A food-responsive switch modulates TFEB and autophagy, and determines susceptibility to coxsackievirus infection and pancreatitis.

Almost a billion people worldwide are chronically undernourished. Herein, using a mouse model of coxsackievirus B3 (CVB3) infection, we report that a single day of food restriction (FR) markedly increases susceptibility to attenuated enterovirus infection, replication, and disease. These "pro-viral" effects, which are rapidly-reversed by the restoration of food, are mediated by several genes whose expression is altered by FR, and which support CVB3 replication. Central to this is TFEB, a protein whose expression and activation status are rapidly increased by FR. TFEB, which regulates the transcription of >100 genes involved in macroautophagy/autophagy and lysosomal biogenesis, responds similarly to both FR and CVB3 infection and plays a pivotal role in determining host susceptibility to CVB3. We propose that, by upregulating TFEB, FR generates an intracellular environment that is more hospitable to the incoming virus, facilitating its replication. This interplay between nutritional status and enterovirus replication has implications for human health and, perhaps, for the evolution of these viruses. Atg/ATG: autophagy-related; CAR: Coxsackievirus and adenovirus receptor; Cas9: CRISPR associated protein 9; Cre: recombinase that causes recombination; CRISPR: clustered regularly interspaced short palindromic repeats; /CTSB: cathepsin B; CVB3: coxsackievirus B3; DsRedCVB3: a recombinant CVB3 that encodes the Discosoma red fluorescent protein; EL: elastase; FR: food restriction; GFP: green fluorescent protein; gRNA: guide RNA; HBSS: Hanks Buffered Salt Solution; LYNUS: lysosomal nutrient sensing machinery; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MFI: mean fluorescence intensity; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; Nluc: nanoluciferase; NlucCVB3: a recombinant CVB3 encoding nanoluciferase; pfu: plaque-forming unit(s); p.i.: post infection; rCVB: recombinant coxsackievirus B3; RPS6KB/p70S6K: ribosomal protein S6 kinase; RT: room temperature; siRNA: small interfering RNA; TFEB: transcription factor EB; tg: transgenic; TUBB: β-tubulin; UNINF: uninfected; wrt: with respect to; WT: wild type.