Developmental origin and plasticity of sex-specific immunity against pathogens
Foetal immune development is modulated by challenges of the modern environment, such as high maternal stress perception. In turn, prenatal stress increases the risk for infections later in life of the offspring. Surprisingly, the offspring’s sex has been overlooked in most of these studies, despite the well-known sex disparities in infection risks. We aim to close this gap in knowledge. We hypothesize that prenatal stress exposure causes variation of the sex-specific disease tolerance to pathogens in offspring. differentially affects immunity to pathogens throughout postnatal life of male and female offspring. We also hypothesize that such variations of sex-specific immunity to pathogens segues into evolutionary trade-offs. We will use influenza A virus-induced infection in a mouse model, which we established during the first funding period. The translational relevance of these preclinical insights will be tested using data and bio-samples from children born into a prospectively designed pregnancy study. In synergy with other projects of the RU 5068, our focus lies on dissecting distinct innate and adaptive immune pathways and their modulation by sex and steroid hormones. Since genes encoded by the X chromosome may be affected by prenatal stress, we plan to use expertise within the RU 5068 to investigate this aspect. Collectively, this project will provide valuable insights into the mechanisms underlying prenatally imprinted, sex-specific susceptibilities to infections throughout life. Our study holds the potential to specify health guidelines and vaccination regimen for specific sex and age groups which have a greater susceptibility to infections.
PROJECT-RELATED PUBLICATIONS
Zazara DE, Giannou O, Schepanski S, Pagenkemper M, Giannou AD, Pincus M, Belios I, Bonn S, Muntau AC, Hecher K, Diemert A#, Arck PC#. (2024)
Fetal lung growth predicts the risk for early-life respiratory infections and childhood asthma.
World J Pediatr I 20:481-495
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Yüzen D, Urbschat C, Schepanski S, Thiele K, Arck PC, Mittrücker H-W. (2023)
Pregnancy-induced transfer of pathogen-specific T cells from mother to fetus in mice.
EMBO Rep I 24:e56829
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Yüzen D, Graf I, Tallarek A-C, Hollwitz B, Wiessner C, Schleussner E, Stammer D, Padula A, Hecher K, Arck PC, Diemert A. (2023)
Increased late preterm birth risk and altered uterine blood flow upon exposure to heat stress.
EBioMedicine I 93:104651
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Stelzer IA, Urbschat C, Schepanski S, Thiele K, Triviai I, Wieczorek A, Alawi M, Ohnezeit D, Kottlau J, Huang J, Fischer N, Mittrücker HW, Solano E, Fehse B, Diemert A, Stahl F, Arck PC. (2021)
Vertically transferred maternal immune cells promote neonatal immunity against early life infections.
Nat Commun I 12:4706
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Zazara DE, Wegmann M, Giannou AD, Hierweger AM, Alawi M, Thiele K, Huber S, Pincus M, Muntau AC, Solano ME, Arck PC. (2020)
A prenatally disrupted airway epithelium orchestrates the fetal origin of asthma in mice.
J Allergy Clin Immunol I 145:1641-1654
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Wieczorek A*, Perani CV*, Nixon M, Constancia M, Sandovici I, Zazara DE, Leone G, Zhang MZ, Arck PC*, Solano ME*. (2019)
Sex-specific regulation of stress-induced fetal glucocorticoid surge by the mouse placenta.
Am J Physiol Endocrinol Metab I 317:E109-E120
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Zazara DE, Arck PC. (2019)
Developmental origin and sex-specific risk for infections and immune diseases later in life.
Semin Immunopathol I 41:137-151
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Zazara DE, Perani CV, Solano ME, Arck PC. (2018)
Prenatal stress challenge impairs fetal lung development and asthma severity sex-specifically in mice.
J Reprod Immunol I 125:100-105
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Diemert A, Goletzke J, Barkmann C, Jung R, Hecher K, Arck PC. (2017)
Maternal progesterone levels are modulated by maternal BMI and predict birth weight sex-specifically in human pregnancies.
J Reprod Immunol I 121:49-55
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Kinder JM, Stelzer IA, Arck PC, Way SS. (2017)
Immunological implications of pregnancy-induced microchimerism.
Nat Rev Immunol I 17:483-494
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Engels G, Hierweger AM, Hoffmann J, Thieme R, Thiele S, Bertram S, Dreier C, Resa-Infante P, Jacobsen H, Thiele K, Alawi M, Indenbirken D, Grundhoff A, Siebels S, Fischer N, Stojanovska V, Muzzio D, Jensen F, Karimi K, Mittrücker HW, Arck PC*, Gabriel G*. (2017)
Pregnancy-Related Immune Adaptation Promotes the Emergence of Highly Virulent H1N1 Influenza Virus Strains in Allogenically Pregnant Mice.
Cell Host Microbe I 21:321-333
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Solano ME, Kowal MK, O'Rourke GE, Horst AK, Modest K, Plösch T, Barikbin R, Remus CC, Berger RG, Jago C, Ho H, Sass G, Parker VJ, Lydon JP, DeMayo FJ, Hecher K, Karimi K, Arck PC. (2015)
Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation.
J Clin Invest I 125:1726-38
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Hartwig IR, Sly PD, Schmidt LA, van Lieshout RJ, Bienenstock J, Holt PG, Arck PC. (2014)
Prenatal adverse life events increase the risk for atopic diseases in children, which is enhanced in the absence of a maternal atopic predisposition.
J Allergy Clin Immunol I 134:160-9
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Arck PC, Hecher K. (2013)
Fetomaternal immune cross-talk and its consequences for maternal and offspring's health.
Nat Med I 19:548-56
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Hartwig IR, Pincus MK, Diemert A, Hecher K, Arck PC. (2013)
Sex-specific effect of first-trimester maternal progesterone on birthweight.
Hum Reprod I 28:77-86
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Pincus M, Keil T, Rücke M, Bruenahl C, Magdorf K, Klapp BF, Douglas AJ, Paus R, Wahn U, Arck P. (2010)
Fetal origin of atopic dermatitis.
J Allergy Clin Immunol I 125:273-5.e1-4
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* equal contribution
