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Development of Innate and Adaptive Immune Responses to Pneumonia in the Newborn Lung Is Uniquely Programmed by Gut Microbiota /

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Development of Innate and Adaptive Immune Responses to Pneumonia in the Newborn Lung Is Uniquely Programmed by Gut Microbiota // Joseph Jacob Stevens.
Author:	Stevens, Joseph Jacob,
Description:	1 electronic resource (314 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
基督教聖經之智慧書導讀 :	Newborns and young children are particularly susceptible to infection compared to other age groups. Lower respiratory tract infections, such as pneumonia, comprise the majority of cases and are the leading cause of mortality for children under 5 years old. This vulnerability was largely attributed to immature immune responses in newborns. Recent studies support a newer paradigm in which neonatal immunity is uniquely situated for balancing responses to pathogens with tolerance to developmental processes and environmental exposures. After birth, there is an immediate and immense environmental exposure to the world of microbes, some of which go on to colonize the intestinal tract and live commensally with the newborn. Prior work in the lab showed that exposure to antibiotics early in life, and the resulting disruption of the microbiota, causes impaired pulmonary immune responses. It is unknown though whether this connection between development of the commensal microbiota and pulmonary immunity is translationally relevant to human newborns and their susceptibility to lower respiratory tract infections. It is also unclear whether the commensal microbiota is important more broadly for control of both innate and adaptive pulmonary immune responses early in life, and if so, how. Chapter 2 of this dissertation uses a Rhesus macaque model to show that exposure to a clinically relevant cocktail of antibiotics disrupts the developing microbiota early in life, which then compromises pulmonary neutrophil responses to bacterial pneumonia. Newborn macaques exposed to antibiotics have worsened outcomes to pneumonia, which associated with the emergence of an aged, hyperinflammatory subset of neutrophils. Importantly, fecal transfer from control to antibiotic-exposed newborns restored normal pulmonary neutrophil responses, showing that the commensal microbiota is sufficient to program pulmonary immunity to pneumonia early in life. Chapter 3 demonstrates a novel role for the developing commensal microbiota in establishing adaptive pulmonary CD8+ T cell responses to viral pneumonia through the gene NFIL3. Disruption of the microbiota in newborn mice caused worsened outcomes to infection with Influenza A, which associated with a significant reduction in number and intrinsic function of pulmonary influenzaspecific CD8+ T cells. Using single-cell RNA sequencing (scRNAseq), we show that NFIL3 is predicted to control the behavior of pulmonary CD8+ T cells early in life. Using a genetic knockout model (dLCKΔNFIL3), we show the necessity of NFIL3 in establishing protective T cell responses to influenza early in life.Overall, this dissertation details important new findings about the commensal microbiota's role in the balance between protective and pathogenic immune responses in newborns. The models and techniques in this work attempt to maximize the relevance of these insights to humans by using both a non-human primate model and samples from a human newborn cohort. In the final chapter, the possibility of new therapeutics is discussed in light of these studies, including preliminary data for a promising, metabolite-based therapy aimed at restoring protective pulmonary CD8+ T cell responses. The work here embodies advances in the fields of pulmonary immunology and the microbiome, which will hopefully lead to better outcomes for respiratory infections in newborns and young children.
Contained By:	Dissertations Abstracts International86-12B.
Subject:	Immunology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=32156351
ISBN:	9798280770119

Development of Innate and Adaptive Immune Responses to Pneumonia in the Newborn Lung Is Uniquely Programmed by Gut Microbiota /
Stevens, Joseph Jacob,

Development of Innate and Adaptive Immune Responses to Pneumonia in the Newborn Lung Is Uniquely Programmed by Gut Microbiota /Joseph Jacob Stevens. - 1 electronic resource (314 pages)

Source: Dissertations Abstracts International, Volume: 86-12, Section: B.

Newborns and young children are particularly susceptible to infection compared to other age groups. Lower respiratory tract infections, such as pneumonia, comprise the majority of cases and are the leading cause of mortality for children under 5 years old. This vulnerability was largely attributed to immature immune responses in newborns. Recent studies support a newer paradigm in which neonatal immunity is uniquely situated for balancing responses to pathogens with tolerance to developmental processes and environmental exposures. After birth, there is an immediate and immense environmental exposure to the world of microbes, some of which go on to colonize the intestinal tract and live commensally with the newborn. Prior work in the lab showed that exposure to antibiotics early in life, and the resulting disruption of the microbiota, causes impaired pulmonary immune responses. It is unknown though whether this connection between development of the commensal microbiota and pulmonary immunity is translationally relevant to human newborns and their susceptibility to lower respiratory tract infections. It is also unclear whether the commensal microbiota is important more broadly for control of both innate and adaptive pulmonary immune responses early in life, and if so, how. Chapter 2 of this dissertation uses a Rhesus macaque model to show that exposure to a clinically relevant cocktail of antibiotics disrupts the developing microbiota early in life, which then compromises pulmonary neutrophil responses to bacterial pneumonia. Newborn macaques exposed to antibiotics have worsened outcomes to pneumonia, which associated with the emergence of an aged, hyperinflammatory subset of neutrophils. Importantly, fecal transfer from control to antibiotic-exposed newborns restored normal pulmonary neutrophil responses, showing that the commensal microbiota is sufficient to program pulmonary immunity to pneumonia early in life. Chapter 3 demonstrates a novel role for the developing commensal microbiota in establishing adaptive pulmonary CD8+ T cell responses to viral pneumonia through the gene NFIL3. Disruption of the microbiota in newborn mice caused worsened outcomes to infection with Influenza A, which associated with a significant reduction in number and intrinsic function of pulmonary influenzaspecific CD8+ T cells. Using single-cell RNA sequencing (scRNAseq), we show that NFIL3 is predicted to control the behavior of pulmonary CD8+ T cells early in life. Using a genetic knockout model (dLCKΔNFIL3), we show the necessity of NFIL3 in establishing protective T cell responses to influenza early in life.Overall, this dissertation details important new findings about the commensal microbiota's role in the balance between protective and pathogenic immune responses in newborns. The models and techniques in this work attempt to maximize the relevance of these insights to humans by using both a non-human primate model and samples from a human newborn cohort. In the final chapter, the possibility of new therapeutics is discussed in light of these studies, including preliminary data for a promising, metabolite-based therapy aimed at restoring protective pulmonary CD8+ T cell responses. The work here embodies advances in the fields of pulmonary immunology and the microbiome, which will hopefully lead to better outcomes for respiratory infections in newborns and young children.

English

ISBN: 9798280770119Subjects--Topical Terms:

187040
Immunology.
Subjects--Index Terms:

Immunology

Development of Innate and Adaptive Immune Responses to Pneumonia in the Newborn Lung Is Uniquely Programmed by Gut Microbiota /
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520 $a Newborns and young children are particularly susceptible to infection compared to other age groups. Lower respiratory tract infections, such as pneumonia, comprise the majority of cases and are the leading cause of mortality for children under 5 years old. This vulnerability was largely attributed to immature immune responses in newborns. Recent studies support a newer paradigm in which neonatal immunity is uniquely situated for balancing responses to pathogens with tolerance to developmental processes and environmental exposures. After birth, there is an immediate and immense environmental exposure to the world of microbes, some of which go on to colonize the intestinal tract and live commensally with the newborn. Prior work in the lab showed that exposure to antibiotics early in life, and the resulting disruption of the microbiota, causes impaired pulmonary immune responses. It is unknown though whether this connection between development of the commensal microbiota and pulmonary immunity is translationally relevant to human newborns and their susceptibility to lower respiratory tract infections. It is also unclear whether the commensal microbiota is important more broadly for control of both innate and adaptive pulmonary immune responses early in life, and if so, how. Chapter 2 of this dissertation uses a Rhesus macaque model to show that exposure to a clinically relevant cocktail of antibiotics disrupts the developing microbiota early in life, which then compromises pulmonary neutrophil responses to bacterial pneumonia. Newborn macaques exposed to antibiotics have worsened outcomes to pneumonia, which associated with the emergence of an aged, hyperinflammatory subset of neutrophils. Importantly, fecal transfer from control to antibiotic-exposed newborns restored normal pulmonary neutrophil responses, showing that the commensal microbiota is sufficient to program pulmonary immunity to pneumonia early in life. Chapter 3 demonstrates a novel role for the developing commensal microbiota in establishing adaptive pulmonary CD8+ T cell responses to viral pneumonia through the gene NFIL3. Disruption of the microbiota in newborn mice caused worsened outcomes to infection with Influenza A, which associated with a significant reduction in number and intrinsic function of pulmonary influenzaspecific CD8+ T cells. Using single-cell RNA sequencing (scRNAseq), we show that NFIL3 is predicted to control the behavior of pulmonary CD8+ T cells early in life. Using a genetic knockout model (dLCKΔNFIL3), we show the necessity of NFIL3 in establishing protective T cell responses to influenza early in life.Overall, this dissertation details important new findings about the commensal microbiota's role in the balance between protective and pathogenic immune responses in newborns. The models and techniques in this work attempt to maximize the relevance of these insights to humans by using both a non-human primate model and samples from a human newborn cohort. In the final chapter, the possibility of new therapeutics is discussed in light of these studies, including preliminary data for a promising, metabolite-based therapy aimed at restoring protective pulmonary CD8+ T cell responses. The work here embodies advances in the fields of pulmonary immunology and the microbiome, which will hopefully lead to better outcomes for respiratory infections in newborns and young children.
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653 $a Neonatology
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