Abstract
Staphylococcus aureus is a well-known colonizer of the human skin and nose, but also a human pathogen that causes a wide spectrum of diseases. It is well established that S. aureus secretes an arsenal of virulence factors that have evolved to circumvent the human immune system. A major group of S. aureus virulence factors is the bi-component β-barrel pore-forming toxins, also known as leukocidins. These pore-forming toxins target specific cells of the innate and adaptive immune system by interacting with specific receptors expressed on the cell membrane. Even though still heavily debated, clinical and epidemiological studies suggest the involvement of one of the bi-component toxin, Panton-Valentine Leukocidin (PVL), as an important factor contributing to the epidemic spread and increased virulence of CA-MRSA strains. However, the host- and cell-specificity of PVL and other leukocidins, and the lack of adequate in vivo models, fuels the controversy and impairs the appropriate assessment of their role in S. aureus pathophysiology. Currently, the mechanisms of pore-formation and the contribution of PVL and other leukocidins to S. aureus pathophysiology are incompletely understood. This review summarizes our current understanding of leukocidin pore-formation, knowledge gaps, and highlights recent findings identifying novel host-factors involved in the toxin-host interface. As a result, this review furthers emphasizes the complexity behind S. aureus leukocidin cytotoxicity and the challenges associated in the quest to study and understand these major virulence factors.
Highlights
Staphylococcus aureus is a major bacterial pathogen in humans that, combined with the acquisition of antibiotic resistance, is of serious concern to public health (Katayama et al, 2000; Whitby et al, 2001; Thwaites et al, 2011; David and Daum, 2017)
Even though still heavily debated, clinical and epidemiological studies suggest a paradoxal involvement of the bi-component toxin Panton-Valentine Leukocidin (PVL) as an important factor contributing to the epidemic spread and increased virulence of CA-MRSA strains (Lina et al, 1999; Alonzo and Torres, 2014; Li et al, 2016; Wang et al, 2018)
OUR UNSETTLED UNDERSTANDING OF LEUKOCIDINS. It was long questioned why S. aureus would secrete multiple bicomponent toxins that lyse phagocytes, a seemingly redundant strategy deployed by S. aureus to evade the host innate immune system
Summary
Staphylococcus aureus is a major bacterial pathogen in humans that, combined with the acquisition of antibiotic resistance, is of serious concern to public health (Katayama et al, 2000; Whitby et al, 2001; Thwaites et al, 2011; David and Daum, 2017). LukED targets neutrophils, monocytes and NK-cells via CXCR1 and CXCR2, which promote S. aureus pathogenesis in mice in vivo (Reyes-Robles et al, 2013). Another leukocidin, HlgAB, targets CCR2, CXCR1 and CXCR2. The human specific nature of leukocidins has hindered the full assessment and contribution of leukocidins in S. aureus pathogenesis (Spaan et al, 2017) Animals such as mice have been used as preclinical models in S. aureus vaccine and drug development, possibly resulting in the neglection of potential relevant targets in humans. The development of humanized mice, either via the engraftment of human hematopoietic stem cells (Knop et al, 2015) or the transgenic expression of human proteins (Pishchany et al, 2010), offers an alternative to investigate human tropic factors such as leukocidins in vivo
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