Phagocyte Escape of Leptospira: The Role of TLRs and NLRs

Abstract

The spirochetal bacteria Leptospira spp. are causative agents of leptospirosis, a globally neglected and reemerging zoonotic disease. Infection with these pathogens may lead to an acute and potentially fatal disease but also to chronic asymptomatic renal colonization. Both forms of disease demonstrate the ability of leptospires to evade the immune response of their hosts. In this review, we aim first to recapitulate the knowledge and explore the controversial data about the opsonization, recognition, intracellular survival, and killing of leptospires by scavenger cells, including platelets, neutrophils, macrophages, and dendritic cells. Second, we will summarize the known specificities of the recognition or escape of leptospire components (the so-called microbial-associated molecular patterns; MAMPs) by the pattern recognition receptors (PRRs) of the Toll-like and NOD-like families. These PRRs are expressed by phagocytes, and their stimulation by MAMPs triggers pro-inflammatory cytokine and chemokine production and bactericidal responses, such as antimicrobial peptide secretion and reactive oxygen species production. Finally, we will highlight recent studies suggesting that boosting or restoring phagocytic functions by treatments using agonists of the Toll-like or NOD receptors represents a novel prophylactic strategy and describe other potential therapeutic or vaccine strategies to combat leptospirosis.

Inflammatory Signatures of Pathogenic and Non-Pathogenic Leptospira Infection in Susceptible C3H-HeJ Mice

“…However, studies on how the cellular arm of the immune system distinguishes between pathogenic and non-pathogenic Leptospira during early infection are very limited in mouse models ( da Silva et al., 2009 ; Domingos et al., 2017 ). The first line of defense to pathogenic versus non-pathogenic Leptospira should be characterized by production of different signatures of attractant chemokines and cytokines that recruit specialized immune cells and drive inflammation ( Santecchia et al., 2020 ) which ultimately leads to early elimination of the pathogen from the host and further modulate pathogenesis and disease progression.…”

“…As such, this species is generally associated with resistance to infection ( Adler and Faine, 1977 ). A possible factor underlying susceptibility to infection in humans may be a lack of recognition of leptospiral-LPS by human TLR4, whereas resistance in mice has been linked to production of antibody within 48-72h post infection ( Adler and Faine, 1976 ) and the murine TLR4 ability to engage leptospiral-LPS ( Werts et al., 2001 ; Nahori et al., 2005 ; Santecchia et al., 2020 ). However, mouse strains that express an impaired TLR4 in their immune cells (C3H-HeJ) are susceptible to lethal and sublethal leptospirosis ( Pereira et al., 1998 ; Nally et al., 2005 ; Viriyakosol et al., 2006 ; Richer et al., 2015 ) and those that have been engineered to not express TLR4 (C57BL/6J-TLR4 ko ) succumb to infection ( Chassin et al., 2009 ).…”

Role of TLR4 in Persistent Leptospira interrogans Infection: A Comparative In Vivo Study in Mice

“…This somewhat altered TLR4 response could explain the dissemination and kidney colonization after Leptospira infection in mice and it can provide a clue about the lack of profound differences between huTLR4 and WT mice after infection. In addition, Leptospira evade different PRRs, such as TLR5 and NOD proteins, which could contribute to the poor efficiency of macrophages and phagocytes facing Leptospira ( 24 ). In this context, the overall role of TLR4 sensing Leptospira could be minimal although its presence would still be important.…”

Scavenger receptor A1 participates in uptake of Leptospira interrogans serovar Autumnalis strain 56606v and inflammation in mouse macrophages

“…At the early stages of Leptospira infection, macrophages play a complicated role against Leptospira by phagocytosis and induction of signaling pathways to produce pro-inflammatory cytokines and antigen presentation [4,5,6].…”