Staphylococcus aureusLukAB cytotoxin kills human neutrophils by targeting the CD11b subunit of the integrin Mac-1

Abstract

Staphylococcus aureus causes diseases ranging from superficial wound infections to more invasive manifestations like osteomyelitis and endocarditis. The evasion of host phagocytes recruited to the site of infection is essential to the success of S. aureus as a pathogen. A single S. aureus strain can produce up to five different bicomponent pore-forming leukotoxins that lyse immune cells by forming pores in the cellular plasma membrane. Although these leukotoxins have been considered redundant due to their cytotoxic activity toward human neutrophils, each toxin displays varied species and celltype specificities. This suggests that cellular factors may influence which cells each toxin targets. Here we describe the identification of CD11b, the α subunit of the αM/β2 integrin (CD11b/CD18), macrophage-1 antigen, or complement receptor 3, as a cellular receptor for leukocidin A/B (LukAB), an important toxin that contributes to S. aureus killing of human neutrophils. We demonstrate that CD11b renders human neutrophils susceptible to LukAB-mediated killing by purified LukAB as well as during S. aureus infection ex vivo. LukAB directly interacts with human CD11b by binding to the I domain, a property that determines the species specificity exhibited by this toxin. Identification of a LukAB cellular target has broad implications for the use of animal models to study the role of LukAB in S. aureus pathogenesis, explains the toxin's tropism toward human neutrophils and other phagocytes, and provides a cellular therapeutic target to block the effect of LukAB toward human neutrophils.toxin receptor | pore-forming cytotoxin

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).…”

“…Also, direct comparison of the immune response between these mice and humans is not possible because of the production of cytokines from both stromal and immune cells in humans. The humanized mice used in these studies, while having excellent reconstitution of T cells, monocytes, and macrophages, all of which are targets of S. aureus toxins [4,14,15,19,21], does not yet fully replicate a functioning human immune system. It has been recognized that neutrophil numbers are not optimal in the peripheral blood of humanized mice, and hence there may be a more limited number of cells to recruit; thus, this is an area to improve in subsequent models [38,39].…”

“…The molecular basis for this discrepancy was ascribed to the high human (and rabbit) specificity for the PVL receptors, C5aR and C5L2 [14]. Additional toxins, LukAB and HlgCB, have also been shown to have high specificity to the human forms of the receptors, CD11b and C5aR, respectively [4,14,15]. These toxins with human receptor specificity are in contrast to those such as α-toxin, which recognizes ADAM-10 on murine cells, as well as human cells [16].…”

The Pore-Forming Toxin Listeriolysin O Is Degraded by Neutrophil Metalloproteinase-8 and Fails To Mediate Listeria monocytogenes Intracellular Survival in Neutrophils

“…It would be of considerable interest to study neutrophil degranulation and membrane repair mechanisms in response to various families of pore-forming toxins as well as to evaluate the antitoxin activity of neutrophil GP. This is especially interesting in regards to toxins produced by pathogens known to resist killing by neutrophils, such as Staphylococcus aureus (92)(93)(94).…”

Розвиток Імунної Відповіді При Стафілококовій Пневмонії (Частина 2)

“…[71], вероятно, недо-оценено из-за данных, полученных при исследова-нии стафилококковой инфекции у мышей, клетки которых устойчивы к LukAB-опосредованному ли-зису. Лейкоцидин LukAB связывается с человече-ским интегрином CD11b почти в 1000 раз активней, чем с мышиным CD11b [23].…”