Abstract
Autophagy degrades pathogens in vitro. The autophagy gene Atg5 has been reported to be required for IFN-γ-dependent host protection in vivo. However, these protective effects occur independently of autophagosome formation. Thus, the in vivo role of classic autophagy in protection conferred by adaptive immunity and how adaptive immunity triggers autophagy are incompletely understood. Employing biochemical, genetic and morphological studies, we found that CD40 upregulates the autophagy molecule Beclin 1 in microglia and triggers killing of Toxoplasma gondii dependent on the autophagy machinery. Infected CD40−/− mice failed to upregulate Beclin 1 in microglia/macrophages in vivo. Autophagy-deficient Beclin 1+/− mice, mice with deficiency of the autophagy protein Atg7 targeted to microglia/macrophages as well as CD40−/− mice exhibited impaired killing of T. gondii and were susceptible to cerebral and ocular toxoplasmosis. Susceptibility to toxoplasmosis occurred despite upregulation of IFN-γ, TNF-α and NOS2, preservation of IFN-γ-induced microglia/macrophage anti-T. gondii activity and the generation of anti-T. gondii T cell immunity. CD40 upregulated Beclin 1 and triggered killing of T. gondii by decreasing protein levels of p21, a molecule that degrades Beclin 1. These studies identified CD40-p21-Beclin 1 as a pathway by which adaptive immunity stimulates autophagy. In addition, they support that autophagy is a mechanism through which CD40-dependent immunity mediates in vivo protection and that the CD40-autophagic machinery is needed for host resistance despite IFN-γ.
Highlights
The lysosomal system is an effector of microbial degradation
CD402/2 mice are susceptible to ocular toxoplasmosis and toxoplasmic encephalitis despite upregulation of IFN-c, TNF-a and NOS2 B6 and CD402/2 mice were infected with T. gondii
The cascades by which adaptive immunity activates autophagic killing of an intracellular pathogen and the in vivo role of autophagy in protection conferred by adaptive immunity are incompletely understood
Summary
The lysosomal system is an effector of microbial degradation. Many pathogens including the intracellular protozoan Toxoplasma gondii have developed various strategies to avoid lysosomal degradation. Autophagy is a mechanism that can re-route pathogens to lysosomes. Fusion between autophagosomes and endosomes-lysosomes culminates in the formation of autolysosomes and degradation of their contents. Autophagy can mediate in vitro anti-microbial activity against various pathogens [3,4,5,6,7]. In the case of T. gondii infection, the CD40 – CD154 pathway triggers killing of the parasite within macrophages that is dependent on the autophagy pathway [6,8]. The interaction between T. gondii-reactive T cells and infected macrophages results in CD40-dependent killing of the parasite through the autophagy pathway [6]
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