Oral Presentation 20th Lancefield International Symposium on Streptococci and Streptococcal Diseases 2017

Regulation of innate immunity to Streptococcus (#64)

Jacqueline M Kimmey 1 , Victor Nizet 1
  1. UCSD, La Jolla, CA, United States

Bacterial pneumonia remains a leading cause of disease and mortality worldwide, and the most vulnerable patients are those with the weakest immune systems, such as neonates or the elderly. Approximately 25% of adults are colonized with group B Streptococcus (GBS), but typically do not experience symptoms. In contrast, GBS remains the leading cause of death in neonates, causing pneumonia, sepsis, and meningitis. Similarly, S. pneumoniae is the leading cause of bacterial pneumonia, and is disproportionately lethal in the elderly. To prevent disease, innate immunity in the lung must effectively limit bacterial replication and spread, while minimizing damage to the host. Disease outcomes are almost uniformly dictated by differential immune responses, however the mechanisms underlying these differences are not well understood.

Hypoxia Inducible Factor-1α (HIF-1α), a host transcription factor, was discovered by our laboratory to play a critical role in immune cell function. Genetic modifications or drugs that increase HIF-1α levels increase the antibacterial capacity of PMNs, macrophages and epithelial cells, and mice lacking HIF-1α are more susceptible to many infections. Here, we investigate the role of HIF-1α in resistance to Streptococcus in mice and compare HIF-1α function in neonatal and adult human neutrophils. In addition, we describe a role for murine cathelicidin (CRAMP), a HIF-1α regulated gene, in mediating progression of Streptococcal pneumonia. These data demonstrate how failure of innate immunity allows for progression to more severe forms of disease such as sepsis and meningitis.