Innate immune memory through TLR2 and NOD2 contributes to the control of leptospira interrogans infection

Ignacio Santecchia, Frédérique Vernel-Pauillac, Orhan Rasid, Jessica Quintin, Maria Gomes-Solecki, Ivo G. Boneca, Catherine Werts

Research output: Contribution to journalArticle

Abstract

Leptospira interrogans are pathogenic spirochetes responsible for leptospirosis, a worldwide reemerging zoonosis. Many Leptospira serovars have been described, and prophylaxis using inactivated bacteria provides only short-term serovar-specific protection. Therefore, alternative approaches to limit severe leptospirosis in humans and morbidity in cattle would be welcome. Innate immune cells, including macrophages, play a key role in fighting infection and pathogen clearance. Recently, it has been shown that functional reprograming of innate immune cells through the activation of pattern recognition receptors leads to enhanced nonspecific antimicrobial responses upon a subsequent microbial encounter. This mechanism is known as trained immunity or innate immune memory. We have previously shown that oral treatment with Lactobacillus plantarum confers a beneficial effect against acute leptospirosis. Here, using a macrophage depletion protocol and live imaging in mice, we established the role of peritoneal macrophages in limiting the initial dissemination of leptospires. We further showed that intraperitoneal priming of mice with CL429, a TLR2 and NOD2 agonist known to mimic the modulatory effect of Lactobacillus, alleviated acute leptospiral infection. The CL429 treatment was characterized as a training effect since i.) it was linked to peritoneal macrophages that produced ex vivo more pro-inflammatory cytokines and chemokines against 3 different pathogenic serovars of Leptospira, independently of the presence of B and T cells, ii.) it had systemic effects on splenic cells and bone marrow derived macrophages, and iii.) it was sustained for 3 months. Importantly, trained macrophages produced more nitric oxide, a potent antimicrobial compound, which has not been previously linked to trained immunity. Accordingly, trained macrophages better restrict leptospiral survival. Finally, we could use CL429 to train ex vivo human monocytes that produced more cytokines upon leptospiral stimulation. In conclusion, host-directed treatment using a TLR2/NOD2 agonist could be envisioned as a novel prophylactic strategy against acute leptospirosis.

Original languageEnglish (US)
Article numbere1007811
JournalPLoS Pathogens
Volume15
Issue number5
DOIs
StatePublished - May 1 2019

Fingerprint

Leptospira interrogans
Leptospirosis
Macrophages
Leptospira
Infection
Peritoneal Macrophages
Cytokines
Pattern Recognition Receptors
Lactobacillus plantarum
Spirochaetales
Zoonoses
Lactobacillus
Chemokines
Innate Immunity
Monocytes
Immunity
Nitric Oxide
B-Lymphocytes
Morbidity
Bacteria

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Innate immune memory through TLR2 and NOD2 contributes to the control of leptospira interrogans infection. / Santecchia, Ignacio; Vernel-Pauillac, Frédérique; Rasid, Orhan; Quintin, Jessica; Gomes-Solecki, Maria; Boneca, Ivo G.; Werts, Catherine.

In: PLoS Pathogens, Vol. 15, No. 5, e1007811, 01.05.2019.

Research output: Contribution to journalArticle

Santecchia, Ignacio ; Vernel-Pauillac, Frédérique ; Rasid, Orhan ; Quintin, Jessica ; Gomes-Solecki, Maria ; Boneca, Ivo G. ; Werts, Catherine. / Innate immune memory through TLR2 and NOD2 contributes to the control of leptospira interrogans infection. In: PLoS Pathogens. 2019 ; Vol. 15, No. 5.
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