Immunometabolism and Pulmonary Infections: Implications for Protective Immune Responses and Host-Directed Therapies

Abstract

The biology and clinical efficacy of immune cells from patients with infectious diseases or cancer are associated with metabolic programming. Host immune- and stromal-cell genetic and epigenetic signatures in response to the invading pathogen shape disease pathophysiology and disease outcomes. Directly linked to the immunometabolic axis is the role of the host microbiome, which is also discussed here in the context of productive immune responses to lung infections. We also present host-directed therapies (HDT) as a clinically viable strategy to refocus dysregulated immunometabolism in patients with infectious diseases, which requires validation in early phase clinical trials as adjuncts to conventional antimicrobial therapy. These efforts are expected to be continuously supported by newly generated basic and translational research data to gain a better understanding of disease pathology while devising new molecularly defined platforms and therapeutic options to improve the treatment of patients with pulmonary infections, particularly in relation to multidrug-resistant pathogens.

Keywords: immunological memory; immunometabolism; inflammation; lung infections; protective immune responses.

FIGURE 1

Targeting the host immunometabolism to treat lung infections. A schematic representation of the central role played by glucose and lipid metabolism in immune-cell homeostasis and control of pulmonary infection(s). Uptake of free fatty acids as well as glucose by T and B cells is important for immunological effector functions and maintenance of immune-cell memory. In this regard, saturated fatty acids may have a higher likelihood of promoting anti-inflammatory activity in T cells, while unsaturated fatty acids may lead to the contrary. Antigen-presenting cells (APCs), encompassing macrophages, dendritic cells and B cells, are affected by the intake and endogenous production of fatty acids in their capacity to generate phagolysosomes and upregulate HLA-DR on the cell surface to activate T cells. Similarly, glucose metabolism in B cells is important for cellular proliferation and antibody production. However, infected myeloid cells, represented here by an M.tb-infected macrophage (Mf), can disrupt the fatty acid-metabolic balance by increasing consumption of both nutrient types as indicated by the thicker arrows. This loss of equilibrium results in bacterial proliferation, subdued immune activation/modulation and survival of the pathogen in the lung. Furthermore, high levels of circulating low-density lipoprotein (LDL) are also taken up by infected host cells to support intracellular survival of the pathogen. Interspersed in this intricate immuno-metabolic circuit are NK cells, which can also acquire adaptive, memory-like functions and contribute to effective host immune control of pulmonary pathogens. Glucose uptake is also necessary for effector NK cells with regard to IFN-γ production, which is essential for protection against intracellular pathogens. This is concomitant with mTOR upregulation and responsiveness to IL-2. However, the regulation of lipid immunometabolism in NK cells requires further investigation. Also shown in the figure are several drugs (in yellow/orange boxes), most of which are clinically approved except for ADU-S100 and dactolisib, which may be used for targeting the immunometabolic axis in lung infections. Metformin, via the activation of AMPK, can induce oxidative phosphorylation (OXPHOS) in macrophages and improve memory CD8+ T-cell responses (IFN-γ production). Statins block intracellular HMG-CoA reductase and induce an increase in LDL accumulation in exposed cells by upregulating surface expression of the LDL receptor, which can affect both T and B cells by reducing inflammatory responses. Conversely, ezetimibe, which also regulates cholesterol homeostasis, does so by blocking uptake of exogenous LDL. Ezetimibe, like statins, shows a rather anti-inflammatory effect and can induce nitric oxide (NO) production. Aspirin (acetylsalicylic acid), which was already proposed as a possible anti-inflammatory HDT for TB, may also induce NO expression in cells – which is crucial for killing intracellular pathogens. Resveratrol can improve the uptake of free fatty acids by T cells by activating host sirtuin1 (SIRT1) – to fine-tune cellular immune responses while reducing the occurrence of adverse tissue pathology. Although not directly shown, anti-PD-1 and anti-CTLA-4 therapy have been shown to improve glucose metabolism in T-cell populations, in part adding to their clinical anti-tumor activity and may also apply to TB. The investigational clinical drug candidate ADU-S100 mimics cyclic guanosine-monophosphate-adenosine-monophosphate (cGAMP) and can activate the stimulator of interferon genes (STING) protein, thus qualifying it as an immunomodulatory drug candidate with effects on immunometabolism. Dactolisib is currently in early-phase clinical trials to treat patients with solid cancers and has been shown to be beneficial in a preclinical murine influenza infection model – by targeting glycolysis and may apply to TB and staphylococcal infections, where increased glycolysis in host cells supports pathogen growth.