Toll-Like Receptor 2 Agonist Pam3CSK4 Alleviates the Pathology of Leptospirosis in Hamster

Abstract

dLeptospirosis, caused by pathogenic spirochetes, is a zoonotic disease of global importance. The detailed pathogenesis of leptospirosis is still unclear, which limits the ideal treatment of leptospirosis. In this study, we analyzed the expression of Toll-like receptor 2 (TLR2) and TLR4 in target organs of both resistant mice and susceptible hamsters after Leptospira interrogans serovar Autumnalis infection. TLR2 but not TLR4 transcripts in mouse organs contrasted with delayed induction and overexpression in hamster organs. Coinjection of leptospires and the TLR2 agonist Pam3CSK4 into hamsters improved their survival rate, alleviated tissue injury, and decreased the abundance of leptospires in target organs. The production of interleukin-10 (IL-10) from tissues was enhanced in hamsters of the group coinjected with leptospires and Pam3CSK4 compared with the leptospira-injected group. Similarly, IL-10 levels in TLR2-deficient mice were lower than those in wild-type mice. A high ratio of IL-10/tumor necrosis factor alpha (TNF-␣) levels was found in both infected wild-type mice and hamsters coinjected with leptospires and Pam3CSK4. Moreover, TLR2-dependent IL-10 expression was detected in peritoneal macrophages after leptospira infection. Our data demonstrate that coinjection of leptospires and Pam3CSK4 alleviates the pathology of leptospirosis in hamsters; this effect may result from the enhanced expression of TLR2-dependent IL-10. L eptospirosis, caused by pathogenic spirochetes, is responsible for a worldwide zoonotic disease. Infected hosts present a diverse array of clinical manifestations ranging from asymptomatic forms to jaundice, renal failure, and even death (1). After infection of maintenance hosts, leptospires rapidly disseminate to almost all tissues during early stages, followed by clearance, except from the kidney, causing chronic infection (2). As the main maintenance hosts, rodents can shed pathogenic leptospires in their urine, which contaminate water and soil. Humans and animals may acquire this disease by direct contact with urine or indirectly from contaminated water (3). Thus, the renal carrier state constitutes an important aspect of the persistence and epidemiology of leptospirosis (3). Although the mechanisms of leptospira-induced immunoreaction have been noted in several studies, the role of innate immune responses in protection against leptospirosis is poorly understood (4).Toll-like receptors (TLRs) acting as pattern recognition receptors (PRRs) can recognize a variety of pathogen-associated molecular patterns (PAMPs) (5). Genetic data from mouse studies have demonstrated that the sole receptor for classical enterobacterial lipopolysaccharide (LPS) is indeed TLR4 (6), but highly purified leptospiral LPS utilizes both TLR2 and TLR4 in mice and only TLR2 in humans (7). Previous studies have shown that TLR4 is vital for the control of the leptospiral burden in vivo, whereas both TLR2 and TLR4 control the leptospiral burden in the kidney, and tissue differences in TLR signaling may exist (8, ...

Recent findings related to immune responses against leptospirosis and novel strategies to prevent infection

“…Up-regulation of IL-10 by leptospires would dampen the IFN-g expression, which would limit the bacterial clearance, hence favoring a chronic infection. Interestingly, it has recently been shown that the IL-10 secretion in the kidneys relies on the TLR2 pathway triggered by leptospires [49]. These data should encourage novel strategies aimed at enhancing phagocytic activity to avoid or limit leptospiral colonization in kidneys.…”

Spirochetal Lipoproteins and Immune Evasion

“…IL-10, unlike cytokines such as IL-1 and IL-12, is known to reduce inflammation via TLR-pathway downregulation and can therefore assist in combatting the spirochetal infection as well as any possible chronic effects such as arthritis (76, 77). The above was confirmed in recent mice studies that utilized a TLR2 agonist, Pam3CSK4, to induce IL-10 production which attenuated inflammatory response to Leptospira (78). Thus, spirochetal lipoproteins exert their pro-inflammatory effects through several pathways including CD14, TLR, and NF-κB signaling and induce both pro-inflammatory (such as IL-1) and anti-inflammatory cytokines (IL-10) production in myeloid cells such as M/M.…”

Murine Models for Leptospirosis Kidney Disease

“…Recently, it has been shown that IL-10 was decreased in TLR2ko mice infected with leptospires [37] , suggesting that TLR2 activation leads to IL-10 production and would thus be crucial to favor the renal colonization by leptospires. Therefore, TLR2 would exert a dual role ( Fig.…”

“…2 ). On the one hand, TLR2 plays a protective role, being involved in the production of protective antibodies and cytokines and/or helping the host to survive the acute phase of leptospirosis when activated by a synthetic agonist [37] , but, on the other hand, it sustains the leptospires' ability to escape the immune response and survive, hidden in the kidney.…”