University of Massachusetts Medical School Faculty Publications
UMMS Affiliation
Department of Microbiology and Physiological Systems; Graduate School of Biomedical Sciences
Publication Date
2019-10-03
Document Type
Article Preprint
Disciplines
Bacterial Infections and Mycoses | Hemic and Immune Systems | Immunopathology | Immunoprophylaxis and Therapy | Microbiology | Therapeutics
Abstract
In 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.
Keywords
Microbiology, IL-1, tuberculosis, therapeutics, rifampicin, drug resistance
Rights and Permissions
The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.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.
DOI of Published Version
10.1101/792390
Source
bioRxiv 792390; doi: https://doi.org/10.1101/792390. Link to preprint on bioRxiv service.
Journal/Book/Conference Title
bioRxiv
Repository Citation
Winchell CG, Mishra BB, University of Massachusetts Medical School, Nelson SJ, Sassetti CM, Flynn JL. (2019). Evaluation of IL-1 blockade as a host-directed therapy for tuberculosis in mice and macaques. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1101/792390. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1643
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Included in
Bacterial Infections and Mycoses Commons, Hemic and Immune Systems Commons, Immunopathology Commons, Immunoprophylaxis and Therapy Commons, Microbiology Commons, Therapeutics Commons
Comments
Full author list omitted for brevity. For the full list of authors, see article.