Abstract
In 2017 over 550,000 estimated new cases of multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) occurred, emphasizing a need for new treatment strategies. Linezolid (LZD) is a potent antibiotic for drug-resistant Gram-positive infections and is an effective treatment for TB. However, extended LZD use can lead to LZD-associated host toxicities, most commonly bone marrow suppression. LZD toxicities may be mediated by IL-1, an inflammatory pathway important for early immunity during M. tuberculosis infection. However, IL-1 can contribute to pathology and disease severity late in TB progression. Since IL-1 may contribute to LZD toxicity and does influence TB pathology, we targeted this pathway with a potential host-directed therapy (HDT). We hypothesized LZD efficacy could be enhanced by modulation of IL-1 pathway to reduce bone marrow toxicity and TB associated-inflammation. We used two animal models of TB to test our hypothesis, a TB-susceptible mouse model and clinically relevant cynomolgus macaques. Antagonizing IL-1 in mice with established infection reduced lung neutrophil numbers and partially restored the erythroid progenitor populations that are depleted by LZD. In macaques, we found no conclusive evidence of bone marrow suppression associated with LZD, indicating our treatment time may have been short enough to avoid the toxicities observed in humans. Though treatment was only 4 weeks (the FDA approved regimen at the time of study), we observed sterilization of the majority of granulomas regardless of co-administration of the FDA-approved IL-1 receptor antagonist (IL-1Rn), also known as Anakinra. However, total lung inflammation was significantly reduced in macaques treated with IL-1Rn and LZD compared to LZD alone. Importantly, IL-1Rn administration did not impair the host response against Mtb or LZD efficacy in either animal model. Together, our data support that inhibition of IL-1 in combination with LZD has potential to be an effective HDT for TB and the need for further research in this area.
Highlights
Tuberculosis (TB) remains the top cause of death by a single infectious agent, with an estimated 10 million new cases of active TB and 1.3 million deaths in 2017 alone [1]
Given the complex role played by IL-1 during TB, we initially sought to determine the effect of inhibiting this cytokine during TB disease in mice
In relatively resistant C57BL/6 animals, mature IL-1 production is controlled by IFNγdependent nitric oxide production, whereas unregulated IL-1 drives inflammatory disease characterized by increased number of neutrophils (PMNs), bacterial burden (CFU) in the lungs and significant weight loss observed in Mycobacterium tuberculosis (Mtb)-infected Nos2−/− mice that lack this regulatory pathway [9, 10]
Summary
Tuberculosis (TB) remains the top cause of death by a single infectious agent, with an estimated 10 million new cases of active TB and 1.3 million deaths in 2017 alone [1]. Antibiotic treatment regimens are long and multi-drug resistant (MDR) and extensive-drug resistant (XDR) Mycobacterium tuberculosis (Mtb) strains have emerged, complicating treatment. Even those patients that are cured of the infection can suffer permanent deficits in lung function that result from inflammation and fibrosis [2]. HDTs can function to enhance antimicrobial immune responses and shorten therapy, or inhibit pathological inflammation [3]. Since HDTs would be used as part of a multidrug regimen, targeting mechanisms that increase drug exposure or decrease toxicity are possible. While some HDT strategies hold promise, very few have been rigorously tested in pre-clinical models [4]
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