Evaluation of IL-1 Blockade as an Adjunct to Linezolid Therapy for Tuberculosis in Mice and Macaques
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 L...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.00891/full |
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| author | Caylin G. Winchell Bibhuti B. Mishra Bibhuti B. Mishra Jia Yao Phuah Mohd Saqib Samantha J. Nelson Pauline Maiello Chelsea M. Causgrove Cassaundra L. Ameel Brianne Stein H. Jacob Borish Alexander G. White Edwin C. Klein Matthew D. Zimmerman Véronique Dartois Philana Ling Lin Christopher M. Sassetti JoAnne L. Flynn |
| author_facet | Caylin G. Winchell Bibhuti B. Mishra Bibhuti B. Mishra Jia Yao Phuah Mohd Saqib Samantha J. Nelson Pauline Maiello Chelsea M. Causgrove Cassaundra L. Ameel Brianne Stein H. Jacob Borish Alexander G. White Edwin C. Klein Matthew D. Zimmerman Véronique Dartois Philana Ling Lin Christopher M. Sassetti JoAnne L. Flynn |
| author_sort | Caylin G. Winchell |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T06:50:59Z |
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| id | doaj.art-cb9c7db12abd401b9c0a88eb06a4e51b |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-19T06:50:59Z |
| publishDate | 2020-05-01 |
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| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-cb9c7db12abd401b9c0a88eb06a4e51b2022-12-21T20:31:43ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-05-011110.3389/fimmu.2020.00891533399Evaluation of IL-1 Blockade as an Adjunct to Linezolid Therapy for Tuberculosis in Mice and MacaquesCaylin G. Winchell0Bibhuti B. Mishra1Bibhuti B. Mishra2Jia Yao Phuah3Mohd Saqib4Samantha J. Nelson5Pauline Maiello6Chelsea M. Causgrove7Cassaundra L. Ameel8Brianne Stein9H. Jacob Borish10Alexander G. White11Edwin C. Klein12Matthew D. Zimmerman13Véronique Dartois14Philana Ling Lin15Christopher M. Sassetti16JoAnne L. Flynn17Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, United StatesDepartment of Immunology and Microbial Disease, Albany Medical College, Albany, NY, United StatesDepartment of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, United StatesDepartment of Immunology and Microbial Disease, Albany Medical College, Albany, NY, United StatesDepartment of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, United StatesDepartment of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDivision of Laboratory Animal Research, University of Pittsburgh, Pittsburgh, PA, United StatesCenter for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United StatesCenter for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United StatesDepartment of Pediatrics, UPMC Children's Hospital of the University of Pittsburgh, Pittsburgh, PA, United StatesDepartment of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, United StatesDepartment of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesIn 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.https://www.frontiersin.org/article/10.3389/fimmu.2020.00891/fulltuberculosisMDR-TBIL-1linezolidhost-directed therapy |
| spellingShingle | Caylin G. Winchell Bibhuti B. Mishra Bibhuti B. Mishra Jia Yao Phuah Mohd Saqib Samantha J. Nelson Pauline Maiello Chelsea M. Causgrove Cassaundra L. Ameel Brianne Stein H. Jacob Borish Alexander G. White Edwin C. Klein Matthew D. Zimmerman Véronique Dartois Philana Ling Lin Christopher M. Sassetti JoAnne L. Flynn Evaluation of IL-1 Blockade as an Adjunct to Linezolid Therapy for Tuberculosis in Mice and Macaques Frontiers in Immunology tuberculosis MDR-TB IL-1 linezolid host-directed therapy |
| title | Evaluation of IL-1 Blockade as an Adjunct to Linezolid Therapy for Tuberculosis in Mice and Macaques |
| title_full | Evaluation of IL-1 Blockade as an Adjunct to Linezolid Therapy for Tuberculosis in Mice and Macaques |
| title_fullStr | Evaluation of IL-1 Blockade as an Adjunct to Linezolid Therapy for Tuberculosis in Mice and Macaques |
| title_full_unstemmed | Evaluation of IL-1 Blockade as an Adjunct to Linezolid Therapy for Tuberculosis in Mice and Macaques |
| title_short | Evaluation of IL-1 Blockade as an Adjunct to Linezolid Therapy for Tuberculosis in Mice and Macaques |
| title_sort | evaluation of il 1 blockade as an adjunct to linezolid therapy for tuberculosis in mice and macaques |
| topic | tuberculosis MDR-TB IL-1 linezolid host-directed therapy |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.00891/full |
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