Epigenetic programming during chronic infectious diseases: tiring out and training the innate immune system

Abstract

Epigenetic mechanisms are associated with training/programming and polarization of immune cells, which can be induced by the presence of cytokines and molecules present in the microenvironment, like PAMPs (Pathogen-associated molecular pattern) or other mediators of inflammation. Our hypothesis is that during chronic infections such as HIV and TB, PAMPs, cytokines or extracellular vesicles containing epigenetic modifiers, act on non-stimulated cells, causing them to undergo deleterious epigenetic changes that will define the prognosis of diseases. During pulmonary M. tuberculosis infection, cytokines and PAMPs may fall into the circulation and act on circulating or progenitor cells, inducing the training of the innate immune response. On the other hand, in HIV patients, there is a cytokine storm due to disruption of the intestinal barrier and virus immune response. The exacerbated inflammation is associated with the induction of the senescence of innate immune system during infection and uncontrolled inflammatory response. We have shown that monocytes from HIV-infected individuals undergo epigenetic changes that are related to the lack of control in the production of inflammatory cytokines by these cells and in their effector function. In this project, we will test the possibility that extracellular vesicles produced by leukocytes during HIV infection could act in the expansion of the immune senescence phenotype and determine the content of extracellular vesicles present in the plasma of HIV-infected patients. In Tuberculosis, we will evaluate how different conditioning environments can train neutrophils, also determining the epigenetic signature of these profiles and associating the functions and phenotypes of each cell subtype. In addition, we will also evaluate the effects of epidrugs in modulating the function and phenotype of immune cells. (AU)