There is a fundamental gap in our understanding of how unique aspects of host physiology influences infection susceptibility, particularly in high-ris individuals who carry a disproportionate burden of morbidity and mortality. Though primarily a hematological disorder, one of the most frequent complications of sickle cell disease (SCD) is severe bacterial infection, particularly with Streptococcus pneumoniae (pneumococcus), which manifests as a fulminant sepsis. This host is 400 times more likely to experience lethal pneumococcal infection than healthy hosts. Despite both vaccination and penicillin prophylaxis, pneumococcal colonization and invasive pneumococcal disease persists in SCD patients. The long-term goal is to understand the bacterial and host factors that predispose SCD patients to greater infection risk and to leverage this knowledge to develop novel therapies tailored to this high-risk group. The objective in this particular application is the application of both genetic tools, namely transposon mutagenesis and sequencing, and the SCD murine system to precisely define pneumococcal pathogenesis in the context of SCD. The central hypothesis is that pneumococcal genetics can be exploited to more precisely define the selective pressures encountered in an altered host, reflecting the unique host physiology that drives heightened infection risk. Guided by preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Define the pneumococcal genes under differential selective pressure during colonization and pneumonia in SCD, 2) Ascertain the mechanisms underlying the retention of invasiveness by both atypical capsular types and altered core genome pneumococcal variants in SCD, and 3) Establish the metabolic factors in the SCD host rendering the host more permissive to invasive pneumococcal disease. These studies will close a significant gap in current knowledge by leveraging data from extensive genomic analysis of pneumococcal isolates from SCD patients and the capacity to model both infection and the contribution of genes to pathogenesis using Tn-seq, allowing a unique opportunity to investigate aspects of pneumococcal disease in the context of SCD in a clinically relevant setting. The research proposed enables the application of recently developed genetic tools to address fundamental questions about how invasive pneumococcal disease differs between those with SCD and their healthy peers from both the bacterial and host perspectives. Understanding the differences of host-pathogen interactions in the context of SCD will establish that this population requires distinct vaccine strategies and therapeutics to both prevent and treat bacterial infections and what these modified strategies should encompass. These results will have an important positive impact on human health by increasing understanding of invasive pneumococcal disease in the SCD population, revealing the factors underlying the increased risk of fatal infection despite current prophylaxis, and identifying potentially targetable pathways to mitigate the severity of infection.

Public Health Relevance

The proposed research is relevant to public health because the discovery of the factors underlying the continued heightened infection risk from pneumococcal infection in patients with sickle cell disease will enhance our understanding of bacterial pathogenesis in high-risk hosts. This is relevant to the mission of both NIH sections NHLBI and NIAID that pertains to developing fundamental knowledge to reduce the severity of bacterial infections in high-risk patient populations, such as sickle cell disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI110618-03
Application #
9171341
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Lu, Kristina
Project Start
2014-12-01
Project End
2019-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Margolis, Elisa; Rosch, Jason W (2018) Fitness Landscape of the Immune Compromised Favors the Emergence of Antibiotic Resistance. ACS Infect Dis 4:1275-1277
Penkert, Rhiannon R; Young, Neal S; Surman, Sherri L et al. (2017) Saccharomyces cerevisiae-derived virus-like particle parvovirus B19 vaccine elicits binding and neutralizing antibodies in a mouse model for sickle cell disease. Vaccine 35:3615-3620
Honsa, Erin S; Cooper, Vaughn S; Mhaissen, Mohammed N et al. (2017) RelA Mutant Enterococcus faecium with Multiantibiotic Tolerance Arising in an Immunocompromised Host. MBio 8:
Karlsson, Erik A; Oguin, Thomas H; Meliopoulos, Victoria et al. (2017) Vascular Permeability Drives Susceptibility to Influenza Infection in a Murine Model of Sickle Cell Disease. Sci Rep 7:43308
Johnson, Michael D L; Kehl-Fie, Thomas E; Rosch, Jason W (2015) Copper intoxication inhibits aerobic nucleotide synthesis in Streptococcus pneumoniae. Metallomics 7:786-94
Johnson, Michael D L; Echlin, Haley; Dao, Tina H et al. (2015) Characterization of NAD salvage pathways and their role in virulence in Streptococcus pneumoniae. Microbiology 161:2127-36
Johnson, Michael D L; Kehl-Fie, Thomas E; Klein, Roger et al. (2015) Role of copper efflux in pneumococcal pathogenesis and resistance to macrophage-mediated immune clearance. Infect Immun 83:1684-94