Immunomodulatory and antibacterial effects of cystatin 9 against Francisella tularensis

Tonyia Eaves-Pyles, Jignesh Patel, Emma Arigi, Yingzi Cong, Anthony Cao, Nisha Garg, Monisha Dhiman, Richard B. Pyles, Bernard Arulanandam, Aaron L. Miller, Vsevolod L. Popov, Lynn Soong, Eric D. Carlsen, Ciro Coletta, Csaba Szabo, Igor C. Almeida

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Cystatin 9 (CST9) is a member of the type 2 cysteine protease inhibitor family, which has been shown to have immunomodulatory effects that restrain inflammation, but its functions against bacterial infections are unknown. Here, we report that purified human recombinant (r)CST9 protects against the deadly bacterium Francisella tularensis (Ft) in vitro and in vivo. Macrophages infected with the Ft human pathogen Schu 4 (S4), then given 50 pg of rCST9 exhibited significantly decreased intracellular bacterial replication and increased killing via preventing the escape of S4 from the phagosome. Further, rCST9 induced autophagy in macrophages via the regulation of the mammalian target of rapamycin (mTOR) signaling pathways. rCST9 promoted the upregulation of macrophage proteins involved in antiinflammation and antiapoptosis, while restraining proinflammatory-associated proteins. Interestingly, the viability and virulence of S4 also was decreased directly by rCST9. In a mouse model of Ft inhalation, rCST9 significantly decreased organ bacterial burden and improved survival, which was not accompanied by excessive cytokine secretion or subsequent immune cell migration. The current report is the first to show the immunomodulatory and antimicrobial functions of rCST9 against Ft. We hypothesize that the attenuation of inflammation by rCST9 may be exploited for therapeutic purposes during infection.

Original languageEnglish (US)
Pages (from-to)263-275
Number of pages13
JournalMolecular Medicine
Volume19
Issue number1
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Eaves-Pyles, T., Patel, J., Arigi, E., Cong, Y., Cao, A., Garg, N., Dhiman, M., Pyles, R. B., Arulanandam, B., Miller, A. L., Popov, V. L., Soong, L., Carlsen, E. D., Coletta, C., Szabo, C., & Almeida, I. C. (2013). Immunomodulatory and antibacterial effects of cystatin 9 against Francisella tularensis. Molecular Medicine, 19(1), 263-275. https://doi.org/10.2119/molmed.2013.00081