CD40 Induces Anti-Toxoplasma gondii Activity in Nonhematopoietic Cells Dependent on Autophagy Proteins

CD40 ligand exhibits a direct antiviral effect on Herpes Simplex Virus type-1 infection via a PI3K-dependent, autophagy-independent mechanism

“…The aforementioned observations coupled with the reported effects of CD40L on autophagy [17,19,20] prompted us to investigate whether this process is implicated in CD40-mediated anti-viral responses. To that end, we explored a variety of pharmacological inhibitors to block autophagy including the pan-class I/II/III PI3K inhibitor LY294002 that affects autophagosome formation, spautin-1 that leads to degradation of Beclin-1 and the JNK inhibitor SP600125 which induces the downregulation of Beclin-1.…”

“…On APCs, CD40 interaction with its ligand causes the production of cytokines and costimulatory molecules and enhances cross presentation [16]. The CD40 pathway also protects against opportunistic pathogens such as Toxoplasma gondii, an effect attributed to the CD40-mediated activation of the autophagy machinery [17][18][19][20]. Interestingly, patients with X-linked hyper-IgM syndrome are also susceptible to encephalitis Cellular Signalling 27 (2015) [1253][1254][1255][1256][1257][1258][1259][1260][1261][1262][1263] caused by T. gondii [21] further highlighting the importance of CD40-CD40L signaling in humoral and adaptive immunity.…”

Identification of Signaling Pathways by Which CD40 Stimulates Autophagy and Antimicrobial Activity against Toxoplasma gondii in Macrophages

“…CD40 signaling results in autophagydependent killing of T. gondii characterized by the encasement of the parasites by LC3 and parasite killing dependent on Atg5, Atg7, Beclin 1, PI3KC3, and lysosomal enzymes (19,21,23,24). We examined the role of JNK, CaMKK␤, AMPK, and ULK in CD40-induced parasite killing.…”

“…This synchronization likely optimizes the ability of CD40 to stimulate autophagy. The roles of these molecules are relevant to the killing of T. gondii induced by CD40, a process mediated by autophagy (19,21,23,24). Not only TNF-␣ (22) but also JNK, CaMKK␤, AMPK, and ULK1 are required for T. gondii killing induced by CD40.…”

“…The interaction of CD40 with CD154 (CD40 ligand) increases the formation of autophagosomes and autolysosomes (increased autophagy flux) and increases the conversion of the autophagy protein LC3 I to LC3 II, events that require Atg5, Atg7, and Beclin 1 (19)(20)(21)(22)(23)(24). CD40 triggers autophagy-mediated killing of Toxoplasma gondii (19-21, 23, 24) and probably of Mycobacterium tuberculosis (25).…”