CD40 induces macrophage anti-Toxoplasma gondii activity by triggering autophagy-dependent fusion of pathogen-containing vacuoles and lysosomes.
Many intracellular pathogens, including Toxoplasma gondii, survive within macrophages by residing in vacuoles that avoid fusion with lysosomes. It is important to determine whether cell-mediated immunity can trigger macrophage antimicrobial activity by rerouting these vacuoles to lysosomes. We report that CD40 stimulation of human and mouse macrophages infected with T. gondii resulted in fusion of parasitophorous vacuoles and late endosomes/lysosomes. Vacuole/lysosome fusion took place even when CD40 was ligated after the formation of parasitophorous vacuoles. Genetic and pharmacological approaches that impaired phosphoinositide-3-class 3 (PIK3C3), Rab7, vacuolar ATPase, and lysosomal enzymes revealed that vacuole/lysosome fusion mediated antimicrobial activity induced by CD40. Ligation of CD40 caused colocalization of parasitophorous vacuoles and LC3, a marker of autophagy, which is a process that controls lysosomal degradation. Vacuole/lysosome fusion and antimicrobial activity were shown to be dependent on autophagy. Thus, cell-mediated immunity through CD40 stimulation can reroute an intracellular pathogen to the lysosomal compartment, resulting in macrophage antimicrobial activity.
Andrade
Rosa M
RM
Division of Infectious Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Wessendarp
Matthew
M
Gubbels
Marc-Jan
MJ
Striepen
Boris
B
Subauste
Carlos S
CS
D000818:Animals; D030801:Animals, Genetically Modified; D001343:Autophagy; D019013:CD40 Antigens / Q000276:immunology*; D018929:Cell Culture Techniques; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000172:deficiency; D008247:Lysosomes / Q000502:physiology*; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology; D014122:Toxoplasma / Q000235:genetics / Q000276:immunology*; D014123:Toxoplasmosis / Q000276:immunology*; D014617:Vacuoles / Q000502:physiology*
D019013:CD40 Antigens; D007371:Interferon-gamma; D015500:Chloramphenicol O-Acetyltransferase