Leptospiraspecies promote a pro‐inflammatory phenotype in human neutrophils

Abstract

Leptospirosis is a global zoonosis caused by pathogenic Leptospira. Neutrophils are key cells against bacterial pathogens but can also contribute to tissue damage. Because the information regarding the role of human neutrophils in leptospirosis is scant, we comparatively analysed the human neutrophil's response to saprophytic Leptospira biflexa serovar Patoc (Patoc) and the pathogenic Leptospira interrogans serovar Copenhageni (LIC). Both species triggered neutrophil responses involved in migration, including the upregulation of CD11b expression, adhesion to collagen, and the release of IL‐8. In addition, both species increased levels of pro‐inflammatory IL‐1β and IL‐6 associated with the inflammasome and NFκB pathway activation and delayed neutrophil apoptosis. LIC was observed on the neutrophil surface and not phagocytized. In contrast, Patoc generated intracellular ROS associated with its uptake. Neutrophils express the TYRO3, AXL, and MER receptor protein tyrosine kinases (TAM), but only LIC selectively increased the level of AXL. TLR2 but not TLR4‐blocking antibodies abrogated the IL‐8 secretion triggered by both Leptospira species. In summary, we demonstrate that Leptospira species trigger a robust neutrophil activation and pro‐inflammatory response. These findings may be useful to find new diagnostic markers and therapeutic strategies against leptospirosis.

Phagocyte Escape of Leptospira: The Role of TLRs and NLRs

“…Live pathogenic leptospires seem to be resistant to internalization unless they are opsonized. In contrast, saprophytic leptospires are rapidly internalized and killed ( 13 , 54 , 55 ). Leptospires do not trigger apoptosis ( 58 , 59 ), and they have an anti-apoptotic effect on infected cells ( 55 ).…”

“…In contrast, saprophytic leptospires are rapidly internalized and killed ( 13 , 54 , 55 ). Leptospires do not trigger apoptosis ( 58 , 59 ), and they have an anti-apoptotic effect on infected cells ( 55 ). Intracellular uptake of leptospires triggers cellular responses characterized by the production of antibacterial components such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) ( 54 , 55 , 57 , 58 , 61 , 62 , 64 ).…”

“…Intracellular uptake of leptospires triggers cellular responses characterized by the production of antibacterial components such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) ( 54 , 55 , 57 , 58 , 61 , 62 , 64 ). In addition, infection triggers TLR2-mediated production of IL-8 and NLRP3-dependent production of IL-1β ( 55 ). Moreover, infection triggers the production of other antibacterial mediators, such as cytokines and chemokines ( 55 , 57 ), but does not induce or inhibit neutrophil myeloperoxidase (MPO) activity ( 55 , 60 ).…”

“…In addition, infection triggers TLR2-mediated production of IL-8 and NLRP3-dependent production of IL-1β ( 55 ). Moreover, infection triggers the production of other antibacterial mediators, such as cytokines and chemokines ( 55 , 57 ), but does not induce or inhibit neutrophil myeloperoxidase (MPO) activity ( 55 , 60 ). Cellular responses tend to be more robust for live leptospires than heat- or formalin-inactivated leptospires ( 54 , 55 , 60 , 63 ).…”

“…Moreover, infection triggers the production of neutrophil extracellular traps (NETSs) ( 57 ). The bactericidal activity of neutrophils has not always been observed, and it seems to be dependent on the sources of cells, the serovar used, and the use of opsonizing antibodies ( 13 , 55 , 57 , 60 ).…”