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Host-pathogen interactions in group B streptococcal sepsis

English title Host-pathogen interactions in group B streptococcal sepsis
Applicant Giannoni Eric
Number 197618
Funding scheme Project funding
Research institution Service de Néonatologie Département femme-mère-enfant Centre Hospitalier Universitaire Vaudois
Institution of higher education University of Lausanne - LA
Main discipline Paediatrics
Start/End 01.11.2020 - 31.10.2024
Approved amount 705'407.00
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All Disciplines (2)

Discipline
Paediatrics
Immunology, Immunopathology

Keywords (10)

sepsis; infants; bacteria; innate immunity; Streptococcus agalactiae; infection; macrophages; virulence; Group B Streptococcus; newborns

Lay Summary (French)

Lead
Les infections sont une des causes principales de décès au début de la vie et les survivants sont à risque de handicap permanent. Le Streptocoque du groupe B (SGB) est l’une des bactéries les plus fréquemment impliquées dans les infections invasives du nouveau-né et de l’enfant de moins d’un an, alors que cette même bactérie cause très rarement des infections chez le sujet plus âgé. Pour trouver de nouvelles pistes en vue d’améliorer la prévention et le traitement des infections néonatales, il est essentiel de mieux comprendre comment l’interaction entre le nouveau-né et les microorganismes peut résulter en une infection potentiellement fatale.
Lay summary

Notre recherche combinant une approche expérimentale à une analyse de données cliniques et échantillons biologiques de nouveau-nés atteints de sepsis à SGB permettra de définir la relation entre les souches de SGB, l’expression de facteurs de virulence bactériens, la réponse immunitaire du nouveau-né et la sévérité de l’infection.

Le sepsis est une infection menaçant la vie, caractérisée par une invasion de l’organisme par la bactérie et une réponse de l’hôte dysrégulée induisant un fonctionnement anormal des organes vitaux. Notre hypothèse est que le SGB possède des facteurs de virulence spécifiques permettant à cette bactérie d’échapper au contrôle du système immunitaire du nouveau-né et d’induire une réponse immunitaire dysrégulée.  Nous allons tester cette hypothèse en utilisant des modèles d’infection in vitro. Des cellules du système immunitaire de nouveau-nés, enfants et adultes seront cultivées au laboratoire et exposées à des souches de SGB. La réponse immunitaire sera quantifiée en mesurant le nombre de bactéries phagocytées et tuées et en déterminant la réponse transcriptionnelle. Le rôle de facteurs de virulence spécifiques sera investigué en utilisant des souches de SGB modifiées génétiquement. Nous allons également analyser, par génomique, les caractéristiques de souches de SGB impliquées dans le sepsis néonatal, afin d’explorer la relation entre l’expression de facteurs de virulence et la sévérité de la maladie.

Direct link to Lay Summary Last update: 27.10.2020

Responsible applicant and co-applicants

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Associated projects

Number Title Start Funding scheme
146838 Impaired neonatal innate immune responses to bacteria involved in early-onset neonatal sepsis: the role of monocytes 01.06.2013 Project funding

Abstract

Every year, 2.5 million children aged less than five years, including over half a million newborns die from sepsis. Despite improvements in perinatal care, Group B Streptococcus (GBS) remains a leading pathogen of sepsis in newborns and infants. GBS is among the first bacteria to get into contact with infants born to colonized mothers, most often interacting with its host in a transient or harmless manner. However, under still undetermined circumstances, GBS causes invasive disease that presents with a spectrum of severity, ranging from uncomplicated bacteremia to life-threatening dysfunction of vital organs. Mortality rate is 8%, and long-term disability occurs in 20-30% of survivors. GBS rarely causes infection beyond the neonatal period, and few cases have been associated with primary immune deficiencies. Therefore, it is believed that the immune status of neonates plays a key role in the pathogenesis of GBS disease. Yet, our limited knowledge of the host-pathogen interactions underlying the shift from a colonizing to an invasive microorganism, and progression to life-threatening infection strongly hampers conception and development of innovative strategies targeting GBS disease. Our preliminary results indicate that newborn innate immune cells have an exaggerated inflammatory response to GBS, and a reduced capacity to clear the bacteria. Based on this observation, our working hypothesis is that GBS isolates causing neonatal sepsis have specific genomic signatures associated with the expression of virulence factors that target the developing immune system. These virulence factors may trigger dysregulated host responses, and evasion from clearance mechanisms in newborns, contributing to the pathogenesis of sepsis and sepsis-related adverse outcomes. To test this hypothesis, we will use an approach combining in vitro functional studies of innate immune responses to GBS with analyses of clinical data, biological samples, and GBS isolates from septic newborns and infants included in a prospective cohort, the Swiss Pediatric Sepsis Study (SPSS).The first objective is to determine whether specific virulence factors and genes regulating expression of virulence factors are associated with distinct age-dependent immune responses. Monocyte-derived macrophages and whole blood from newborns, infants and adults will be exposed to genetically modified GBS strains deficient for virulence factors and regulators, and isolates from blood cultures of newborns with GBS sepsis to quantify cytokine response, bacterial killing, and immune cell viability. The second objective is to identify key molecules, pathways and networks activated in whole blood and macrophages following exposure to GBS, and define shared and distinct programs between newborns, infants and adults. Functional studies will be designed to elucidate the mechanisms underlying age-dependent differences. The third objective is to define, using bacterial genomics, the capsular serotype, sequence type, virulence factors and virulence regulatory systems of GBS strains involved in neonatal and infant sepsis, and to explore associations with disease severity. Overall, the unique clinical dataset and collection of pathogens and biological samples will allow a comprehensive investigation of GBS interactions with its hosts, integrating findings from experimental studies into a highly relevant clinical perspective. We expect to improve our comprehension of the virulence mechanisms used by GBS to subvert neonatal immune responses. This is an essential step towards the development of novel preventive and therapeutic strategies for GBS disease in particular, and possibly for other inflammatory and infectious diseases that occur in early life.
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