TY - JOUR
T1 - High density lipoproteins mediate in vivo protection against staphylococcal phenol-soluble modulins
AU - Hommes, Josefien W.
AU - Kratofil, Rachel M.
AU - Wahlen, Sigrid
AU - de Haas, Carla J. C.
AU - Hildebrand, Reeni B.
AU - Hovingh, G. Kees
AU - Otto, Micheal
AU - van Eck, Miranda
AU - Hoekstra, Menno
AU - Korporaal, Suzanne J. A.
AU - Surewaard, Bas G. J.
N1 - Funding Information: We thank Trecia Nussbaumer for mice husbandry. We also thank the staff at the University of Calgary Live Cell Imaging Facility for their assistance and K. Poon at the Nicole Perkins Microbial Communities Core Labs for assistance with flow cytometry. This work was supported by Canadian Institutes of Health Research (CIHR), CIHR fellowship (B.G.J.S.), Marie Curie Action FP7-PEOPLE-2013-IOF (grant no. 627575) (B.G.J.S.). Publisher Copyright: © 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Staphylococcus aureus virulence has been associated with the production of phenol-soluble modulins (PSMs). These PSMs have distinct virulence functions and are known to activate, attract and lyse neutrophils. These PSM-associated biological functions are inhibited by lipoproteins in vitro. We set out to address whether lipoproteins neutralize staphylococcal PSM-associated virulence in experimental animal models. Serum from both LCAT an ABCA1 knockout mice strains which are characterised by near absence of high-density lipoprotein (HDL) levels, was shown to fail to protect against PSM-induced neutrophil activation and lysis in vitro. Importantly, PSM-induced peritonitis in LCAT−/− mice resulted in increased lysis of resident peritoneal macrophages and enhanced neutrophil recruitment into the peritoneal cavity. Notably, LCAT−/− mice were more likely to succumb to staphylococcal bloodstream infections in a PSM-dependent manner. Plasma from homozygous carriers of ABCA1 variants characterized by very low HDL-cholesterol levels, was found to be less protective against PSM-mediated biological functions compared to healthy humans. Therefore, we conclude that lipoproteins present in blood can protect against staphylococcal PSMs, the key virulence factor of community-associated methicillin resistant S. aureus.
AB - Staphylococcus aureus virulence has been associated with the production of phenol-soluble modulins (PSMs). These PSMs have distinct virulence functions and are known to activate, attract and lyse neutrophils. These PSM-associated biological functions are inhibited by lipoproteins in vitro. We set out to address whether lipoproteins neutralize staphylococcal PSM-associated virulence in experimental animal models. Serum from both LCAT an ABCA1 knockout mice strains which are characterised by near absence of high-density lipoprotein (HDL) levels, was shown to fail to protect against PSM-induced neutrophil activation and lysis in vitro. Importantly, PSM-induced peritonitis in LCAT−/− mice resulted in increased lysis of resident peritoneal macrophages and enhanced neutrophil recruitment into the peritoneal cavity. Notably, LCAT−/− mice were more likely to succumb to staphylococcal bloodstream infections in a PSM-dependent manner. Plasma from homozygous carriers of ABCA1 variants characterized by very low HDL-cholesterol levels, was found to be less protective against PSM-mediated biological functions compared to healthy humans. Therefore, we conclude that lipoproteins present in blood can protect against staphylococcal PSMs, the key virulence factor of community-associated methicillin resistant S. aureus.
UR - http://www.scopus.com/inward/record.url?scp=85111499075&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41598-021-94651-1
DO - https://doi.org/10.1038/s41598-021-94651-1
M3 - Article
C2 - 34321507
SN - 2045-2322
VL - 11
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 15357
ER -