Genome-wide Dissection of Human Immunity to Streptococcus Pneumoniae

Damien Chaussabel, Ph.D.

Baylor Research Institute

Funded in June, 2007: $600000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Exploring a Genetic Basis for Childhood Susceptibility to Pneumococcal Disease

Investigators will combine human immune research with genetic and genomics studies to identify immune pathways that are normally effective against pneumococcal bacteria but are deficient in children who develop invasive pneumococcal disease (IPD).

While streptococcus pneumoniae is a bacterium that commonly causes benign upper respiratory infections, in rare instances it becomes invasive and causes potentially deadly diseases such as septicemia and meningitis.  Invasive IPD typically occurs in children who are less than two years old. The researchers hypothesize that unknown genetic abnormalities create increased susceptibility to IPD, and they will seek to identify a genetically-determined molecular basis for immune dysfunction in 100 children with IPD. Necker Institute researchers will undertake studies of possible mutations in the children’s immune system genes, while the Baylor researchers will explore the relationship between gene activity and immune dysfunction in the children. 

Significance:  If a genetic basis for deficient immunity against childhood IPD is found, the findings are expected eventually to lead to development of treatment and, in the short-term, to provide a method for identifying at-risk children and providing genetic counseling to their families.

ABSTRACT

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Genome-wide Dissection of Human Immunity to Streptococcus Pneumoniae

Streptococcus pneumoniae (pneumococcus) is a commensal organism of the human nasopharynx that causes common benign infections of the upper respiratory tract. In rare cases, it may cause invasive disease, such as septicemia and meningitis. Invasive pneumococcal disease (IPD) typically occurs in children under two years of age.

We hypothesize that invasive pneumococcal disease (IPD) in childhood is favored by unknown Mendelian disorders of the immune system, at least in some children. We intend to develop hypothesis-generating, genome-wide approaches for identifying pathways normally involved in immunity to pneumococcus but deficient in patients with IPD. We will combine genetic and genomic approaches to achieve this goal.

We aim 1) to recruit children with unexplained IPD, including children born to consanguineous and/or multiplex kindreds; 2) to identify novel primary immunodeficiencies in children with IPD, using a genetic approach (gene positional mapping); and 3) to identify immunological pathways deficient in patients with IPD, using a genomic approach (genome-wide immune reactivity profiles).

A cohort of 45 children with unexplained, “idiopathic” IPD, with no detectable immunological defect, has already been set up, forming the core study population. Over the next three years, an additional 55 children will be recruited, resulting in the enrollment of 100 children with IPD in total. The genetic approach will be based on the genotyping of polymorphic markers (SNPs) throughout the genome (genome-wide scan) in a series of unrelated kindreds, each consanguineous and containing at least one child with IPD with no detectable cellular phenotype.

The genomic approach will investigate the immune responses of patients with IPD in a blood re-stimulation assay. Blood samples, unstimulated and stimulated with killed S. pneumoniae, TNF-a, IL-1b and various Toll-like receptor agonists, will serve as templates for mRNA extraction and genome-wide expression profiling. A reference dataset will be generated, using samples from patients with known deficiencies (IRAK4 -/-; NEMO -/-; MYD88 -/-), and profiles will be generated under the same experimental conditions for blood obtained from patients with IPD carrying no known mutation. The mutations identified will be validated at the mRNA (northern blot, RT-PCR) and protein (western blot, immunoprecipitation, flow cytometry) levels, and by gene transfer experiments.

INVESTIGATOR BIOGRAPHIES

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Damien Chaussabel, Ph.D.

Damien Chaussabel, Ph.D., is an Assistant Investigator at the Baylor Institute for Immunology Research (BIIR) in Dallas, where he also leads the translational Genomics and Bioinformatics group.

He earned his Ph.D. in Immunology from the University of Brussels in 1999. During this time, he studied Chagas Disease, which infects an estimated sixteen to eighteen million people worldwide, mostly in Central and South America. From 2000-2004, Dr. Chaussabel was a Postdoctoral Fellow at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland. He joined Baylor Institute for Immunology Research in 2004 to develop a research program at the interface of human immunology and genomics. He participates together with colleagues at BIIR in research involving patients with cancer and infectious and autoimmune diseases, as well as transplant recipients.

Jean-Laurent Casanova is a Professor of Pediatrics at the Necker School of Medicine, University Paris René Descartes and INSERM, France.  He is the director and founder (with Laurent Abel) of the Laboratory of Human Genetics of Infectious Diseases. His laboratory focuses on the human genetics of infectious diseases, invasive pneumococcal disease in particular.