Excreted Cytoplasmic Proteins Contribute to Pathogenicity in Staphylococcus aureus

Abstract

Excretion of cytoplasmic proteins in pro-and eukaryotes, also referred to as "nonclassical protein export," is a well-known phenomenon. However, comparatively little is known about the role of the excreted proteins in relation to pathogenicity. Here, the impact of two excreted glycolytic enzymes, aldolase (FbaA) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), on pathogenicity was investigated in Staphylococcus aureus. Both enzymes bound to certain host matrix proteins and enhanced adherence of the bacterial cells to host cells but caused a decrease in host cell invasion. FbaA and GAPDH also bound to the cell surfaces of staphylococcal cells by interaction with the major autolysin, Atl, that is involved in host cell internalization. Surprisingly, FbaA showed high cytotoxicity to both MonoMac 6 (MM6) and HaCaT cells, while GAPDH was cytotoxic only for MM6 cells. Finally, the contribution of external FbaA and GAPDH to S. aureus pathogenicity was confirmed in an insect infection model.

Non-classical Protein Excretion Is Boosted by PSMα-Induced Cell Leakage

“…Recently it has been shown that FbaA and GAPDH interact with the surface exposed major autolysin (Atl) (Ebner et al, 2016). Therefore, we considered the question whether FbaA is not excreted but bound to the cell surface from where it might be detached by PSMα and released then into the supernatant.…”

“…Despite affecting viability, ECP should have an advantage in infection, which we don’t understand yet. Some of the excreted CPs such as FbaA and GAPDH may contribute to pathogenicity due to their cytotoxic activity against host cells (Ebner et al, 2016). Another possibility is that the release of CPs and RNA might overload the immune system to the benefit of the bacterium.…”

“…But what we know is that pathogenic strains excrete more CPs than non-pathogenic strains and species (Ebner et al, 2016; Pasztor et al, 2010). For example in the agr -negative S. aureus SA113 strain only a defined set of CPs were found in the secretome, while other highly expressed CPs were absent (Pasztor et al, 2010), suggesting, that in this strain background only defined CPs were excreted.…”

“…By analyzing some features of ECP in the agr -negative SA113 it has also been shown that ECP takes place mainly during the exponential growth phase, that the amount of excreted CPs is substantial and comparable to Sec-secreted proteins and that CPs are translocated particularly at the septal cleft of dividing cells (Ebner et al, 2015a; Ebner et al, 2015b). By investigating the potential role of excreted CPs in pathogenicity of S. aureus , it has been shown that the two model proteins, aldolase (FbaA) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), increased adherence to host cells and exerted cytoxicity to various host cells (Ebner et al, 2016). The accessory gene regulator ( agr ) positively controls the expression of many toxins and has been assigned a central role in the pathogenesis of staphylococci, particularly in S. aureus (Novick, 2003).…”

What is behind the epidemiological difference between community-acquired and health-care associated methicillin-resistant Staphylococcus aureus?

“…These features were also observed using an insect infection model. 9 Surprisingly, when Mekonnen and collaborators correlated the virulence-gene patterns and exoprotein profiles of USA300-related isolates, they found more similarities between HA-MRSA from the Dutch and German border (HA NL-DE ; Spa t008) and HA-MRSA isolates collected in Denmark (HA DK ; Spa t024) than between these HA-MRSA and CA-MRSA from Denmark (CA DK ; Spa t008); despite the HA DK /CA DK core genome being more closely related. Interestingly, they found few differences in the expression of proteins associates with virulence including IsdA, IsdB, SCIN and Vwb.…”