Staphylococcus aureus Leukocidin A/B (LukAB) Kills Human Monocytes via Host NLRP3 and ASC when Extracellular, but Not Intracellular

Abstract

Staphylococcus aureus infections are a growing health burden worldwide, and paramount to this bacterium’s pathogenesis is the production of virulence factors, including pore-forming leukotoxins. Leukocidin A/B (LukAB) is a recently discovered toxin that kills primary human phagocytes, though the underlying mechanism of cell death is not understood. We demonstrate here that LukAB is a major contributor to the death of human monocytes. Using a variety of in vitro and ex vivo intoxication and infection models, we found that LukAB activates Caspase 1, promotes IL-1β secretion and induces necrosis in human monocytes. Using THP1 cells as a model for human monocytes, we found that the inflammasome components NLRP3 and ASC are required for LukAB-mediated IL-1β secretion and necrotic cell death. S. aureus was shown to kill human monocytes in a LukAB dependent manner under both extracellular and intracellular ex vivo infection models. Although LukAB-mediated killing of THP1 monocytes from extracellular S. aureus requires ASC, NLRP3 and the LukAB-receptor CD11b, LukAB-mediated killing from phagocytosed S. aureus is independent of ASC or NLRP3, but dependent on CD11b. Altogether, this study provides insight into the nature of LukAB-mediated killing of human monocytes. The discovery that S. aureus LukAB provokes differential host responses in a manner dependent on the cellular contact site is critical for the development of anti-infective/anti-inflammatory therapies that target the NLRP3 inflammasome.

Humanized Mice Exhibit Increased Susceptibility toStaphylococcus aureusPneumonia

“…LukAB is a bicomponent S. aureus toxin with specificity for CD11b and targets human neutrophils [15], as well as monocytes/macrophages by activating NLRP3 [22] and inducing necroptosis [19]. Using the same model of infection in the Δpvl infection of humanized mice, we found no differences in the clearance of WT and lukAB MRSA or in the cell populations recruited ( Figure 7A) or differences in the populations of human immune cells recruited to the lungs ( Figure 7B).…”

“…However, single lukAB mutants have been shown to have a phenotype in a mouse renal abscess model [42] but not in models of bacteremia or rabbit skin and abscess formation [43]. LukAB is also recognized to activate the NLRP3 inflammasome, which can be associated with airway damage and decreased clearance of S. aureus [22,[44][45][46]. Thus, despite our increasing understanding of how these human toxins interact with their receptors, there are likely additional interactions that are highly relevant to human infection that remain to be identified.…”

“…Recent studies suggest that the resident alveolar macrophage populations are especially important in orchestrating staphylococcal clearance [19], whereas dendritic cells [20] and even CD4 + T cells have not been found to be essential in murine models of pneumonia [21]. The human-specific bicomponent toxins PVL and LukAB have been associated with activation of the NLRP3 inflammasome [22][23][24]. However, the relative contribution of these toxins The Journal of Infectious Diseases Staphylococcus aureus is a highly successful human pathogen that has evolved in response to human immune pressure.…”

Розвиток Імунної Відповіді При Стафілококовій Пневмонії (Частина 2)

“…Во время стафилококковой инфекции тригге-рами NLRP3-инфламмасомы являются порофор-мирующие токсины: α-токсин, лейкоцидины A и B (LukAB) и лейкоцидин Пантона -Валентина (PVL) бактерий Staphylococcus aureus [38,48,71].…”

“…Jason H. Melehani и соавт. [71] установили, что действие лейкоцидина LukAB Staphylococcus aureus достаточно для индукции такого уровня ка-спазы-1 и секреции IL-1 и IL-18 в CD14 + моноци-тах, который может вызвать гибель клеток. Данные эффекты LukAB характеризуются зависимостью от связывания LukAB с его клеточным рецептором CD11b, которое приводит к активации NLRP3-инфламмасомы моноцитов.…”