Covid Immunometabolism Therapy

Immunometabolism to treat lung infections and control of pulmonary infection(s) approach involves uptake of free fatty acids as well as glucose by T and B cells, which 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. Similarly, glucose metabolism in B cells is important for cellular proliferation and antibody production. 

However, infected myeloid cells (M.tb) -infected macrophage (Mf), can disrupt the fatty acid-metabolic balance by increasing consumption of both nutrient types. This loss of equilibrium results in bacterial proliferation, subdued immune activation/modulation and survival of the pathogen in the lung. 

Glucose uptake is also necessary for effector NK cells with regard to IFN-γ production, which is essential for protection against intracellular pathogens. 

Also drugs, most of which are clinically approved, 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 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. 

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. 

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.