Cystatins 9 and C as a novel immunotherapy treatment that protects against multidrug-resistant New Delhi metallo-beta-lactamase-1-producing klebsiella pneumoniae

Alex J. Holloway, Jieh Juen Yu, Bernard P. Arulanandam, Sarah M. Hoskinson, Tonyia Eaves-Pyles

    Research output: Contribution to journalArticlepeer-review

    6 Scopus citations

    Abstract

    Multidrug-resistant (MDR) bacterial pneumonia can induce dysregulated pulmonary and systemic inflammation leading to morbidity and mortality. Antibiotics to treat MDR pathogens do not function to modulate the extent and intensity of inflammation and can have serious side effects. Here we evaluate the efficacy of two human cysteine proteinase inhibitors, cystatin 9 (CST9) and cystatin C (CSTC), as a novel immunotherapeutic treatment to combat MDR New Delhi metallo-beta-lactamase-1 (NDM-1)-producing Klebsiella pneumoniae. Our results showed that mice infected intranasally (i.n.) with a 90% lethal dose (LD 90 ) challenge of NDM-1 K. pneumoniae and then treated with the combination of human recombinant CST9 (rCST9) and rCSTC (rCSTs; 50 pg of each i.n. at 1 h postinfection [p.i.] and/or 500 pg of each intraperitoneally [i.p.] at 3 days p.i.) had significantly improved survival compared to that of infected mice alone or infected mice treated with individual rCSTs (P 0.05). Results showed that both of our optimal rCST treatment regimens modulated pulmonary and systemic proinflammatory cytokine secretion in the serum, lungs, liver, and spleen in infected mice (P 0.05). Treatment also significantly decreased the bacterial burden (P 0.05) while preserving lung integrity, with reduced inflammatory cell accumulation compared to that in infected mice. Further, rCST treatment regimens reduced lipid peroxidation and cell apoptosis in the lungs of infected mice. Additionally, in vitro studies showed that rCSTs (50 or 500 pg of each) directly decreased the viability of NDM-1 K. pneumoniae. In conclusion, the data showed that rCST9/ rCSTC worked synergistically to modulate host inflammation against MDR NDM-1 K. pneumoniae pneumonia, which significantly improved survival. Therefore, rCST9/rCSTC is a promising therapeutic candidate for the treatment of bacterial pneumonia.

    Original languageEnglish (US)
    Article numbere01900-17
    JournalAntimicrobial agents and chemotherapy
    Volume62
    Issue number3
    DOIs
    StatePublished - Mar 2018

    Keywords

    • Antimicrobial
    • Cystatin 9
    • Cystatin C
    • Immunomodulation
    • Immunotherapy
    • Inflammation
    • Multidrug resistant
    • New Delhi metallo-beta-lactamase-1-producing K. pneumoniae
    • Pneumonia

    ASJC Scopus subject areas

    • Pharmacology
    • Pharmacology (medical)
    • Infectious Diseases

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