Shi Liu

Glucose metabolism and innate immunity evolved side-by-side. It is unclear if and how the two systems interact with each other during hepatitis B virus (HBV) infections and, if so, which mechanisms are involved. Here, we report that HBV activates glycolysis to impede retinoic acid-inducible gene I (RIG-I)-induced interferon production. We demonstrate that HBV sequesters MAVS from RIG-I by forming a ternary complex including hexokinase (HK). Using a series of pharmacological and genetic approaches, we provide in vitro and in vivo evidence indicating that HBV suppresses RLR signaling via lactate dehydrogenase-A-dependent lactate production. Lactate directly binds MAVS preventing its aggregation and mitochondrial localization during HBV infection. Therefore, we show that HK2 and glycolysis-derived lactate have important functions in the immune escape of HBV and that energy metabolism regulates innate immunity during HBV infection.

-GlcNAcylation regulates IRF5 function during IAV infection, highlighting the importance of glucose metabolism in IAV-induced cytokine storm.

Following outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2002 and 2012, respectively, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third highly pathogenic emerging human coronavirus (hCoV). SARS-CoV-2 is currently causing the global coronavirus disease 2019 (COVID-19) pandemic. CoV infections in target cells may stimulate the formation of numerous double-membrane autophagosomes and induce autophagy. Several studies provided evidence that hCoV infections are closely related to various cellular aspects associated with autophagy. Autophagy may even promote hCoV infection and replication. However, so far it is unclear how hCoV infections induce autophagy and whether the autophagic machinery is necessary for viral propagation. Here, we summarize the most recent advances concerning the mutual interplay between the autophagic machinery and the three emerging hCoVs, SARS-CoV, MERS-CoV, and SARS-CoV-2 and the model system mouse hepatitis virus. We also discuss the applicability of approved and well-tolerated drugs targeting autophagy as a potential treatment against COVID-19.

Trained immunity refers to the long-term memory of the innate immune cells. However, little is known about how environmental nutrient availability influences trained immunity. This study finds that physiologic carbon sources impact glucose contribution to the tricarboxylic acid (TCA) cycle and enhance cytokine production of trained monocytes. Our experiments demonstrate that trained monocytes preferentially employe lactate over glucose as a TCA cycle substrate, and lactate metabolism is required for trained immune cell responses to bacterial and fungal infection. Except for the contribution to the TCA cycle, endogenous lactate or exogenous lactate also supports trained immunity by regulating histone lactylation. Further transcriptome analysis, ATAC-seq, and CUT&Tag-seq demonstrate that lactate enhance chromatin accessibility in a manner dependent histone lactylation. Inhibiting lactate-dependent metabolism by silencing lactate dehydrogenase A (LDHA) impairs both lactate fueled the TCA cycle and histone lactylation. These findings suggest that lactate is the hub of immunometabolic and epigenetic programs in trained immunity. Here, Cai et al. demonstrate that environmental metabolite availability directly impacts glucose utilization and function in trained immunity - trained monocytes prefer lactate over glucose as a physiologic fuel, and lactate regulates trained immunity by altering histone lactylation.