Research Article: Innate immune memory through TLR2 and NOD2 contributes to the control of Leptospira interrogans infection

Date Published: May 20, 2019

Publisher: Public Library of Science

Author(s): Ignacio Santecchia, Frédérique Vernel-Pauillac, Orhan Rasid, Jessica Quintin, Maria Gomes-Solecki, Ivo G. Boneca, Catherine Werts, Dana J. Philpott.


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.

Partial Text

Leptospira belong to the phylum Spirochetes and are the etiological agents of leptospirosis, a reemerging worldwide zoonosis [1]. Pathogenic leptospires, including Leptospira interrogans, can infect and colonize multiple hosts, and leptospirosis constitutes a global burden affecting both human health and agricultural economics. Leptospires enter their hosts through abraded skin or mucosa and then disseminate in blood, potentially leading to renal infection [2]. Leptospirosis is underdiagnosed at its onset because of unspecific symptoms common to other viral and bacterial infections, such as fever, headaches and jaundice. Leptospirosis can cause multiorgan failure in humans and leads to a mortality rate of 6–10%. More than 300 serovars of pathogenic leptospires have been described [2]. Thus, vaccination is possible only in certain contexts, like in endemic areas when the circulating serovars are known. A few human vaccines based on inactivated whole bacteria are available, but they confer only serovar-specific and short-term protection [3]. In the absence of prophylactic drugs, preventive antibiotic therapy and wearing adapted clothes constitute the most effective prevention against this neglected disease.

In this study, we explored the role of macrophages in a mouse model of leptospirosis. On the one hand, we used a depletion approach with a treatment with clodronate liposomes that suggests a role for macrophages in the early stages of leptospiral infection. On the other hand, we showed that pretreatment with CL429, a bifunctional TLR2/NOD2 ligand, induces protection against leptospiral infection. Pretreatment with CL429 modified the environment of the peritoneal cavity with macrophage enrichment and boosted the responses of macrophages against a subsequent leptospiral infection. These effects in mice correspond to the described trained immunity characteristics and were recapitulated in human monocytes. These results suggest that CL429 pretreatment could be used to boost human and animal cellular responses, which could potentially open up prophylactic strategies to control acute L. interrogans infection.




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