Human cytomegalovirus controls a new autophagy-dependent cellular antiviral defense mechanism.
Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that remains the major infectious cause of birth defects, as well as being an important opportunistic pathogen. Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved process responsible for the degradation of cytoplasmic macromolecules, and the elimination of damaged organelles via a lysosomal pathway. This process is also triggered in organisms by stressful conditions and by certain diseases. Previous observations have suggested that autophagy (also known as xenophagy in this case) may contribute to innate immunity against viral infections. Recent studies on HSV-1, another herpesvirus, have shown that HSV-1 is able to avoid this cellular defense by means of a viral protein, ICP34.5, which antagonizes the host autophagy response. However, it was not known whether HCMV was also able to counteract autophagy. Here, we show that HCMV infection drastically inhibits autophagosome formation in primary human fibroblasts. Autophagy was assessed by GFP-LC3 redistribution, LC3-II and p62 accumulation and electron microscopy. Inhibition of autophagy occurred early in the infection by a mechanism involving viral protein(s). Indeed, only infected cells expressing viral proteins displayed a striking decrease of autophagy; whereas bystander, non-infected cells displayed a level of autophagy similar to that of control cells. HCMV activated the mTOR signaling pathway, and rendered infected cells resistant to rapamycin-induced autophagy. Moreover, infected cells also became resistant to the stimulation of autophagy by lithium chloride, an mTOR-independent inducer of autophagy. These findings suggest that HCMV has developed efficient strategies for blocking the induction of autophagy during infection.
Chaumorcel
Magali
M
INSERM UMR756, Université Paris-Sud-11, Faculté de Pharmacie, Châtenay Malabry, France.
Souquère
Sylvie
S
Pierron
Gérard
G
Codogno
Patrice
P
Esclatine
Audrey
A
D001343:Autophagy / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects / Q000201:enzymology / Q000472:pathogenicity*; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000648:ultrastructure / Q000821:virology*; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology
D011480:Protease Inhibitors; D018021:Lithium Chloride