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Long-term consequences of microbiota alterations for host physiology after acute respiratory infections in childhood

English title Long-term consequences of microbiota alterations for host physiology after acute respiratory infections in childhood
Applicant Schmolke Mirco
Number 182475
Funding scheme Project funding (Div. I-III)
Research institution Dépt Microbiologie et Médecine Moléculaire Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Experimental Microbiology
Start/End 01.10.2018 - 30.09.2022
Approved amount 775'394.00
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All Disciplines (3)

Discipline
Experimental Microbiology
Immunology, Immunopathology
Physiology : other topics

Keywords (5)

Respiratory infection; Metabolism; Virus; Microbiota; Asthma

Lay Summary (German)

Lead
Bakterielle Ökosysteme im menschlichen Körper sind wichtig für viele physiologische ProzesseVirusinfektionenen können diese Ökosysteme zerstören.Viruserkrankungen in der Kindheit prägen unsere bakterielle Flora für lange Zeit.
Lay summary

Im menschliche Körper koexistieren 10 Billionen Zellen mit etwa genauso vielen Bakterien. Diese natürliche Flora hat Teil and einer Vielzahl von physiologischen Prozessen und die Stabilität dieses bakteriellen Ökosystems ist entscheidend für die menschliche Gesundheit. Wir verstehen heute sehr wenig vom Einfluss viraler Infektionen auf die Zusammensetzung und Stabilität der bakteriellen Flora und noch weniger ist bekannt über die Konsequenzen von virus-verursachten Veränderungen der Flora für den Körper. In erwachsenen Modellsystemen konnten wir zeigen, das Virusinfektionen sowohl die lokale Flora (im Fall von Influenza die Lunge) als auch entfernte bakterielle Ökosysteme wie den Darm verändern können. Die so betroffenen Individuen waren empfänglicher für die Besiedlung mit bakteriellen Krankheitserregern, eine sehr häufige Komplikation von Virus Infektionen.

Im hier vorgestellten Projekt untersuchen wir die Langzeiteffekte von Viruserkrankungen in der Kindheit auf Stoffwechselerkrankungen und Allergien. Wir testen in diesem Zusammenhang die Hypothese, ob Viruserkrankungen im Kindesalter das Allergierisiko in Erwachsenen beeinflussen und eventuell zu Stoffwechselerkrankungen beitragen. Wir glauben, dass unser Projekt dazu beitragen wird, dass permanente Veränderungen der bakteriellen Flora korrigiert werden können.

Direct link to Lay Summary Last update: 01.10.2018

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Associated projects

Number Title Start Funding scheme
155949 Interaction of Influenza A virus with pathogenic and commensal bacteria 01.10.2014 Project funding (Div. I-III)

Abstract

Bacteria constitute up to 90% of cells in the human body (1). Bacterial microbiota just recently began to unravel its contribution to a wide spectrum of physiological host functions. Indeed commensal microbiota is thought to provide essential amino acids to the host, break down nutritional components (2), educate the immune system (3) and even influence behavior (4). Importantly, commensal bacteria occupy ecological niches, which could otherwise be colonized by pathogenic bacteria (5). Misbalance of microbial composition (dysbiosis) consequently affects many physiological processes in the host and is well documented in chronic disease state (6, 7). We demonstrated recently that acute diseases (e.g. influenza A virus infection) also result in higher susceptibility to bacterial super infection in adult mice in lung and intestine as a consequence of microbiota changes ((8) and unpublished finding). These changes were transient and microbiota composition returned to baseline, coinciding with virus clearance. This indicates that the microbiota of adult mice are a self-stabilizing system and minor influences do not permanently impact its long-term status. In contrast, infant human and mice have a less robust and less complex microbiota (9, 10). Since early childhood is also a phase in human development coinciding with numerous acute respiratory infections, we were curious, whether these infections could permanently change microbiota composition, potentially resulting in long-term pathophysiological effects. In preliminary mouse experiments we established that acute infection of neonatal mice with influenza A virus (IAV) indeed causes long lasting effects on microbiota composition. We are now aiming to understand the consequences of this microbiota "imprinting" by focusing on physiological processes that have been tightly linked to microbiota changes in animal models and human patients. We propose that long-term and potentially permanent changes of local (lung) and systemic (intestinal) microbiota caused by acute childhood respiratory infections could 1) affect metabolic processing of nutrients and 2) impact sensitivity to allergens or inflammatory stimuli in adulthood. Both processes are well described to correlate with microbiota changes in human patients (11). To demonstrate causal relationship between infection driven microbiota changes and proposed physiological readouts we will use mouse models. Coming from the basically sterile environment of the uterus, newborn mammals are abruptly exposed to a broad spectrum of inflammatory stimuli upon birth, mainly provided by colonizing commensals. They go through a phase of low responsiveness towards these stimuli, potentially to avoid detrimental immune pathology (12). In a preliminary infection studies in 7 days (D7) old mice (developmentally corresponding to newborn humans), we were surprised to observe no virus-induced pathology with viral doses lethal in adult animals (see rebuttal letter). We believe this could be due to a tolerance mechanism towards inflammatory stimuli, which has not yet been reported, potentially involving inflammatory monocytes. Interestingly, we can show that human cord blood monocytes show reduced inflammatory responses to IAV infection when compared to infected adult monocytes of human patients.
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