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<p>Allelic variants in the leucine-rich repeat kinase-2 (<i>LRRK2</i>) gene are linked to Parkinson’s disease, Crohn’s disease and leprosy; however, a consensus role of LRRK2 in infection has not yet emerged. Parkinson’s disease-linked <i>p.G2019S</i> mutation of <i>LRRK2</i> results in increased kinase activity. We evaluated the impact of the <i>p.G2019S</i> mutation during the infection of mice with <i>Salmonella typhimurium</i> (ST) or <i>Listeria monocytogenes</i>. We demonstrate that the <i>p.G2019S</i> mutation promotes the phosphorylation of the p40phox and p47phox subunits of the NADPH oxidase-2 complex in the cytosol of neutrophils, leading to their relocation to lysosomes for enhanced bacterial control. Activation of Cathepsin B, Rab10 or PKC was not modulated by <i>p.G2019S</i>. Activation of the cytosolic subunits of NADPH oxidase-2 subunits was inhibited by the virulence factor SifA, which promotes the phagosomal localization of ST. Deletion of <i>SifA</i> resulted in an even greater effect of the <i>p.G2019S</i> mutation on the control of ST by neutrophils. These results suggest a mechanism by which the <i>p.G2019S</i> mutation promotes better control of infections at the cost of excessive tissue damage via NADPH oxidase-2 activity under chronic inflammatory conditions.</p>

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The Parkinson’s disease-linked G2019S mutation of LRRK2 increases NADPH oxidase-2 activity in neutrophils for superior control of bacterial infections

  • 期刊论文

  • 发表日期：

    2026年7月17日

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  • Kate Hurley,
  • Rachel Kaul,
  • Sahil Yadav,
  • Dikchha Rijal,
  • Leila Sam,
  • Avni Bhan,
  • Rayan El Hamra,
  • Ardeshir Ariana,
  • Adam Mahdi,
  • Willem Brandt,
  • Julianna J. Tomlinson,
  • Michael G. Schlossmacher,
  • Subash Sad

摘要

Allelic variants in the leucine-rich repeat kinase-2 (LRRK2) gene are linked to Parkinson’s disease, Crohn’s disease and leprosy; however, a consensus role of LRRK2 in infection has not yet emerged. Parkinson’s disease-linked p.G2019S mutation of LRRK2 results in increased kinase activity. We evaluated the impact of the p.G2019S mutation during the infection of mice with Salmonella typhimurium (ST) or Listeria monocytogenes. We demonstrate that the p.G2019S mutation promotes the phosphorylation of the p40phox and p47phox subunits of the NADPH oxidase-2 complex in the cytosol of neutrophils, leading to their relocation to lysosomes for enhanced bacterial control. Activation of Cathepsin B, Rab10 or PKC was not modulated by p.G2019S. Activation of the cytosolic subunits of NADPH oxidase-2 subunits was inhibited by the virulence factor SifA, which promotes the phagosomal localization of ST. Deletion of SifA resulted in an even greater effect of the p.G2019S mutation on the control of ST by neutrophils. These results suggest a mechanism by which the p.G2019S mutation promotes better control of infections at the cost of excessive tissue damage via NADPH oxidase-2 activity under chronic inflammatory conditions.