Open Research Projects

Impact of the mode of delivery on lung homeostasis and health

Prinicipal Investigator

Scientific interest within the context of the graduate college:

The goal of my laboratory is to understand the regulation and control mechanisms of immune responses in the respiratory tract. We are continuously exposed to the environment by filtering liters of air each minute to provide needed oxygen in exchange to carbon dioxide to our body. A unique network of pulmonary cell populations ensures appropriate immune responses not only against pathogens or hazardous materials but to maintain lung function and health at steady state. However, the underlying mechanisms are poorly understood. Group 2 innate lymphoid cells (ILC2) are the major innate lymphoid immune cell population in the lungs, tissue resident and able to orchestrate innate but also adaptive immune responses. Thus, studying the regulatory processes of ILC2 effector function is key to understand immune concepts of pulmonary immunity and health.

Project description:

Immune homeostasis is shaped during the first period of life. Whereas normal, vaginal delivery exposes the neonate immediately to the maternal microbiota and thus microbial stimuli, C. section delivered neonates are exposed in a different manner. Importantly, there is an ongoing debate whether non vaginal delivery disturbs pulmonary homeostasis by environmental maladapation.1 Yet, the impact on resident pulmonary cell populations due to changes in mode of delivery are poorly understood. Group 2 innate lymphoid cells (ILC2) are present in the lungs at birth and immediate producers of signature cytokines directing immune and non-immune cells.2 Birth is characterized by ILC2 activating and inhibiting stimuli: the first breath of life triggers the release of ILC2 inducing cytokines.3 Moreover, at birth, the neonate enters an environment with abundant microorganisms. Importantly, microbial components induce interferon. We and others could show that ILC2 are controlled by interferon in mice and human.4-6 However, the impact of mode of delivery on ILC2 function is not known (0 Pubmed hits “ILC2, Caesarean section” April 11th, 2022). We hypothesize that ILC2 are “educated” at birth by the quantity and quality of ILC2 directing signals thereby establishing their bioactive profile and shaping pulmonary homeostasis. Using multi-colour flow cytometry, transgenic mouse models and microbiota- and RNAseq analysis, we will investigate the impact of mode on delivery on pulmonary ILC2 and the microbial composition early and late in life. Thereby we will gain insights into the mechanisms of ILC2 regulation and their contribution to the challenging physiological adaption at birth. Further, we hope to provide with our work an expansion of our knowledge of basic research on innate type 2 immune responses in order to better understand health-promoting pathways of pulmonary homeostasis and health.

Aim 1: Characterize ILC2 effector functions and their non-immune target cells upon birth. Pulmonary cells will be immune phenotyped focusing on cytokine expressing ILC2 and their target cells such as endothelial cells shortly after birth and late in life. Our analysis will be complemented by an unbiased RNAseq of ILC2 and non-immune cells early in life in regard to mode of delivery.

Aim 2: Define the pulmonary microbial composition early in life. The respiratory microbiome regulates pulmonary health7 and microbial components indirectly regulate ILC2 function. The microbial composition will be determined shortly after birth and analyzed by culture and qPCR in regard to mode of delivery.

Application details

References

  1. Lloyd CM, Marsland BJ. Lung Homeostasis: Influence of Age, Microbes, and the Immune System. Immunity. 2017; 46:549-561. doi: 10.1016/j.immuni.2017.04.005.
  2. Artis D, Spits H. The biology of innate lymphoid cells. Nature. 2015; 517:293-301. doi: 10.1038/nature14189.
  3. Saluzzo S, Gorki AD, Rana BMJ, […], Mesteri I, McKenzie AHJ, Knapp S. First-Breath-Induced Type 2 Pathways Shape the Lung Immune Environment. Cell Rep. 2017; 18:1893-1905. doi: 10.1016/j.celrep.2017.01.071.
  4. Molofsky AB, Van Gool F, Liang HR, […], Lee J, Bluestone JA, Locksley RM. Interleukin-33 and Interferon-gamma Counter-Regulate Group 2 Innate Lymphoid Cell Activation during Immune Perturbation. Immunity. 2015; 43:161-174. doi: 10.1016/j.immuni.2015.05.019.
  5. Duerr CU, McCarthy CDA, Mindt BC, […], King IL, Sarfati M, Fritz JH. Type I interferon restricts type 2 immunopathology through the regulation of group 2 innate lymphoid cells. Nat Immunol. 2016; 17:65-75. doi: 10.1038/ni.3308.
  6. Moro K, Kabata H, Tanabe M, […], Asano K, Betsuyaku T, Koyasu S. Interferon and IL-27 antagonize the function of group 2 innate lymphoid cells and type 2 innate immune responses. Nat Immunol. 2016; 17:76-86. doi: 10.1038/ni.3309.
  7. Dickson RP, Erb-Downward JR, Martinez FJ, Huffnagle GB. The Microbiome and the Respiratory Tract. Annu Rev Physiol. 2016; 78:481-504. doi: 10.1146/annurev-physiol-021115-105238.