EXPLORING THE IMMUNOMETABOLISM DURING TRYPANOSOMA CRUZI INFECTION

STEMPIN CC

San Luis

Congreso; Simposio de Inmunometabolismo - Invitada por la Sociedad Argentina de Inmunología LXXI Reunión Científica Anual de la Sociedad Argentina de Inmunología. San Luis, Argentina, del 9 al 11 de noviembre de 2023.; 2023

Sociedad Argentina de Inmunología

Chagas disease (CD) is caused by the protozoan T. cruzi. Initially confined toLatin America, CD has now become a global concern due to globalization. It hasa high morbidity and mortality rate and significant social impact posing a majorpublic health threat. The disease progresses from an acute phase (AP) to achronic one, with some individuals remaining asymptomatic while others developprogressive heart disease, leading to end-stage dilated cardiomyopathy in 20-30% of cases. Despite efforts by endemic and non-endemic countries to control,treat, and interrupt disease transmission, finding a cure or eradicating CDremains a pressing global issue.The role of T cells-mediated immune response in controlling intracellularprotozoan parasite infection is well established. However, T. cruzi exhibitsnumerous adaptations that enable it to establish a chronic infection, such asinducing T cell apoptosis delaying the onset of immune response. It is widelydescribed that metabolic pathways dictate the effector functions of immunesystem cells and, therefore, can become targets of immune evasion forpathogens.In this context, our lab has explored T cell metabolism during experimental T.cruzi infection. We focused on the metabolic and mitochondrial phenotypeacquired by CD4 T cells during infection, and its functional consequences thatcould explain failures in this cell compartment. We found that CD4 T cells duringAP of infection acquire an exacerbated glycolytic and oxidative metabolic profile,with high levels of mitochondrial reactive oxygen species (mROS) accumulatingsince early stages of the infection. High mROS levels observed during AP ofinfection correlates with increased mitochondrial damage. We observed thateffector CD4 T cells are strongly affected by these alterations. Furthermore, thesecells are less functional and more prone to apoptosis. Increased apoptosis couldbe related to deficient antioxidant systems, as well as mitochondrial dynamicsalterations. In this sense, in vitro treatment with the antioxidant NAC, reduced thefrequency of apoptosis in CD4 T cells with depolarized mitochondria. Moreover,in vivo treatment with the NAD precursor Nicotinamide Riboside, which is capableof inducing mitophagy, diminished the frequency of mROS-producing cells withdepolarized mitochondria. Even more, we demonstrated that mitochondrialdefects are TCR signaling-dependent and are related to the infection context, asthey do not happen in an immunization model.Altogether, these results are the first in demonstrating that T. cruzi acute infectiontriggers metabolic and mitochondrial alterations in CD4 T cells that are linked toa deficient function and apoptosis induction. Thus, these events would contributeto the host immune response's inability to clear the parasite. Then, these resultsprovide new insights into understanding the molecular and metabolic processesthat drive the dysfunction and the outcome of CD4 T cells during infection.