Identification of LukPQ, a novel, equid-adapted leukocidin of Staphylococcus aureus

Abstract

Bicomponent pore-forming leukocidins are a family of potent toxins secreted by Staphylococcus aureus, which target white blood cells preferentially and consist of an S- and an F-component. The S-component recognizes a receptor on the host cell, enabling high-affinity binding to the cell surface, after which the toxins form a pore that penetrates the cell lipid bilayer. Until now, six different leukocidins have been described, some of which are host and cell specific. Here, we identify and characterise a novel S. aureus leukocidin; LukPQ. LukPQ is encoded on a 45 kb prophage (ΦSaeq1) found in six different clonal lineages, almost exclusively in strains cultured from equids. We show that LukPQ is a potent and specific killer of equine neutrophils and identify equine-CXCRA and CXCR2 as its target receptors. Although the S-component (LukP) is highly similar to the S-component of LukED, the species specificity of LukPQ and LukED differs. By forming non-canonical toxin pairs, we identify that the F-component contributes to the observed host tropism of LukPQ, thereby challenging the current paradigm that leukocidin specificity is driven solely by the S-component.

Leukocidins: staphylococcal bi-component pore-forming toxins find their receptors

“…The other known leukocidins that are produced by S. aureus are Leukocidin MF’ (LukMF’) 15 and Leukocidin PQ (LukPQ) 16 , however, these toxins are not found in human S. aureus isolates and are associated with zoonotic infections (Box 1). Although the first description of leukocidin activity in S. aureus culture supernatants was published around 1895, (the discoveries that lead to the identification of the leukocidins were recently reviewed elsewhere 7 ), the molecular mechanisms that cause pore formation has remained incompletely understood.…”

“…LukMF’ has an exquisite cellular tropism for bovine phagocytes, a property mediated by the targeting of CCR1 39 , a chemokine receptor that is expressed in bovine neutrophils but not in human neutrophils. More recently, a novel bi-component leukocidin, LukPQ, was identified in S. aureus isolated from horses 16 and is highly cytotoxic in equine neutrophils. LukPQ is similar to LukED (91% amino-acid identity between LukE and LukP) 16 , and targets the equine CXCRA and CXCR2 receptors on neutrophils.…”

“…More recently, a novel bi-component leukocidin, LukPQ, was identified in S. aureus isolated from horses 16 and is highly cytotoxic in equine neutrophils. LukPQ is similar to LukED (91% amino-acid identity between LukE and LukP) 16 , and targets the equine CXCRA and CXCR2 receptors on neutrophils.…”

Studying Staphylococcal Leukocidins: A Challenging Endeavor

“…Based on chromatography elution profiles, individual leukocidin subunits are designated as S(slow)or F(fast)-migrating component, and each having a molecular weight of approximately 33kD (Spaan et al, 2017). Non-cognate pairing of other leukocidin S-and F-subunits have been described in vitro (Prevost et al, 1995;Yoong and Torres, 2015;Koop et al, 2017;Spaan et al, 2017). Subsequent hybrid pairing of S-and F-subunits of HlgCB and PVL showed a LukF-PV mediated modulation of hC5aR KI murine neutrophils, but not human neutrophils, to PVL sensitivity.…”

“…Human S. aureus isolates secrete up to five different leukocidins that target phagocytes; PVL, γ-haemolysin AB (HlgAB) and CB (HlgCB), leukocidin ED (LukED) and leukocidin GH (LukGH, also known as LukAB) (Ventura et al, 2010;Vandenesch et al, 2012;Spaan et al, 2017). In addition, S. aureus strains associated with zoonotic infections have been described to secrete leukocidin MF'(LukMF') and leukocidin PQ (LukPQ) (Vrieling et al, 2016;Koop et al, 2017). Murine infection models, to an extent, have proven useful in understanding the role of these leukocidins in S. aureus pathogenesis (Rauch et al, 2012;Parker, 2017).…”