An Immunomodulatory Peptide Confers Protection in an Experimental Candidemia Murine Model

Camila G Freitas; Stella M F Lima; Mirna S Freire; Ana Paula C Cantuária; Nelson G O Júnior; Tatiane S Santos; Jéssica S Folha; Suzana M Ribeiro; Simoni C Dias; Taia M B Rezende; Patrícia Albuquerque; André M Nicola; César de la Fuente-Núñez; Robert E W Hancock; Octávio L Franco; Maria Sueli S Felipe

doi:10.1128/AAC.02518-16

An Immunomodulatory Peptide Confers Protection in an Experimental Candidemia Murine Model

Antimicrob Agents Chemother. 2017 Jul 25;61(8):e02518-16. doi: 10.1128/AAC.02518-16. Print 2017 Aug.

Authors

Camila G Freitas^{1

2

3

4}, Stella M F Lima^{1

3

4

5}, Mirna S Freire^{1

6

7}, Ana Paula C Cantuária^{1

6

8}, Nelson G O Júnior^{1

6

9}, Tatiane S Santos^{6

10}, Jéssica S Folha^{6

10}, Suzana M Ribeiro^{1

11}, Simoni C Dias^{1

3

4}, Taia M B Rezende^{1

3

4

5

6

8}, Patrícia Albuquerque⁶, André M Nicola^{4

6}, César de la Fuente-Núñez^{12

13

14

15

16

17}, Robert E W Hancock¹⁸, Octávio L Franco^{19

20

3

4

6

7

8}, Maria Sueli S Felipe^{1

20

3

4

6}

Affiliations

¹ Centro de Análises Proteômicas e Bioquímicas, Brasília, Distrito Federal, Brazil.
² Instituto Federal de Brasília, Brasília, Distrito Federal, Brazil.
³ Universidade Católica de Brasília, Brasília, Brazil.
⁴ Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília, Brazil.
⁵ Curso de Odontologia, Universidade Católica de Brasília, Brasília, Brazil.
⁶ Universidade de Brasília, Brasília, Brazil.
⁷ Programa de Pós-Graduação em Biotecnologia e Biodiversidade-Rede Centro-oeste, Universidade de Brasília, Brasília, Brazil.
⁸ Pós-Graduação em Ciências da Saúde, Universidade de Brasília, Brasília, Brazil.
⁹ Pós-Graduação em Patologia Molecular, Universidade de Brasília, Brasília, Brazil.
¹⁰ Pós-Graduação em Medicina Tropical Universidade de Brasília, Brasília, Brazil.
¹¹ Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, Mato Grosso do Sul, Brazil.
¹² Synthetic Biology Group, MIT Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
¹³ Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
¹⁴ Department of Biological Engineering and Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
¹⁵ Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
¹⁶ Harvard Biophysics Program, Harvard University, Boston, Massachusetts, USA.
¹⁷ The Center for Microbiome Informatics and Therapeutics, Cambridge, Massachusetts, USA.
¹⁸ Center for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁹ Centro de Análises Proteômicas e Bioquímicas, Brasília, Distrito Federal, Brazil ocfranco@gmail.com.
²⁰ S-Inova Biotech-Universidade Católica Dom Bosco, Campo Grande, Mato Grosso do Sul, Brazil.

Abstract

Fungal Candida species are commensals present in the mammalian skin and mucous membranes. Candida spp. are capable of breaching the epithelial barrier of immunocompromised patients with neutrophil and cell-mediated immune dysfunctions and can also disseminate to multiple organs through the bloodstream. Here we examined the action of innate defense regulator 1018 (IDR-1018), a 12-amino-acid-residue peptide derived from bovine bactenecin (Bac2A): IDR-1018 showed weak antifungal and antibiofilm activity against a Candida albicans laboratory strain (ATCC 10231) and a clinical isolate (CI) (MICs of 32 and 64 μg · ml^-1, respectively), while 8-fold lower concentrations led to dissolution of the fungal cells from preformed biofilms. IDR-1018 at 128 μg · ml^-1 was not hemolytic when tested against murine red blood cells and also has not shown a cytotoxic effect on murine monocyte RAW 264.7 and primary murine macrophage cells at the tested concentrations. IDR-1018 modulated the cytokine profile during challenge of murine bone marrow-derived macrophages with heat-killed C. albicans (HKCA) antigens by increasing monocyte chemoattractant protein 1 (MCP-1) and interleukin-10 (IL-10) levels, while suppressing tumor necrosis factor alpha (TNF-α), IL-1β, IL-6, and IL-12 levels. Mice treated with IDR-1018 at 10 mg · kg^-1 of body weight had an increased survival rate in the candidemia model compared with phosphate-buffered saline (PBS)-treated mice, together with a diminished kidney fungal burden. Thus, IDR-1018 was able to protect against murine experimental candidemia and has the potential as an adjunctive therapy.

Keywords: Candida albicans; IDR-1018 peptide; antifungals; host-directed therapy; immunomodulatory effects; murine experimental candidemia.

MeSH terms

Animals
Antifungal Agents / therapeutic use*
Antimicrobial Cationic Peptides / therapeutic use*
Biofilms / drug effects*
Candida albicans / drug effects*
Candida albicans / immunology
Candida albicans / isolation & purification
Candidemia / drug therapy*
Candidemia / prevention & control*
Cell Line
Chemokine CCL2 / immunology
Disease Models, Animal
Immunologic Factors / therapeutic use*
Interleukin-10 / immunology
Interleukin-12 Subunit p35 / metabolism
Interleukin-1beta / metabolism
Interleukin-6 / metabolism
Macrophages / drug effects
Mice
Microbial Sensitivity Tests
RAW 264.7 Cells
Tumor Necrosis Factor-alpha / metabolism

Substances

Antifungal Agents
Antimicrobial Cationic Peptides
Ccl2 protein, mouse
Chemokine CCL2
IL10 protein, mouse
IL1B protein, mouse
Il12a protein, mouse
Immunologic Factors
Interleukin-12 Subunit p35
Interleukin-1beta
Interleukin-6
Tumor Necrosis Factor-alpha
innate defense regulating peptide 1018
interleukin-6, mouse
Interleukin-10

Grants and funding

CIHR/Canada