Role of Metabolism in Virus Infection and Pathogenesis

代谢在病毒感染和致病性中的作用

Viruses are obligate intracellular parasites, and host cell metabolism is essential for the viral replication cycle. Viruses are dependent on host metabolic networks in order to supply essential building blocks for the production of new virions. The roles of metabolites on viral life cycle will broaden our understanding of virus biology as well as virus-host cell interaction. In addition to their role in biosynthesis and energy production which are critical for viral infections, metabolites play key roles in the pro-inflammatory/anti-inflammatory homeostasis, contributing to both anti-viral immune response and virus-induced inflammation and associated pathologies. The study of metabolites in the context of viral infections offers the opportunity to understand better the host cell-virus interaction and to develop new pathophysiological assessment tools and anti-viral therapeutics. When considering how viruses interact with host metabolism it is critical for virologist to think beyond their copy of a Biochemistry textbook, as computational and analytical advances in recent years have led to novel discoveries in metabolism. The rapidly expanding understanding of metabolism in cancer and metabolic diseases will further enhance general understanding of cell physiology that may be applied to viruses as well.

1. The effects of viral infections on host metabolism 病毒感染重塑宿主代谢

Viruses depend on the host cell to obtain the macromolecules and biosynthesis machinery required for their replication. All viruses rely on host metabolism to provide the energy and materials—e.g., nucleotides, amino acids, or lipids—required for virus replication. Viral infection induces a remarkable metabolic shift in various host metabolic pathways such as photosynthesis, glycolysis, fatty-acid metabolism and nucleotide biosynthesis. The remarkable effect of viruses on cellular metabolism points to the central role of metabolism in shaping the host–virus arms race. The availability of mass spectrometry (MS)-based analysis of the metabolome that enabled fast progress toward an in-depth understanding of the interaction between viruses and host-cell metabolism. Studies of the effects of viruses on metabolism during replication in vitro and infection in animal models or human subjects have provided novel insights into these networks and provided new targets for therapy and biomarker development. Metabolic profiling of the released virions can help to characterize unique virus-derived metabolites and can shed new light on the metabolic requirements of successful viral replication. However, most of our knowledge on the field consists of phenotypic characterizations of the impact of the infection on central pathways in host-cell metabolism, whereas our understanding of the mechanistic basis for these changes is far more limited. The ultimate goal remains to define the metabolic profile at the tissue, organ and body level during immune response against viral infection. Innovative systems, entailing novel engineered animal models and metabolite detection approaches or techniques, are urgently needed to monitor the dynamic changes of metabolites and immune response in real time. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology and evolving imaging techniques may be leveraged in the future to fill this gap.

2. How viruses hijack host metabolism 病毒如何劫持宿主的代谢

How viruses rewire host functions for their benefit. How metabolic pathways can be changed upon virus infection and how host intrinsic metabolic activities and extrinsic events that affect metabolism can influence the expression of infection. Viruses have developed various mechanisms to facilitate viral replication, including manipulating the host metabolism by disrupting critical metabolic pathways and targeting master regulator proteins of metabolism. In addition to identifying virally induced changes in metabolites and lipids, research must be done to define the viral and host mechanisms that drive metabolism to play a supportive or detrimental role in infection. Viruses can remodel metabolism by directly targeting metabolic enzymes, signaling pathways, transcription factors, or organelles with important metabolic functions. Defining the multiple mechanisms and molecular players—both viral and cellular—required for viral remodeling of metabolism will have great value in basic biology and perhaps one day in the clinic as well. To date, a limited number of viral gene products have been implicated in modulating cell metabolism. Although the existence of these virus-induced shifts in carbon metabolism are well documented, there is, for most viruses, a lack of knowledge on the precise molecular mechanisms utilized by the viruses to induce these shifts. This could be a valuable focus for future research. A better understanding of viral mechanisms targeting host metabolism will help us to better understand viral pathogenesis and has the potential to open a new avenue in designing novel antiviral therapies.

3. How metabolism participates in viral pathogenesis 代谢重塑在病毒致病性中的作用

Viral infection alters host metabolism in ways that likely go beyond those required to build a virion. How does cellular metabolism shape the infection outcome? Can modulation of virus-required metabolic pathways be used as host resistance mechanisms? Infection-induced changes in host metabolism influence the pathogenesis of the infection and affect physiological functions in the host. It is necessary to systematically evaluate the pathogenic effect of viral infection due to metabolic disorders and how the body responds and restores metabolite balance to reduce the pathogenic effect. The major question addressed was whether it is possible to reshape the outcome of a viral infection, particularly those where the host response contributes to tissue damage. The topic has received minimal investigation, but some studies do show that controlling events such as glycolysis, glutaminolysis and fatty acid metabolism are showing promise as approaches to limit the severity of some viral infections. Chronic hepatitis B virus (HBV) infection alters serum metabolites and lipids, potentially reflecting liver damage rather than metabolic needs for viral replication. Viruses may potentially take advantage of metabolism to alter an immune response to evade clearance. Shi Liu’s group reported that HBV rigs the cellular metabolome to avoid innate immune recognition. They show that hexokinase 2 (HK2) and glycolysis-derived lactate have important functions in the immune escape of HBV and that energy metabolism regulates innate immunity during HBV infection. Glycolysis and lactate negatively regulate type I interferon induction and the antiviral response. On the other hand, infection could trigger metabolic responses that stimulate immune or other antiviral control measures. Upon viral infections, immune cells increase their glucose uptake and utilization to meet their demand for energy and molecular building blocks. Viral infection can trigger the production of both anti- and pro-inflammatory cytokines, which systemically exert their effects on immune response and metabolism. Hyper-nutrition or dysregulated nutrition may cause overt immune responses and cause immunopathology. Thus, optimal nutritional and metabolic homeostasis is an important part of appropriate immune function and good health.

4. Host sensing of virus-induced metabolic changes 宿主感知病毒引起的代谢变化

Immunometabolism is emerging as a new inter-discipline that integrates and elucidates the interplay between host metabolism and immune responses. Viral infection reprograms host metabolism and causes metabolic dysfunction, while hosts implement metabolic changes to mount effective defensive antiviral responses. Viruses depend on altering host cell metabolism for successful replication. It therefore seems reasonable to assume that we, as hosts, have developed mechanisms to sense such changes with the purpose of initiating counter-acting anti-viral responses. The changes that are sensed by the infected host could be metabolites themselves or metabolic by-products formed as part of the metabolic processes. The metabolic sensors and the anti-viral programs they could induce are also only scarcely described still. Identification of such sensors and characterization of the anti-viral programs they might control will significantly improve our understanding of virus-host interactions. So far, this area has received little research attention.

Finally, the infected host seems to take advantage of the dependency of the virus on distinct metabolites to prevent viral replication. A few anti-viral genes that target host metabolism with this aim have already been described; these are likely to increase in numbers in the near future. In conclusion, both the virus and the infected host aim to either gain or maintain control over host metabolism in a battle to either secure or prevent viral replication. That such intervention has potential for treatment of viruses is supported by our latest finding that 4-octyl-itaconate and dimethul-fumarate, derivatives of two TCA-cycle associated metabolites, can induce potent anti-viral cellular programs against important viruses. Currently, the majority of reports that target metabolism for disease control have dealt with autoimmunity or cancer, but viral diseases especially chronic persistent infections, could be a fruitful field for investigation.

5. Our research interest 我们的研究方向

Cancer cells and virus-infected cells commonly both exhibit the Warburg effect (increased glycolytic metabolism in the presence of adequate oxygen). Increased nucleotide and lipid biosynthesis are two other metabolic alterations associated with tumorigenesis and rapid cell proliferation that are also seen in various virus infections. However, it remains to be determined whether metabolic reprogramming by cancer-causing viruses contributes to oncogenesis. The future is certainly ripe for discovery in the viral metabolism field.

Our group focus on host–pathogen interactions at the metabolic level. We are interested in how viruses alter the metabolism of host cells, and how these changes can be exploited to develop antiviral strategies. The metabolic reprogramming induced by oncovirus is critical for the malignant transformation. We are using metabolomic, CRISPR and proteomic approaches to study key metabolic pathways that support HBV replication, and how viral-induced metabolic reprogramming contributes to oncogenesis. We aim to explore novel diagnosis and therapy strategies for virus-related cancers.

We found that hexosamine biosynthesis pathway (HBP) is activated upon HBV infection. The HBP converts glucose to uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a substrate for O-linked β-N-acetylglucosamine (O-GlcNAc) modification (also known as O-GlcNAcylation), which is catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). OGT mediated O-GlcNAcylation of the sterile alpha motif and histidine-aspartic domain-containing protein 1 (SAMHD1) promotes antiviral activity in vitro and in vivo in HBV infection. On the other hand, we discovered that the O-GlcNAcylation of RNA N6-methyladenosine (m6A) reader YTH (YT521-B homology) domain 2 (YTHDF2) is markedly increased upon HBV infection. OGT-mediated YTHDF2 O-GlcNAcylation at Ser263 stabilizes its protein expression and oncogenic activity. YTDHF2 preserves the stability of MCM2/5 transcripts to promote HBV-related hepatocellular carcinoma (HCC) tumorigenesis. 

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