Which influence do intestinal bacteria have on the early development of the immune system and thus on susceptibility to infection?

What is this research project about?

Click to enlarge!

What is this research project about?

Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. The most important threats are infections. About a quarter of all infants born < 32 weeks of gestation develop a serious infection during infancy. Our knowledge is fragmented regarding how immune programming at preterm birth differs from that of term infants and adults. There is increasing evidence that the developing gut microbiome is both an important source
of postnatal microbial challenges and a critical site of postnatal maturation of the immune system. In humans detailed information is not yet available on how age-related programming and microbiota-dependent imprinting influence the individual’s immune status and life-long susceptibility towards infectious diseases.

What’s the current status?

Currently, we cannot predict what baby is at heightened risk of infections. This diagnostic dilemma frequently leads to a preemptive exposure of preterm newborn infants to antibiotics. We neither know what immunomodulatory strategy could aid in immune maturation and prevent severe infections. Epidemiologic and animal studies suggest that reciprocal host-microbiota interactions particularly at the neonatal phase are crucial for the postnatal maturation of the immune system and development of life-long immune homeostasis. However, the host factors and the specific combination of commensal bacteria that are required for promoting host resistance and immune-mediated protection remain largely elusive.

What are the project goals?

An urgent goal is to define clinically applicable markers of the microbiota and the host’s immune profile that predict the risk of infectious diseases in preterm infants to avoid needless preventive antibiotic treatment. This entails the identification of alternative preventive immunomodulatory measures. Therefore, we seek in humans for a better understanding of the dependencies between the baby’s immune phenotype and the coevolution of the gut microbiome to be able to exploit the impact of gut microbiota on the development of human immunity in a preventive and sustainable manner.

How do we get there?

In the recent past, RG Viemann and RG Hansen contributed to the paradigm shift that a specific inflammatory programming of systemic innate immunity at birth does not reflect infection but actually is a protective S100-alarmin-mediated state (Austermann et al., 2014; Heinemann et al., 2017; Ulas et al., 2017; Pirr et al., 2017; Bickes et al., 2019). Therefore, traditionally used biomarkers and risk criteria need to be scrutinized when evaluating preterm infants. Moreover, RG Viemann and others showed in preterm babies that gut dysbiosis precedes late-onset sepsis and necrotizing enterocolitis (Graspeuntner et al., 2018). RG Hühn demonstrated that the neonatal phase is critical for the stable imprinting of tolerogenic properties in mesenteric lymph node stromal cells by microbiota (Pezoldt et al. 2018). RG Strowig focused on the composition of microbiota and revealed that specific microbial communities can initiate inflammation and modulate the host’s ability to produce anti-bacterial effector cytokines (Thiemann et al., 2017; Roy et al., 2017). Within RESIST we combine our expertise and jointly continue the work on how the newly developing microbiota in preterm infants contributes to the age-dependent programming of innate and adaptive immunity and related susceptibility towards sepsis and respiratory infections. For this purpose we use amongst others data from the “Priming Immunity at the beginning of Life” (PRIMAL) cohort.

Large amounts of S100 alarmines are produced in the intestine of the healthy newborn. These prevent excessive inflammatory reactions when the newborn adapts to the new environment and promote the development of a healthy intestinal microbiome. (Click to enlarge!)

Projectleaders

Project title: Impact of microbiota on the development of the immune system in preterm neonates and their susceptibility towards respiratory and septic diseases

Prof. Dr. Dorothee Viemann

Projekte: B1, B3

CV & Contact

Prof. Dr. Till Strowig

Projekte: B1, B2, RESIST-Kohorte

CV & Contact

Prof. Dr. Jochen Hühn

Projekte: A3, B1, RESIST-Kohorte

CV & Contact

Prof. Dr. Gesine Hansen

Projekte: A1, B1

CV & Contact

Publications from the year 2021:

The microbiota is dispensable for the early stages of peripheral regulatory T cell induction within mesenteric lymph nodes. Wiechers C, Zou M, Galvez E, Beckstette M, Ebel M, Strowig T, Huehn J, Pezoldt J. Cell Mol Immunol. 2021 Mar 24. doi: 10.1038/s41423-021-00647-2. Online ahead of print. PMID: 33762684

Lymph node stromal cell subsets-Emerging specialists for tailored tissue-specific immune responses. Zou M, Wiechers C, Huehn J. Int J Med Microbiol. 2021 Apr;311(3):151492. doi: 10.1016/j.ijmm.2021.151492. Epub 2021 Feb 25. PMID: 33676241

Publications from the year 2020:

Evaluation of CD8 T cell killing models with computer simulations of 2-photon imaging experiments. Rastogi A, Robert PA, Halle S, Meyer-Hermann M.PLoS Comput Biol. 2020 Dec 28;16(12):e1008428. doi: 10.1371/journal.pcbi.1008428. Epub ahead of print. PMID: 33370254.

Influenza A viruses limit NLRP3-NEK7-complex formation and pyroptosis in human macrophages. Boal-Carvalho I, Mazel-Sanchez B, Silva F, Garnier L, Yildiz S, Bonifacio JP, Niu C, Williams N, Francois P, Schwerk N, Schöning J, Carlens J, Viemann D, Hugues S, Schmolke M. EMBO Rep. 2020 Nov 12;21(12):e50421. doi: 10.15252/embr.202050421. Epub ahead of print. PMID: 33180976; PMCID: PMC7726813.

Host Factors of Favorable Intestinal Microbial Colonization. Pirr S, Viemann D. Front Immunol. 2020 Oct 7;11:584288. doi: 10.3389/fimmu.2020.584288. PMID: 33117398; PMCID: PMC7576995.

S100A8 and S100A9 Are Important for Postnatal Development of Gut Microbiota and Immune System in Mice and Infants. Willers M, Ulas T, Völlger L, Vogl T, Heinemann AS, Pirr S, Pagel J, Fehlhaber B, Halle O, Schöning J, Schreek S, Löber U, Essex M, Hombach P, Graspeuntner S, Basic M, Bleich A, Cloppenborg-Schmidt K, Künzel S, Jonigk D, Rupp J, Hansen G, Förster R, Baines JF, Härtel C, Schultze JL, Forslund SK, Roth J, Viemann D. Gastroenterology. 2020 Dec;159(6):2130-2145.e5. doi: 10.1053/j.gastro.2020.08.019. Epub 2020 Aug 15. PMID: 32805279.

Acute neonatal Listeria monocytogenes infection causes long-term, organ-specific changes in immune cell subset composition. Zou M, Yang J, Wiechers C, Huehn J. Eur J Microbiol Immunol (Bp). 2020 Jun 19;10(2):98–106. doi: 10.1556/1886.2020.00007. Epub ahead of print. PMID: 32644940; PMCID: PMC7391377.

S100-Alarmins Are Essential Pilots of Postnatal Innate Immune Adaptation. Viemann D. Front Immunol. 2020 Apr 30;11:688. doi: 10.3389/fimmu.2020.00688. PMID: 32425933; PMCID: PMC7203218.

IL-17 regulates DC migration to the peribronchial LNs and allergen presentation in experimental allergic asthma. Jirmo AC, Busse M, Happle C, Skuljec J, Dalüge K, Habener A, Grychtol R, DeLuca DS, Breiholz OD, Prinz I, Hansen G.  Eur J Immunol. 2020 Jul;50(7):1019-1033. doi: 10.1002/eji.201948409. Epub 2020 Mar 29. PMID: 32142593.

Publications from the year 2019:

Constitutive TNF-α signaling in neonates is essential for the development of tissue-resident leukocyte profiles at barrier sites. Bickes MS, Pirr S, Heinemann AS, Fehlhaber B, Halle S, Völlger L, Willers M, Richter M, Böhne C, Albrecht M, Langer M, Pfeifer S, Jonigk D, Vieten G, Ure B, von Kaisenberg C, Förster R, von Köckritz-Blickwede M, Hansen G, Viemann D. FASEB J. 2019 Oct;33(10):10633-10647. doi: 10.1096/fj.201900796R. Epub 2019 Jun 29.

The role of Ames dwarfism and calorie restriction on gut microbiotaWiesenborn DS, Gálvez EJC, Spinel L, Victoria B, Allen B, Schneider A, Gesing A, Al-Regaiey KA, Strowig T, Schäfer KH, Masternak MM. J Gerontol A Biol Sci Med Sci. 2019 Oct 30. pii: glz236. doi: 10.1093/gerona/glz236.

Microbiome Dependent Regulation of Tregs and Th17 Cells in Mucosa. Pandiyan P, Bhaskaran N, Zou M, Schneider E, Jayaraman S, Huehn J.
Front Immunol. 2019 Mar 8;10:426. doi: 10.3389/fimmu.2019.00426. eCollection 2019. Review.

Project B1
Publications