Pathogen manipulation of host metabolism: A common strategy for immune evasion

The immune system is one of the three main consumers of energy in the human body; brain, muscle, and the immune system use similar amounts (approximately 500 kcal/day) [1].Rapid bursts of cellular proliferative, biosynthetic, and secretory activities by leukocytes require considerable metabolic resources that are especially important during periods of infection and inflammation [2,3].Because immune cells have negligible intracellular nutrient stores and rely on aerobic glycolysis for activation and proliferation, they are particularly dependent on the uptake of metabolic substrates [2][3][4][5][6].Indeed, glucose uptake is the primary limiting factor in T-cell activation [5,6].T-cell activation and proliferation are decreased in low-glucose states along with reduced production of cytokine effectors of the immune response, including interferon γ (IFN-γ) [6][7][8].Susceptibility to infections by individuals with metabolic diseases further underscores the significant impact of metabolic disruption on the functions of innate and adaptive immunity [9,10].Pathogens that are well adapted to their hosts have developed an extraordinarily wide range of mechanisms to modulate host immunity in order to facilitate and prolong infection and transmission.Several of these mechanisms are relatively well characterized and appear to act directly on host target tissues.Traditionally, the effects that many pathogens have on host metabolism have been assumed to be downstream consequences of pathogenesis.However, increasing evidence suggests that these pathogen-induced metabolic disturbances may instead reflect aspects of the pathogens' modulation of the immune response to enhance and/or prolong the period of infection and transmissibility (Fig 1).Here, we examine three diverse but highly prevalent global pathogens that disrupt host metabolism during infection and may thereby alter the host immune response: Trypanosoma cruzi, Plasmodium falciparum, and Bordetella pertussis, responsible for Chagas disease, malaria, and whooping cough, respectively.Considering how metabolic changes that pathogens induce in the host can affect the immune response may reveal commonalities that can contribute to understanding, controlling, and treating a wide range of diseases. T. cruziT. cruzi disrupts host glucose homeostasis within 30 days post infection (DPI) [11,12].Parasites are detected as early as 15 DPI within insulin-secreting pancreatic beta cells.T. cruzi's actions in the pancreas are quite selective.Pancreatic islet architecture is significantly disrupted such that beta cells are preferentially targeted by the parasite, and other islet cell types such as glucagon-secreting alpha cells are spared [12].