Physiological studies of infection biology revealed decades ago that there is an intimate relationship between the immune system and the host metabolic system. These interactions begin soon after pathogen detection and continue to evolve over the course of the infection. A relatively recent resurgence in interest in the interface between immunity and metabolism gave rise to the field of ‘immunometabolism’, a term that was coined in 2011. Immunometabolic studies have mainly focused on the cellular level and on non-infectious diseases such as metabolic syndrome, with surprisingly few studies involving infections. In 2019, several studies started to elucidate the relationship between metabolism and the immune response to infectious diseases on both the cellular and the organismal levels. Moreover, 2019 saw the re-emergence of invertebrate animal models to study immunometabolism and infection.
Modulation of host metabolism can influence host immune response to viral infections.
Glycolysis and lactate negatively regulate type I interferon induction and the antiviral response.
Type I interferons act on CD8+ T cells and drive whole body weight loss during chronic viral infections, independent of cell-to-cell intrinsic interactions and classic CD8+ T cell mediated cytotoxicity.
Invertebrate animal models provide an opportunity to elucidate principles of immunometabolism at the organismal level.
Fat wasting caused by an immune response to a perceived pathogenic infection causes a shortened lifespan in Caenorhabditis elegans.
The translational potential of targeting the metabolic regulation of the immune response is significant. Indeed, drugs targeting interleukin-1β (IL-1β), a cytokine that has a metabolic regulatory function, have shown promising results in clinical trials in patients with cardiovascular diseases. For the treatment of infections, in which resistance to antimicrobial agents is a continuous challenge, the targeting of immunometabolic regulators presents a promising translational avenue. In 2019, several studies investigated metabolic changes in response to infection at both the organismal and the cellular levels, reminding us of the importance of metabolism in host defence against infection.
In an elegant study, Zhang et al. examined the metabolic regulation of the antiviral immune response. Upon viral infection of a cell, cytosolic viral RNA is detected by the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family. The activation of RLRs triggers the induction of mitochondrial antiviral signalling protein (MAVS), which is required for the activation of interferon regulatory factor 3 (IRF3) and the type I interferon response. MAVS is tethered to intracellular membranes, mostly the mitochondria, suggesting a potential link to metabolism.
The authors now show that MAVS interacts with hexokinase 2 (HK2)1. Upon RLR activation, this interaction is abolished, reducing the glycolytic flux and leading to a reduction in the levels of glycolytic intermediates downstream of HK2. They found that lactate produced by glycolysis binds to MAVS and thereby suppresses type I interferon gene expression. Cells grown in low glucose conditions or in the presence of a hexokinase inhibitor had enhanced type I interferon responses. On the organismal level, the authors showed that mice with low blood glucose caused by fasting had increased type I interferon gene expression in response to infection with vesicular stomatitis virus (VSV) compared with mice with higher glucose levels. Furthermore, mice that were deficient for lactate dehydrogenase A (LDHA) or treated with an LDHA inhibitor had a more robust type I interferon response and a heightened resistance response to VSV infection. By contrast, treatment of mice with sodium lactate reduced type I interferon in response to viral infection. This study provides important evidence that lactate acts as an immunomodulatory molecule in vivo that can be manipulated to regulate host defence to infections.
Infection-induced changes in host metabolism influence the pathogenesis of the infection and affect physiological functions in the host2. Clinically, the catabolic wasting of energy stores is the most profound metabolic effect of infections3. In humans, the febrile response appears to be the major stimulus for the induction of muscle and fat wasting. In mouse models of infection, mice develop hypothermia rather than fever owing to cold stress in standard facility conditions; however, they still exhibit catabolism of energy stores4.
The pro-inflammatory response to infection induces muscle and fat wasting by acting directly on energy stores and by inducing behavioural responses that result in tissue catabolism. Traditionally, studies have focused on understanding the role of pro-inflammatory cytokines including TNF, IL-1 and IL-6 in the pathogenesis of wasting. In 2019, a new, unexpected player was added to the list of immune mediators of wasting.
Investigators who use the lymphocytic choriomeningitis virus (LCMV) clone 13 mouse model of chronic viral infection have appreciated for decades that infected mice develop an acute and robust anorexic response and a wasting phenotype that is reversible. However, it was not until 2019 that Baazim et al. interrogated this phenotype mechanistically5. LCMV-infected mice lose ~15–20% whole body weight, primarily due to the depletion of fat tissue, which is largely independent of the infection-induced anorexic response. Fat wasting is associated with the loss of lipid stores in adipocytes and the modulation of key regulators of lipid metabolism. Using metabolic cages that measure various physiological parameters, the authors found that LCMV-infected mice preferentially utilize fat as their energy source. Unexpectedly, antibody-mediated neutralization or genetic ablation of canonical mediators of wasting, such as the pro-inflammatory mediators interferon, TNF and IL-6, did not rescue the animals from LCMV-induced wasting. However, these results should be interpreted with caution as the authors did not report on viral burden. If neutralization or genetic ablation of pro-inflammatory cytokines impairs antiviral defences, then a higher viral burden may mask any effects these cytokines have on the pathogenesis of fat wasting.
The authors found that genetic ablation of type I interferon signalling and depletion of CD8+ T cells reduced the severity of whole body wasting. Using cell-specific knockout mice, they showed that CD8+ T cell intrinsic interferon-α and -β receptor 1 (IFNAR1) signalling was required for T cell activation and proliferation and the modulation of lipid metabolism, as well as lipolysis and associated increases in the level of serum glucocorticoids during infection. An analysis of the kinetics of viral infection and T cell activation in bone marrow chimaeras led the investigators to conclude that CD8+ T cells cause whole body weight loss upon antigen-specific stimulation. This was independent of direct cell-to-cell interactions and classic CD8+ T cell mediated cytotoxicity.
Although this work identified a new player in the pathogenesis of wasting, it is unlikely that this mechanism or other immune response mechanisms that drive wasting during infections in general will be promising targets for therapeutic applications as these strategies would likely immunocompromise the host. Strategies that alleviate wasting pathology via disease tolerance mechanisms that do not render the host immunocompromised are likely better therapeutic avenues to explore4.
The question remains as to what exactly the function of wasting is. The hypothesis is that it is an adaptive response to infection to facilitate the re-mobilization of macromolecules for biosynthetic pathways and energy generation to support the immune response to infection2. However, in bacterial infections in fly and mouse models, wasting seems to be maladaptive as the blocking of muscle and fat wasting responses was shown to promote survival of infection without compromising the ability of the host to kill the pathogen4,6. Whether this is also the case for viral infections remains to be shown.
Wasting of energy stores during infection may also represent a physiological trade-off in the context of certain infections, in which the ability of the host to mount an optimal immune response comes at a cost to another physiological function. These trade-offs can ultimately influence the lifespan and potentially the fitness of an organism. Invertebrate model organisms provide an exciting opportunity to define the underlying principles that govern such trade-offs.
A study by Curran and colleagues used Caenorhabditis elegans to define the relationship between immune activation and adipose tissue physiology and investigated how the regulation of these systems affects the lifespan of the organism7. In previous work, Curran and colleagues had demonstrated that the C. elegans transcription factor SKN-1 promotes age-dependent somatic depletion of fat (ASDF)8. In their new work, using a gain-of-function SKN-1 mutant (skn-1gf), Nhan et al.7 found that ASDF caused by SKN-1 activation is associated with the induction of innate immune and pathogen response genes. Consistent with this, feeding skn-1gf C. elegans with dead instead of live bacteria (Escherichia coli) prevented the ASDF phenotype, demonstrating that exposure to live bacteria is required for SKN-1-dependent mobilization of lipids. Using a gain-of-function mutant with a constitutively activated p38 MAPK–PMK-1 pathway, which results in continuous SKN-1 activation and the induction of genes that are important for C. elegans innate immune responses, the investigators showed that the same signalling pathway also drives the depletion of lipid stores. In wild-type worms, exposure to the pathogenic bacterium Pseudomonas aeruginosa was sufficient to induce the ASDF phenotype. This was dependent on signalling through SKN-1 and was important for promoting defence against infection, demonstrating that immune responses against pathogenic bacteria involve the SKN-1-dependent redistribution of somatic lipids. The lipid redistribution comes at the expense of organismal lipid homeostasis, which impairs organismal health later in life.
This work demonstrates that mobilization of energy stores during infection supports host defence against the infection. It also reveals how physiological trade-offs between the immune system and host metabolism can affect the lifespan of the organism.
Schneider and colleagues first established 15 years ago that invertebrate model organisms can be used to study infection-induced pathologies and immunometabolism of infection at the organismal level6,9. The work by Curran and colleagues reminds us that elegant studies can be performed with simple in vivo model systems to define mechanisms and principles of the immunometabolism of infection, and we hopefully will see more studies using these systems in 2020.
We are currently experiencing an exciting time in the field of immunometabolism of infection. 2019 was a particularly noteworthy year, with the re-emergence of studies and models focused on understanding metabolic adaptations during infection at the organismal level. ‘En vogue’ biology oscillates over time and, while I anticipate 2020 will bring ever more fascinating insights into immunometabolism, I encourage anyone interested in metabolism and infection to immerse themselves in the literature from decades ago. You may just find some inspiration for your studies in 2020 and beyond.
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Baazim, H. et al. CD8+ T cells induce cachexia during chronic viral infection. Nat. Immunol. 20, 701–710 (2019).
Dionne, M. S. et al. Akt and FOXO dysregulation contribute to infection-induced wasting in Drosophila. Curr. Biol. 16, 1977–1985 (2006).
Nhan, J. D. et al. Redirection of SKN-1 abates the negative metabolic outcomes of a perceived pathogen infection. Proc. Natl Acad. Sci. USA 116, 22322–22330 (2019).
Lynn, D. A. et al. Omega-3 and -6 fatty acids allocate somatic and germline lipids to ensure fitness during nutrient and oxidative stress in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 112, 15378–15383 (2015).
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The author declares no competing interests.
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Ayres, J.S. Immunometabolism of infections. Nat Rev Immunol 20, 79–80 (2020). https://doi.org/10.1038/s41577-019-0266-9
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