Neutrophils in trained immunity

Trained immunity is defined as a long-term functional modification of innate immune cells which leads to an enhanced responsiveness to a second challenge, either homologous or heterologous. This reprogramming of innate immune cells is occurring both at the metabolic, epigenetic and functional level, which are deeply intertwined. In the bone marrow, long-term alterations are mediated by the reprogramming of hematopoietic stem and progenitor cells. Previous work from the lab demonstrated that mice trained using β-glucan are protected from a broad spectrum of bacterial infections owing to an increase in the number of innate immune cells. Neutrophils are among the most abundant cells of the innate immune system. Their short halflife implies constant replenishment, a process termed granulopoiesis. Neutrophils are phagocytic cells endowed with an antimicrobial arsenal. This arsenal includes the release of toxic molecules which are contained in granules, NETosis, and the secretion of cytokines and chemokines which initiate and regulate the immune response. Hence, neutrophils play a pivotal role in the antimicrobial response. However, their role and their capacity to be reprogrammed during trained immunity is so far unknown. In this doctoral work, we interrogated how trained immunity reprograms neutrophils and influences infection by Streptococcus pneumoniae, a main pathogen responsible for pneumonia and severe conditions such as eningitidis or sepsis. We demonstrated that β-glucan induced training increases neutrophils in the blood, the bone marrow and the spleen of mice in a dose-dependent manner. Single cell transcriptomic analysis allowed us to establish that training induces a reprogramming along the developmental trajectory of neutrophils. Neutrophils exert a key role in the protection against S. pneumoniae, in a preclinical model of pneumonia and a systemic model of infection. Interestingly, protection mechanisms were not superimposable in both models and vary depending on the type of infection. Finally, given that aging is accompanied by a decline in immune surveillance and immunoreactivity, we interrogated the reprogramming capacity of the innate immune system in aged mice. We report that the induction of trained immunity is a very powerful tool for protecting aged mice from lethal bacterial infections and increasing their response to vaccination. This work therefore illustrates the versatility of neutrophils and their reprogramming capacity. Generally, trained immunity opens new avenues to the formulation of adjuvant therapies to the vaccination, or as an adjuvant to myeloablative treatments.