-Line Antitubercular Regimen in Mice

Dutta

Pinn

Karakousis

2017

Antimicrob Agents Chemother

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“…A second and more surprising prediction is that immunosuppression would be effective in some individuals to prevent Candida - and Mycobacteria -related pathology. Vitamin D 3 suppresses human T H 1/T H 17 differentiation, yet promotes resolution of TB pathology in humans and experimental models 238,239 . There are also situations in which steroidal and non-steroidal anti-inflammatory drugs are effective adjuncts to TB chemotherapy 238,239 , as well as host directed therapy for treating TB-IRIS 209 .…”

Section: The Goldilocks Model Of Immune Symbiosis With Candida Andmentioning

confidence: 99%

The Goldilocks model of immune symbiosis with Mycobacteria and Candida colonizers

Robinson

Huppler

2017

Cytokine

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Mycobacteria and Candida species include significant human pathogens that can cause localized or disseminated infections. Although these organisms may appear to have little in common, several shared pathways of immune recognition and response are important for both control and infection-related pathology. In this article, we compare and contrast the innate and adaptive components of the immune system that pertain to these infections in humans and animal models. We also explore a relatively new concept in the mycobacterial field: biological commensalism. Similar to the well-established model of Candida infection, Mycobacterial species colonize their human hosts in equilibrium with the immune response. Perturbations in the immune response permit the progression to pathologic disease at the expense of the host. Understanding the immune factors required to maintain commensalism may aid with the development of diagnostic and treatment strategies for both categories of pathogens.

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“…Faster resolution of neutrophilic inflammation is associated with shorter clinical recovery (10). Thus, this study served as a proof-of-mechanism study to examine whether roflumilast can improve clinical recovery after COPD exacerbations.…”

Section: To the Editormentioning

confidence: 99%

Gene Expression Signatures in Tuberculosis Have Greater Overlap with Autoimmune Diseases Than with Infectious Diseases

Clayton

Polak

Woelk

et al. 2017

Am J Respir Crit Care Med

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Towards host-directed therapies for tuberculosis

Abstract: This is the accepted version of the paper.This version of the publication may differ from the final published version. Permanent repository link:

Cited by 107 publications

References 5 publications

Metformin Adjunctive Therapy Does Not Improve the Sterilizing Activity of the First-Line Antitubercular Regimen in Mice

Metformin Adjunctive Therapy Does Not Improve the Sterilizing Activity of the First-Line Antitubercular Regimen in Mice

The Goldilocks model of immune symbiosis with Mycobacteria and Candida colonizers

Gene Expression Signatures in Tuberculosis Have Greater Overlap with Autoimmune Diseases Than with Infectious Diseases

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