Structure and Function of the Two-Component Cytotoxins of Staphylococcus aureus – Learnings for Designing Novel Therapeutics

Abstract

Staphylococcus aureus can produce up to five different bi-component cytotoxins: two gamma-hemolysins HlgAB and HlgCB, and leukocidins SF-PV (Panton Valentine leukocidin), ED (LukED) and GH (LukGH, also called LukAB). Their major function in S. aureus pathogenesis is to evade innate immunity by attacking phagocytic cells and to support bacterial growth by lysing red blood cells. The five cytotoxins display different levels of amino acid sequence conservation (30-82%), but all form a remarkably similar beta-barrel type pore structure (greatly resembling the mono-component toxin alpha-hemolysin) that inserts into the target cell membrane leading to necrotic cell death. This review provides an overview of the culmination of decades of research on the structure of these toxins, their unique sequence and structural features that helps to explain the observed functional differences, such as toxin potency towards different cell types and species, receptor specificity and formation of functional non-cognate toxin pairs. The vast knowledge accumulated in this field supports novel approaches and the design of therapeutics targeting these cytotoxins to tame virulence and fight S. aureus infections.

Molecular mechanism of leukocidin GH–integrin CD11b/CD18 recognition and species specificity

“…The caveats of using a nonhuman therapeutic protein, particularly for chronic indications, typically arise from the short halflife and formation of antidrug antibodies. However, these could be potentially circumvented for LukGH by exploiting its own ability to blunt the adaptive immunity via dendritic cell targeting (40) and by making use of its numerous and diverse natural sequence variants (41).…”

Preventing lung pathology and mortality in rabbit Staphylococcus aureus pneumonia models with cytotoxin-neutralizing monoclonal IgGs penetrating the epithelial lining fluid

“…In addition to LukSF-PV, four other bi-component leukocidins – two gamma-hemolysins (HlgAB and HlgCB), LukED, and LukGH (also known as LukAB) – are produced by S. aureus . All of them are able to lyse human phagocytes 17,18 . lukED is present in approximately 60% of S. aureus strains, while hlgACB and lukGH are part of the core genome 17,18 .…”

“…All of them are able to lyse human phagocytes 17,18 . lukED is present in approximately 60% of S. aureus strains, while hlgACB and lukGH are part of the core genome 17,18 . Alpha-hemolysin (Hla), the best characterized cytotoxin of S. aureus , is an important virulence factor encoded in the core genome that has been shown to have a major contribution to pneumonia pathogenesis in all animal models tested 6,19–22 .…”

“…Alpha-hemolysin (Hla), the best characterized cytotoxin of S. aureus , is an important virulence factor encoded in the core genome that has been shown to have a major contribution to pneumonia pathogenesis in all animal models tested 6,19–22 . Hla forms a very similar pore structure as the bi-component leukocidins (comprised of polymers of S- and F-components), although assembled from one type of component 18,23 . It disrupts the physical barriers in the lung by lysing epithelial and endothelial cells and therefore promotes bacterial invasion from the mucosal surface to the lung tissue and the blood stream 23 .…”

Convergent Evolution of Neutralizing Antibodies to Staphylococcus aureus γ-Hemolysin C That Recognize an Immunodominant Primary Sequence-Dependent B-Cell Epitope

“…The nine leukocidin members of the PFT family are important contributors to S. aureus strain pathogenic potential (reviewed in reference 11); all share a conserved ␤-barrel structure (12). The leukocidins are secreted as inactive subunits during infection, but upon binding to the membrane receptors of a targeted host cell, these subunits oligomerize to form pores that act as cell-killing machines that break down epithelial barriers, disable immune cells, and aid the scavenging of nutrients (13,14). Certain PFTs are associated with specific clinical infection syndromes.…”