Staphylococcus aureus induces cell-surface expression of immune stimulatory NKG2D ligands on human monocytes
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Staphylococcus aureus induces cell-surface expression of immune stimulatory NKG2D ligands on human monocytes. / Mellergaard, Maiken; Høgh, Rikke Illum; Lund, Astrid; Aldana, Blanca Irene; Guérillot, Romain; Møller, Sofie Hedlund; Hayes, Ashleigh S; Panagiotopoulou, Nafsika; Frimand, Zofija; Jepsen, Stine Dam; Hansen, Camilla Hartmann Friis; Andresen, Lars; Larsen, Anders Rhod; Peleg, Anton Y; Stinear, Timothy P; Howden, Benjamin P; Waagepetersen, Helle S; Frees, Dorte; Skov, Søren.
In: The Journal of Biological Chemistry, Vol. 295, 2020, p. 11803-11821.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Staphylococcus aureus induces cell-surface expression of immune stimulatory NKG2D ligands on human monocytes
AU - Mellergaard, Maiken
AU - Høgh, Rikke Illum
AU - Lund, Astrid
AU - Aldana, Blanca Irene
AU - Guérillot, Romain
AU - Møller, Sofie Hedlund
AU - Hayes, Ashleigh S
AU - Panagiotopoulou, Nafsika
AU - Frimand, Zofija
AU - Jepsen, Stine Dam
AU - Hansen, Camilla Hartmann Friis
AU - Andresen, Lars
AU - Larsen, Anders Rhod
AU - Peleg, Anton Y
AU - Stinear, Timothy P
AU - Howden, Benjamin P
AU - Waagepetersen, Helle S
AU - Frees, Dorte
AU - Skov, Søren
N1 - Published under license by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2020
Y1 - 2020
N2 - Staphylococcus aureus is among the leading causes of bacterial infections worldwide. The pathogenicity and establishment of S. aureus infections are tightly linked to its ability to modulate host immunity. Persistent infections are often associated with mutant staphylococcal strains that have decreased susceptibility to antibiotics; however, little is known about how these mutations influence bacterial interaction with the host immune system. Here, we discovered that clinical S. aureus isolates activate human monocytes, leading to cell-surface expression of immune stimulatory natural killer group 2D (NKG2D) ligands on the monocytes. We found that expression of the NKG2D ligand UL16-binding protein 2 (ULBP2) is associated with bacterial degradability and phagolysosomal activity. Moreover, S. aureus-induced ULBP2 expression was linked to altered host cell metabolism, including increased cytoplasmic (iso)citrate levels, reduced glycolytic flux, and functional mitochondrial activity. Interestingly, we found that the ability of S. aureus to induce ULBP2 and proinflammatory cytokines in human monocytes depends on a functional ClpP protease in S. aureus These findings indicate that S. aureus activates ULBP2 in human monocytes through immunometabolic mechanisms and reveal that clpP inactivation may function as a potential immune evasion mechanism. Our results provide critical insight into the interplay between the host immune system and S. aureus that has evolved under the dual selective pressure of host immune responses and antibiotic treatment. Our discovery of a immune stimulatory pathway consisting of human monocyte-based defense against S. aureus suggests that targeting the NKG2D pathway holds potential for managing persistent staphylococcal infections.
AB - Staphylococcus aureus is among the leading causes of bacterial infections worldwide. The pathogenicity and establishment of S. aureus infections are tightly linked to its ability to modulate host immunity. Persistent infections are often associated with mutant staphylococcal strains that have decreased susceptibility to antibiotics; however, little is known about how these mutations influence bacterial interaction with the host immune system. Here, we discovered that clinical S. aureus isolates activate human monocytes, leading to cell-surface expression of immune stimulatory natural killer group 2D (NKG2D) ligands on the monocytes. We found that expression of the NKG2D ligand UL16-binding protein 2 (ULBP2) is associated with bacterial degradability and phagolysosomal activity. Moreover, S. aureus-induced ULBP2 expression was linked to altered host cell metabolism, including increased cytoplasmic (iso)citrate levels, reduced glycolytic flux, and functional mitochondrial activity. Interestingly, we found that the ability of S. aureus to induce ULBP2 and proinflammatory cytokines in human monocytes depends on a functional ClpP protease in S. aureus These findings indicate that S. aureus activates ULBP2 in human monocytes through immunometabolic mechanisms and reveal that clpP inactivation may function as a potential immune evasion mechanism. Our results provide critical insight into the interplay between the host immune system and S. aureus that has evolved under the dual selective pressure of host immune responses and antibiotic treatment. Our discovery of a immune stimulatory pathway consisting of human monocyte-based defense against S. aureus suggests that targeting the NKG2D pathway holds potential for managing persistent staphylococcal infections.
U2 - 10.1074/jbc.RA120.012673
DO - 10.1074/jbc.RA120.012673
M3 - Journal article
C2 - 32605922
VL - 295
SP - 11803
EP - 11821
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
ER -
ID: 247001091