Thursday, April 25, 2024
4/25/2024
Summary Pneumonia is a leading cause of death in neonates worldwide. Group B Streptococcus (GBS) is a common pathogen in neonates but rarely leads to disease in healthy adults. Neonates are first exposed to GBS around delivery, as GBS frequently colonizes the birth canal. While efforts have focused on reducing maternal colonization and neonatal transmission, little is known about why the neonatal lung is particularly susceptible to GBS infection. We developed a novel mouse GBS pneumonia model to better investigate these mechanisms. Adult mice clear GBS within 24 h, quickly resolve the initial lung inflammation, and universally survive GBS infection. However, neonatal mice fail to efficiently kill GBS, develop persistent lung inflammation and injury, and can die from GBS infection. While macrophages populate the fetal lung early in development, alveolar macrophage differentiation occurs only several days after birth. Therefore, neonates are exposed to inhaled and aspirated bacteria including GBS without having mature alveolar macrophages in their lungs. Our preliminary studies suggest immature neonatal lung macrophages fail to mount a normal immune response against GBS and kill phagocytosed bacteria. GBS avoids detection in the neonatal lung by expressing a capsule coated with sialic acid, mimicking “self” antigens in the host. Neonatal lung macrophages express very low levels of Siglec- 1, which is required for recognition of sialic acid in the GBS capsule in adults. However neonatal lung macrophages do express Siglec-E, which suppresses inflammatory signaling upon sialic acid binding. We hypothesize this combination prevents GBS killing and inhibits the immune response. Neonatal lung macrophages can phagocytose and kill mutant GBS strains lacking sialic acid in their capsule. These data suggest that developmental immaturity of sialic acid-Siglec interactions may render the neonatal lung uniquely susceptible to GBS. This proposal will provide an outstanding opportunity to use novel, state of the art approaches to further investigate the molecular mechanisms regulating neonatal immunity against GBS. Experiments will first use knockout mice lacking Siglec-1 or Siglec-E to determine the role of these sialic acid receptors in fighting GBS infection. Adoptive transfer of adult wild type or Siglec mutant macrophages into neonatal lungs will determine the relative roles of macrophages versus the existing lung environment. The proposal will next investigate GBS virulence factors in neonatal pneumonia. Mutant GBS strains lacking capsule components, sialic acid modifications, and additional virulence factors will be tested in their ability to cause pneumonia and lung injury in both wild type and Siglec mutant mice. Collectively the aims in this proposal will identify the unique molecular mechanisms that make newborns particularly susceptible to GBS pneumonia. The results will lead to development of new strategies for preventing and treating disease.
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