Increased inflammation with crude E. coli LPS protects against acute leptospirosis in hamsters

Abstract

Leptospirosis is a worldwide zoonotic disease that causes acute kidney injury, liver disease, bleeding disorders, and even death. Treatment of the disease is largely dependent on the use of antibiotics, but recent studies on pathogenesis of leptospirosis have shown that immunomodulation may also be an effective treatment for this disease. Since the delay in inflammation correlates with higher pathogenicity of leptospira, we studied the effect of inducing inflammation on leptospirosis by using TLR4 activator LPS. In accordance with our hypothesis, treatment with LPS protected against leptospirosis by enhancing the inflammatory response in hamsters. The gene expression levels of TLR2, TLR4, NLRP3 and inflammatory factors were higher in LPS-treated group during leptospira infection in hamsters. Although the levels of NO and iNOS were higher in LPS-treated group than in Leptospira-infected group, the protective effect induced by LPS is iNOS-independent. Treatment with LPS induced higher anti-leptospira IgG level than infection with leptospira alone. Then, expressions of costimulatory molecules and maturation markers were analysed. The data showed that treatment with LPS enhanced the expression of CD40, CD80 and CD86. Our results indicate that increased inflammation induced by LPS derived from Escherichia coli (E. coli) protects against leptospirosis in hamsters.

Revisiting the Development of Vaccines Against Pathogenic Leptospira: Innovative Approaches, Present Challenges, and Future Perspectives

“…Along the same line, LPS from E. coli, a very well-characterized TLR4 agonist, when administered 24 h before infection followed by 3 days postinfection, produced 100% survival. Untreated hamsters died in the first days after infection, while the administration of a single dose of LPS 24 h post-infection generated about 50% survival, reinforcing the notion that an early inflammatory response is important to control leptospirosis (86). An interesting observation in those studies was that while Pam3CSK4 showed a tendency to reduce the bacterial burden in organs; this was not observed after using LPS.…”

Neutralizing gut-derived lipopolysaccharide as a novel therapeutic strategy for severe leptospirosis

“…Then, it was centrifuged at 12000 rpm and 4 °C for 5 min. The pellets were extracted using the TIANamp Bacteria DNA kit (Tiangen, China) according to the manufacturer's instructions [26] . The concentration of DNA was measured by spectrometry.…”

Phagocyte Escape of Leptospira: The Role of TLRs and NLRs

“…Hence, despite being responsible for cellular activation and inflammation in vitro , TLR2 triggering is not essential to mouse defense. Indeed, in contrast with TLR4 knockout (KO) mice, TLR2KO mice do not die from experimental leptospirosis ( 116 , 126 ). However, activation of TLR2 in addition to TLR4 contributes to host protection in mice by triggering cytokine secretion and leptospire-specific IgG, NO, and IFNγ secretion ( 116 ).…”

“… Enhancement of the immune system to better control leptospires. (A) Coinjection at the time of leptospiral infection of PRR agonists such as Pam3CSK (a TLR2 agonist) ( 138 ), β-glucan (a Dectin-1 agonist that potentially synergizes with TLR2) ( 139 ), or crude Escherichia coli LPS (a TLR2/TLR4 agonist) ( 126 ) leads to enhancement of hamster immune responses along with improved survival or delayed lethality and reductions in the number of survivors in tissue lesions, bacterial loads, and inflammation. (B) Recently, innate immune memory or trained immunity has been explored as a therapeutic strategy against leptospires.…”

“…More recently, the same group investigated the effect of crude E. coli LPS administered in hamsters after infection with leptospires and showed an improved outcome in hamsters, which was correlated with increased inflammation levels ( 126 ). However, the use of nonrepurified crude E. coli LPS, which is known to activate both TLR2 and TLR4 ( 126 , 141 ), made the interpretation of the relative contributions of TLR4 and TLR2 difficult. Nonetheless, an interesting observation is that upon leptospiral infection, cotreatment with E. coli LPS dramatically enhanced both NO secretion and MPO activity.…”