Evaluation of IL-1 blockade as an adjunct to linezolid therapy for tuberculosis in mice and macaques

Abstract

<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>M. tuberculosis</jats:italic> 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.</jats:p>

Tuberculosis alters immune-metabolic pathways resulting in perturbed IL-1 responses

“…These results add to the existing complexities of cytokine responses to M.tb, in which the overall context will determine infection outcome, rather than the presence/absence of particular cytokines. For instance, the timing of IL-1 54,55 or type I IFN signalling 56 is a decisive factor to exert beneficial roles in the context of TB disease. Our study shows how TNF, a critical cytokine for control of M.tb , also induced IL-1ra expression, which can prevent effective IL-1 responses, that are in turn essential for protective immunity.…”

“…This observation shows that there is no intrinsic defect in IL-1β signalling capabilities in TB patients. However the timing of IL-1 responses has been shown to be critical for M.tb control 54,55 , and elevated IL-1 signalling has been associated with lung immunopathology 63,64 . The consequences of IL-1β hyper responsiveness in TB patients therefore warrants further investigation.…”

TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis

“…However, as TB disease progresses, IL-1b becomes a driver of proinflammatory eicosanoids signaling leading to an influx of neutrophilic inflammation that is permissive to bacterial growth (6). In later stages of TB disease in mice, IL-1 blockade is therapeutic and limits tissue damage (8).…”

“…While early IL-1 production following infection with Mycobacterium tuberculosis (Mtb) is critical for control of bacterial replication (7), ongoing IL-1 signaling can lead to upregulation of proinflammatory eicosanoids and an influx of neutrophils, which promote further bacterial replication and tissue destruction (6). IL-1 blockade in macaques with pulmonary TB disease limits tissue inflammation and damage, further supporting a pathologic role for dysregulated IL-1 signaling in pulmonary TB (8).…”

Evaluation of IL-1 Blockade as an Adjunct to Linezolid Therapy for Tuberculosis in Mice and Macaques

“…Special thanks to all the veterinary and research staff for their efforts, expertise and dedication to these studies. This manuscript has been released as a pre-print at bioRxiv Winchell et al (44).…”