We all have different susceptibility
Individuals differ in their susceptibility to viral infections, and the clinical course of any patient infected with a virulent virus is ultimately determined by the complex patient-virus interaction. And this makes perfect sense. Viruses are infective particles that rely on the host’s cellular machinery to replicate, so it is easy to imagine how the host genetic and metabolic background can significantly influence the outcome of a viral infection.
Multiple innate factors (e.g., age, nutritional status, genetics, immune competency, and pre-existing chronic diseases) and external variables (e.g., concurrent drug therapy) influence the overall susceptibility of a person exposed to a virus. For most viruses, whether or not clinical signs develop is determined by a myriad of conditions, some of which can be parsed out and further investigated. Efforts to understand the genetic and metabolic basis of host susceptibility to viral infection and disease have led to the identification of some of the genes and metabolic pathways that play key roles in determining the outcome of virus-host interactions.
The genes involved in our susceptibility to viruses
Viral susceptibility and disease progression are determined by host genetic variation. The contributions of host polymorphisms to susceptibility to viral infection have been reported for multiple viruses. For example, a polymorphism in the cellular co-receptor CCR5 prevents HIV-1 from entering the cell, making some individuals resistant (1,2).
A polymorphism of the RNA trafficking gene hRIP (human Rev-interacting protein) is hypothesized to increase viral replication and is associated with severe pneumonia after Influenza A virus infection (3).
Similarly, multiple-locus polymorphisms have been associated with DENV pathogenesis and disease susceptibility [reviewed in Fang et al., (2012) FEMS Immunol Med Microbiol.]. And we could go on. Potentially, polymorphisms of any genes encoding host factors that interact with a virus could contribute to individual viral susceptibility.
Host genetic polymorphisms that affect the response of viral infection have been studied for only a few viruses. However, investigating the effect of causal polymorphisms in humans is complicated because genetic methods to detect rare or small-effect polymorphisms are limited, and obviously, genetic manipulation is not possible in human populations. So, the genetic basis of individual viral susceptibility remains mostly elusive.
How metabolism contributes to susceptibly to viruses
Viruses (especially those with small genome like DENV) depend on the host metabolism to replicate. Thus, the host’s central metabolism is a key element for viral infections (4). Given this importance of central metabolism, it is easy to imagine how individual physiological and metabolic pathways determined by dietary and environmental factors can influence virulence. Surprisingly, this topic has been little researched.
What seems certain is that the nutritional status of the host is important for susceptibility to (and severity of) infectious diseases; inadequate nutrition impairs the functioning of the immune system, thereby increasing the risk of virulence and disease.
There is also increasing awareness of how viral pathogens hijack the cell, reprogramming host cell metabolism to fulfil their energy requirements, thereby disrupting the metabolic balance. For example, viruses use a range of strategies to activate glycolysis (5; 6) and increase fatty acid synthesis. Reducing glucose metabolism weakens influenza viral infection in laboratory cell cultures (7). Similarly, inhibition of fatty acid synthesis leads to a lower number of infectious viruses in cases of HCMV, influenza virus (8), yellow fever, West Nile, and dengue viruses (9). Very recently, we have shown that Semliki Forest virus and Ross River virus activate cellular glycolysis by manipulating the PI3K/AKT pathway and this metabolic reprogramming impacts the outcome of these viral infections in vivo (10). Because viruses are so dependent on host cell metabolism, pharmacological inhibition of pathways involved in metabolic activation can represent an opportunity for therapeutic intervention.
What determines susceptibility to YF17D?
Chan et al. have asked why flaviviral infection is sometimes asymptomatic, but other times results in an acute febrile illness characterized by fever, malaise, and headache. Counter-intuitively, viremia levels are not always associated with symptomatic outcome in humans, as has been seen using a live-attenuated YFV vaccine (11) or with dengue virus (12). To understand the molecular determinants of symptomatic infection, Chan et al. studied human volunteers before and after inoculation with the live yellow fever viral vaccine (YF17D).
Heightened innate immune response contributes to symptomatic outcome
In a previous study, the authors have reported that infection with live-attenuated YF17D induces acute febrile illness in those subjects who showed activation of innate immune responses in the first day after vaccination. This was not due to a significant increase in inflammation-modulating proteins. The team next gathered data from two independent human studies and analyzed the blood transcriptomic and metabolomic profiles of the volunteers immediately before and after vaccination. They found that those with an increased susceptibility to symptomatic outcome showed an increased abundance of transcripts/metabolites involved with the ER stress response and reduced activity of the tricarboxylic acid (TCA) cycle (also known as the citric acid cycle or Krebs cycle).
ER stress and the TCA cycle
ER stress is caused by perturbation of the three major functions of the ER: protein folding, lipid and sterol biosynthesis, and storing intracellular Ca2+. Invading pathogens can induce ER stress, which in turn activates an intracellular signaling pathway known as the unfolded protein response (UPR). The UPR is well situated to sense pathogenic danger and transduce the stress signal into an immune response. The TCA cycle occurs in the matrix of the mitochondria and is a major metabolic pathway used in most quiescent or non-proliferative cell settings. The TCA cycle and oxidative phosphorylation are highly efficient modes of ATP generation used by cells whose primary requirements are energy and longevity. Activated immune cells are known to switch from oxidative phosphorylation to glycolysis for energy. In contrast, lymphocytes with reduced ER stress response and greater dependency on the TCA cycle for energy have a greater capacity to cope with the anabolic demands of infection without disruption of homeostasis; and this is what happens in asymptomatic individuals. Increased stress and altered metabolism resulted in earlier than expected activation of the immune response, and this was linked with the development of symptoms.
Are transcriptional differences responsible for changes in plasma metabolite levels?
To determine whether transcriptional differences in metabolic pathways are responsible for alterations in plasma metabolite levels, the authors performed an analysis in plasma collected before and at 1-day post-infection. They found that TCA cycle metabolites were the most important discriminant of the symptomatic outcome. However, no difference in plasma glucose was observed between the two groups, suggesting that the decreased TCA cycle activity was independent of the substrate concentration for upstream glycolysis. Citrate, isocitrate, and malate were all notably lower in symptomatic subjects, which reflects the reduced activity of the TCA cycle.
Genes, diet, and environment all contribute to our reactions to virus infection
Genetic, dietary, and environmental factors might all influence ER stress. Also, the use of certain metabolic pathways, as well as the host-microbiome, have recently been shown to profoundly influence the immune system and might, therefore, affect the immunometabolic state at baseline. This interesting work by Chan et al. once again highlights the importance of understanding host metabolism to gain a better understanding of pathogens’ infection processes.
References
1 Liu R et al, Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection, Cell, 1996
2 Samson M et al., Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene, Nature, 1996
3 Zúñiga J et al., Genetic variants associated with severe pneumonia in A/H1N1 influenza infection, Eur. Respir., 2012
4 Biswas SK and Mantovani A. Orchestration of metabolism by macrophages. Cell Metab., 2012
5 Fontaine KA et al., Dengue virus induces and requires glycolysis for optimal replication. J Virol., 2015
6 Thai M et al., Adenovirus E4ORF1-Induced MYC Activation Promotes Host Cell Anabolic Glucose Metabolism and Virus Replication. Cell Metabolism, 2014
7 Hinissan P et al., Glycolytic control of vacuolar-type ATPase activity: A mechanism to regulate influenza viral infection. Virology, 2013
8 Munger J et al., Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy, Nat Biotechnol., 2008
9 Heaton NS et al., Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis, Proc Natl Acad Sci, 2010
10 Mazzon M, Castro C et al., Alphavirus-induced hyperactivation of PI3K/AKT directs pro-viral metabolic changes, Plos Path, 2018
11 Chan CY et al., Early molecular correlates of adverse events following yellow fever vaccination, JCI Insight, 2017
12 Simon-Loriere E et al., Increased adaptive immune responses and proper feedback regulation protect against clinical dengue, Sci Transl Med., 2017
