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Molecular Medicine

, Volume 19, Issue 1, pp 263–275 | Cite as

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 Article

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.

Notes

Acknowledgments

This work was supported by Eaves-Pyles’ NIH/NIAID (R21-A106877402). We would like to thank Istvan Boldogh (Department of Microbiology and Immunology, University of Texas Medical Branch) for his advice, suggestions and input on the in vivo studies presented herein and Bill Calhoun (Department of Internal Med-Pulmonary, University of Texas Medical Branch) for his contribution to the autophagy results. We are gratefuly to the Biomolecule Analysis Core Facility at the BBRC/Biology/UTEP (NIH grants G12M0007592, 5G12RR008124-16A1 and 5G12RR008124-16A1S1) for proteomic analysis.

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Authors and Affiliations

  • Tonyia Eaves-Pyles
    • 1
  • Jignesh Patel
    • 1
  • Emma Arigi
    • 2
  • Yingzi Cong
    • 1
  • Anthony Cao
    • 1
  • Nisha Garg
    • 1
  • Monisha Dhiman
    • 1
  • Richard B. Pyles
    • 1
    • 3
  • Bernard Arulanandam
    • 4
  • Aaron L. Miller
    • 3
  • Vsevolod L. Popov
    • 5
  • Lynn Soong
    • 1
  • Eric D. Carlsen
    • 1
  • Ciro Coletta
    • 6
  • Csaba Szabo
    • 6
  • Igor C. Almeida
    • 2
  1. 1.Department of Microbiology and ImmunologyUniversity of Texas Medical BranchGalvestonUSA
  2. 2.The Border Biomedical Research Center, Department of Biological SciencesUniversity of Texas at El PasoEl PasoUSA
  3. 3.Department of PediatricsUniversity of Texas Medical BranchGalvestonUSA
  4. 4.College of SciencesUniversity of Texas at San AntonioSan Antonio TexasUSA
  5. 5.Department of PathologyUniversity of Texas Medical BranchGalvestonUSA
  6. 6.AnesthesiologyUniversity of Texas Medical BranchGalvestonUSA

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