<p class="first" id="d5174252e138">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.
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