Targeting innate immunity during neonatal period, with NOD2 based ligands, to fight Cryptosporidiosis

International audience

English. During the neonatal period, the immune system is still immature, giving at newborns susceptibility to infections such as Cryptosporidiosis. C. parvum is the causative agent for the zoonosis Cryptosporidiosis, This parasitic disease is due to an orally transmitted protozoan that develops in intestinal epithelial cells and causes a moderate-to-severe diarrhea in children under 2 years of age, responsible for 18% of the deaths in children under 5 years [1]. In addition to children, Cryptosporidiosis causes also acute diarrhea in very young ruminants and immune-compromised hosts. Today, there is no vaccine to prevent infection nor efficient treatment, and there is therefore an urgent need for the development of new methods to control this zoonosis directly involved in a One Health process. The immune system is traditionally divided into innate and adaptive arms. The innate response is the first line of defense in the host, and sets up very rapidly. In contrast, adaptive immune responses are slower to develop, but are antigen specific and lead to long-term immunological memory. However, it has recently been discovered that in some circumstances, innate immune cells can also display memory. This recent concept has been coined as “Trained immunity”. Following a first stimulation of innate immunity with, for example a ß-glucan or a NOD2 agonist, the innate immune response is increased and this leads to an increased innate immune response upon a subsequent viral, parasitic or bacterial infections and a non-specific control of infections [2]. For my PhD project, we hypothesize that modulation of the innate immune system during the neonatal period could (I) enhance the immune defense at young ages and favor the control of cryptosporidiosis and (II) that the innate stimulation during this peculiar period can “train” innate cells for a long-lasting response later in life. During my first year of PhD, we performed different assays to study the impact of in vivo stimulation of the innate immune system of neonatal mice with NOD2-based agonists to improve their immediate defense against C. parvum infection. Secondly, we also investigated whether these treatments administered during the neonatal window could induce trained immunity. This project combines fundamental and applied work, it will provide new fundamental knowledge in the innate immune system during neonatal period, and potentially NOD2 based treatments for use in the control of neonatal enteric disease. References:[1]. Striepen B. Parasitic infections: Time to tackle cryptosporidiosis. Nature. 2013;503(7475):189-91[2]. Netea MG, Joosten LA, Latz E, Mills KH, Natoli G, Stunnenberg HG, et al. Trained immunity: A program of innate immune memory in health and disease. Science. 2016;352(6284):aaf1098.