Investigating reprogramming of the immune system by parasitic helminths and environmental antigens

National Institute Of Allergy And Infectious Diseases

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Abstract

An individual’s environment, infection history and genetic factors play a huge role in determining their outcome during exposure to a subsequent inflammatory stimulus. While most research has thus far focused on studying these factors individually, interactions between host genetic factors and environment are now been recognized and quantified as a major contributor to determining an individuals’ response following exposure to an inflammatory stimulus including during parasitic helminth infections. Our program is focused on assessing these interactions in various inflammatory contexts together with understanding the role of innate cells, tissues microenvironment and its associated mediators in driving these differences. Over the past fiscal year, we investigated how genetic and environmental factors interact to drive immune variation, within the airway mucosa using two different inbred strain of mice - C57BL/6 and B10.BR strain of mice and the rewilding model, a method of exposing mice to the outdoor environment. Our preliminary results from bulk RNA sequencing and flow-cytometry analysis from lung tissue of lab (SPF) and rewilded C57BL/6 and B10.BR strains of mice demonstrate that both genetic and environmental factors contribute individually to immune variations in the lungs and that the extent of an environment driven variation in the immune changes in the lungs is influenced by the mouse strain. Furthermore, we identified key tissue related factors that are induced following these environmental change as well as factors driving the genetic differences between the different two inbred strain of mice. Similarly, in the bone marrow of these mice, we observed that changes induced following an environmental change is dependent on the strain of mice examined. Together, this suggest that regardless of the tissue site examined, the contribution of an environmental change on the immune system is dependent on the genetics of the individual. Furthermore, we have used a helminth parasite model, Nippostrongylus brasiliensis, to investigate how genetic factors can interact with previous Nb exposure to shape immune responses following subsequent viral infection. Similarly, we found that Nb reprogramming prior to viral infection protected all three strains of mice from death and improved weight gain recovery as previously reported; however, we also found genotype specific differences that is dependent on the pulmonary environment that dictate the outcome following a viral challenge. We are now investigating the immune mechanism that might be important in driving these differences. In conclusion, our results using both the rewilding model and the helminth model demonstrate that an individual genetic factor is important in determining the state of the tissue micro-environment following an infection as well as outcomes to subsequent injury or insults.