Sweet talk: Metabolic conversations between host and microbe during infection

Abstract

In this issue, we introduce the second part of a series of reviews focusing on how immunometabolism influences host and pathogen interactions during infection. This part of the collection addresses the interface between metabolism and specific types of infection, including immunometabolism in macrophages during helminth infection, the role of metabolism in T‐cell exhaustion during chronic viral infections and host immunometabolism in the defence against Mycobacterium tuberculosis infection. These reviews, together with the four articles published in part 1 of the series in November 2020, offer new insights into the complex interactions between mammalian hosts and microbial pathogens through the lens of cellular metabolic regulation.

The immune response to infection is a dynamic interaction whose outcome is life or death for both the host and the pathogen. The field of immunometabolism has recently given a new perspective to our understanding of immune activity, ¹ , ² and in this review series, we are highlighting the contribution of metabolites and metabolism to the dynamic conversation between host and pathogen. The regulation of metabolism can control the size, speed, quality and location of an immune response, ³ and a wily pathogen can manipulate host cell metabolism as part of its strategy of immune evasion. ⁴ , ⁵ Understanding these metabolic interactions offers hope of new therapies and new strategies for controlling infection.

Our review series illustrates an exciting range of mechanisms by which immunometabolism can influence the outcome of infection. We have published the series in two parts. The first four reviews were included in the November 2020 issue of this journal. ⁶ They provide an overview of metabolic mechanisms for regulating immune activity and defence against infection, including the influence of cellular metabolism on epigenetic regulation, ⁷ post‐translational protein modification, ⁸ immune cell trafficking ⁹ and intestinal homeostasis. ¹⁰ This second part of the series provides specific examples of immunometabolism in action during particular infections, highlighting metabolic regulation in macrophages during helminth infection, ¹¹ in T cells during chronic viral infections (CVIs) ¹² and at the interface between innate and adaptive immunity to Mycobacterium tuberculosis infection. ¹³

In the first article in this issue, Cortes‐Selva and Fairfax discuss the elegance of macrophage metabolic regulation during helminth infection, with a particular emphasis on their expertise in Schistosoma mansoni infection. ¹¹ Readers who enjoyed the review from Gerós et al. in the first part of this series will appreciate Cortes‐Selva and Fairfax’s discussion of the central role of macrophages in iron regulation. Infections with helminth parasites are typically chronic by nature, often at least in part due to immune suppression by the parasite. Metabolic mechanisms for reprogramming the immunological microenvironment can therefore be an important aspect of the replicative success of these pathogens. This review describes how helminth‐derived molecules are able to modulate both glycolytic and mitochondrial metabolisms to condition macrophage responses to a less inflammatory state, closely associated with macrophage ‘alternative activation’. The authors discuss the impact of S. mansoni infection on the metabolism of perivascular macrophages and Kupffer cells in the liver, both of which play particularly important roles in this infection. Excitingly, they describe recent evidence that helminth infection can modulate systemic metabolic parameters, potentially providing protection against metabolic disease. Such protection may be sex‐dependent, as S. mansoni infection protects against metabolic disease in male but not female mice.

Cortes‐Selva and Fairfax also evaluate similarities and differences between metabolic regulation in infections with different helminths, comparing the impact of soil‐transmitted helminths with that of S. mansoni infection. Their review handles the complexity of macrophage lineages and immune plasticity adeptly, providing readers with a comprehensive overview of macrophage metabolic regulation during helminth‐mediated disease. Continuing the theme of chronic infection and the associated immune cell metabolism, our second review by Sears et al. addresses the metabolic underpinnings of CD8⁺ T‐cell exhaustion during CVIs. ¹² The authors discuss the metabolic shifts associated with T‐cell activation and memory formation and describe how persistent T‐cell receptor stimulation during chronic infection results in less glycolysis and more fatty acid oxidation and TCA cycle usage. Sears et al. explain that such metabolic remodelling of T cells during CVIs is thought to be caused by epigenetic modulation, inhibitory receptor regulation (PD‐1 and LAG‐3), IL‐10 signalling and virus‐stimulated increases in regulatory microRNA expression. A major strength of this review is its emphasis on therapy. The authors provide a detailed assessment of the ability of metabolic mediators to reverse chronic T‐cell exhaustion and reignite cytotoxic lymphocyte responses. Their work outlines the therapeutic promise of directly targeting immune cell metabolism, especially by re‐enabling the glycolytic machinery typically suppressed in exhausted lymphocytes during CVI.

The final review article of the series by Sheedy and Divangahi nicely bridges the conceptual framework of the previous two, considering innate and adaptive immunometabolism in another chronic infection context, Mycobacterium tuberculosis (Mtb) ¹³ . The authors characterize the unique features of the lung microenvironment (including low glucose levels compared with serum) that foster a permissive space for Mtb infection characterized by a nutrient environment that favours fatty acid oxidation and TCA cycle activity, which in turn supports the attenuated inflammatory potential of lung alveolar macrophages compared with classic inflammatory macrophages. The authors discuss the enhanced glycolytic profiles of macrophages recruited to the lung during Mtb infection, compared with alveolar macrophages, and argue that these macrophages and their distinct metabolism are important for pathogen control. They also provide a nuanced discussion of other risk factors and comorbidities, such as smoking and hyperlipidaemia, that impact the inflammatory potential of cells recruited to lung tissue during infection. The authors highlight disease tolerance rather than pathogen elimination in Mtb infection and discuss how the regulation of T‐cell glycolysis influences the balance between Th17 and T regulatory cells, with important implication for disease control and immunopathology. The authors conclude with a thought‐provoking discussion of the therapeutic potential of harnessing ‘trained immunity’, an epigenetic and perhaps metabolic reprogramming of innate immune cells, to provide better vaccination strategies against Mtb infection.

The three reviews here each provide exciting examples of immunometabolism ‘in action’, in three very different infection contexts. They highlight the elegant biology involved, and they suggest new routes for therapeutic and preventative strategies. Together with the first part of our series, we provide a platform to engage with some of the latest findings in the fields of immunometabolism and infection biology. We hope you enjoy diving in.