Evaluation of IL-1 blockade as a host-directed therapy for tuberculosis in mice and macaques [preprint]
AuthorsWinchell, Caylin G.
Mishra, Bibhuti B.
University of Massachusetts Medical School
Nelson, Samantha J.
Sassetti, Christopher M.
Flynn, JoAnne L.
UMass Chan AffiliationsGraduate School of Biomedical Sciences
Department of Microbiology and Physiological Systems
Bacterial Infections and Mycoses
Hemic and Immune Systems
Immunoprophylaxis and Therapy
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AbstractIn 2017, there were over 550,000 estimated new cases of multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB), emphasizing a need for new treatment strategies. Linezolid (LZD) is a potent antibiotic for antibiotic-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, a pathway important for early immunity during M. tuberculosis infection that later contributes to pathology. We hypothesized LZD efficacy could be enhanced by modulation of IL-1 pathway to reduce BM toxicity and TB associated-inflammation. We used two animal models of TB to test our hypothesis, mice and cynomolgus macaques. Antagonizing IL-1 in chronically-infected mice reduced lung neutrophil numbers and partially restored the erythroid progenitor populations that are depleted by LZD. In macaques, we found no conclusive evidence of BM suppression associated with LZD, indicating our treatment time may have been short enough to avoid the toxicities observed in humans. Though treatment was only 1 month, the majority of granulomas were sterilized with reduced inflammation (assessed by PET/CT) in animals treated with both LZD and IL-1 receptor antagonist (IL-1Rn). However, overall lung inflammation was significantly reduced in macaques treated with both IL-1Rn and LZD, compared to LZD alone. Importantly, IL-1Rn administration did not noticeably 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.
bioRxiv 792390; doi: https://doi.org/10.1101/792390. Link to preprint on bioRxiv service.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/29415
Full author list omitted for brevity. For the full list of authors, see article.
RightsThe copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY 4.0 International license.
Except where otherwise noted, this item's license is described as The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY 4.0 International license.