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

ABSTRACT

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.Abbreviations 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/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 ß-tubulin; UNINF uninfected; wrt with respect to; WT wild type.