NADPH Oxidase and Guanylate Binding Protein 5 Restrict Survival of Avirulent Type III Strains of Toxoplasma gondii in Naive Macrophages

MBio
Sumit K MattaL David Sibley

Abstract

Phagocytic cells are the first line of innate defense against intracellular pathogens, and yet Toxoplasma gondii is renowned for its ability to survive in macrophages, although this paradigm is based on virulent type I parasites. Surprisingly, we find that avirulent type III parasites are preferentially cleared in naive macrophages, independent of gamma interferon (IFN-γ) activation. The ability of naive macrophages to clear type III parasites was dependent on enhanced activity of NADPH oxidase (Nox)-generated reactive oxygen species (ROS) and induction of guanylate binding protein 5 (Gbp5). Macrophages infected with type III parasites (CTG strain) showed a time-dependent increase in intracellular ROS generation that was higher than that induced by type I parasites (GT1 strain). The absence of Nox1 or Nox2, gp91 subunit isoforms of the Nox complex, reversed ROS-mediated clearance of CTG parasites. Consistent with this finding, both Nox1-/- and Nox2-/- mice showed higher susceptibility to CTG infection than wild-type mice. Additionally, Gbp5 expression was induced upon infection and the enhanced clearance of CTG strain parasites was reversed in Gbp5-/- macrophages. Expression of a type I ROP18 allele in CTG prevented clearance i...Continue Reading

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Citations

Mar 19, 2020·Parasite Immunology·Jeongho Park, Christopher A Hunter
Feb 14, 2019·The Journal of Experimental Medicine·Kyle TretinaJohn D MacMicking
May 14, 2019·Frontiers in Microbiology·Wanbo ZhuLi Yu
Aug 16, 2019·Proceedings of the National Academy of Sciences of the United States of America·Sumit K MattaL David Sibley
May 2, 2019·Frontiers in Cellular and Infection Microbiology·Tatiane S Lima, Melissa B Lodoen
Aug 17, 2020·Journal of Virology·Zhaolong LiWenyan Zhang
Mar 7, 2021·Antioxidants·Marc Herb, Michael Schramm
Feb 26, 2021·Nature Reviews. Microbiology·Sumit K MattaL David Sibley
Jun 3, 2021·International Journal of Molecular Sciences·Karolina Szewczyk-GolecCelestyna Mila-Kierzenkowska
Dec 22, 2021·Pathogens and Disease·Daniel FischEva-Maria Frickel

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Methods Mentioned

BETA
GTPases
ubiquitination
Transmission electron microscopy
flow cytometry
PCR
Infection
ELISA
lavage
protein assay
enzyme-linked immunosorbent assay

Software Mentioned

Prism
Gen5
AMT Image Capture Engine V602
CellProfiler
QuantStudio
Cytation3
GraphPad
Percentinfection
GraphPad )
Prism (

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