iNOS is necessary for GBP-mediated T. gondii clearance in murine macrophages via vacuole nitration and intravacuolar network collapse

Xiao-Yu Zhao, Samantha L. Lempke, Jan C. Urbán Arroyo, Isabel G. Brown, Bocheng Yin, Magdalena M. Magaj, Nadia K. Holness, Jamison Smiley, Stefanie Redemann and Sarah E. Ewald ()
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Xiao-Yu Zhao: University of Virginia School of Medicine
Samantha L. Lempke: University of Virginia School of Medicine
Jan C. Urbán Arroyo: University of Virginia School of Medicine
Isabel G. Brown: University of Virginia School of Medicine
Bocheng Yin: University of Virginia School of Medicine
Magdalena M. Magaj: University of Virginia School of Medicine
Nadia K. Holness: University of Virginia School of Medicine
Jamison Smiley: University of Virginia School of Medicine
Stefanie Redemann: University of Virginia School of Medicine
Sarah E. Ewald: University of Virginia School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Toxoplasma gondii is an obligate intracellular parasite of rodents and humans. Interferon-inducible guanylate binding proteins (GBPs) are mediators of T. gondii clearance, however, this mechanism is incomplete. Here, using automated spatially targeted optical micro proteomics we demonstrate that inducible nitric oxide synthetase (iNOS) is highly enriched at GBP2+ parasitophorous vacuoles (PV) in murine macrophages. iNOS expression in macrophages is necessary to limit T. gondii load in vivo and in vitro. Although iNOS activity is dispensable for GBP2 recruitment and PV membrane ruffling; parasites can replicate, egress and shed GBP2 when iNOS is inhibited. T. gondii clearance by iNOS requires nitric oxide, leading to nitration of the PV and collapse of the intravacuolar network of membranes in a chromosome 3 GBP-dependent manner. We conclude that reactive nitrogen species generated by iNOS cooperate with GBPs to target distinct structures in the PV that are necessary for optimal parasite clearance in macrophages.

Date: 2024
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DOI: 10.1038/s41467-024-46790-y

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