Search for coherent gene modules that predict Streptococcus - - PowerPoint PPT Presentation
Search for coherent gene modules that predict Streptococcus pneumoniae strain invasiveness Rui Ribeiro Catarino S Streptococcus Pneumoniae S Streptococcus pneumoniae , or pneumococcus, is a commensal gram positive bacteria in the human
Rui Ribeiro Catarino
S Streptococcus pneumoniae, or pneumococcus, is a commensal
gram positive bacteria in the human respiratory tract.
S Pathogen responsible for diseases such as pneumonia, otitis,
meningitis and sepsis.
UNICEF/WHO,Pneumonia: The forgotten killer of children,2006
Nasopharyngeal carriage may occur in up to 60% of healthy pre-school children and up to 30% of healthy older children and adults
Nasopharynx: site
Trachea Dissemination Inhalation Patient with pneumococcal disease Asymptomatic carrier Aerosol Nasal cavity
Fedson, Musher, in Vaccines, 1994 Musher, in Principles and Practice of Infectious Diseases, 1995
S Strain invasiveness is related with its probability to be isolated
from patient with pneumococcal invasive disease.
S From observational studies: S Invasiveness OR=ad/(cb) Carriage Invasive Disease Clone A a b Not Clone A c d
Sá Leão et al 2011
S S. pneumoniae is very diverse. The pangenome is estimated to
be more than 2 times the size the average strain. (Donati, C et el,
Genome Biology, 2010 vol 11(10) p R107)
S Naturally competent S High frequency of homologous recombination - a single
nucleotide changes by recombination 50 times more frequently than by mutation (Feil, EJ et al, Genetics. 2000 Apr;154(4):
1439-50)
S Genomotyping of test strains. S Control strains R6, Tigr4 and G54 are from different
serotypes and have different invasive behaviors.
Strain 1 Strain ... Strain 72 Gene 1 1 ... 1 Gene 2 ... 1 Gene 3 ... Gene ... ... ... ... Gene 3620 1 ...
S Invasiveness Determinants - Genes whose presence is
associated, experimentally or observationally, with diseases caused by pneumococcus.
S Capsule genes, adesines and toxines are well documented
Invasiveness Determinants.
S Contradictory results spawn from the highly variable
genome between strains.
S It is a cellular process that is associated with invasive
disease (or colonization)
S A strain can be a colonizer because it lacks a few genes
S An analysis of all possible gene combinations would be
interactions.
S Biological network limit the number of gene
combinations and assure an easy interpretation.
S A gene distance matrix was created using the aCGH
and epidemiological data.
S Genes distance depends on their co-occurrence in
invasive strains.
S Modules with different sizes were created from each
gene, joining the closest neighbors on the distance matrix.
S These modules were later evaluated in order of
classification performance and statistical significance.
S A threshold (t) is selected for each
module to maximize the Invasive Predictive Value (IPV).
S A module is present in a strain if there
are at least t genes of the module in the strain.
S IPV is the ratio of invasive strains where
the module is present.
6 6 5 4 4 1
S Invasive behavior depends on several independent features. S We hypothesize the genes identified play roles in some of
these features such as:
S adaptation to new environments S survival with different nutrient sources S interaction with the host S generating genetic diversity.
Adaptation to the Environment Anaerobic response ( 3 ) Osmotic regulation ( 2 )
Nutrient Availability
Proteolysis ( 4 ) Amino acid metabolism ( 8 ) Carbohydrates metabolism ( 10 ) Transport ( 19 )
Interaction with the Host
Choline Binding Proteins ( 2 ) Toxins ( 11 ) Cellular Envelope ( 7 )
Genetic Diversity
Competence ( 4 ) DNA recombination and repair ( 12 ) IS/Transposons ( 6 ) tRNA ( 4 )
S It was possible to identify 26 (highly overlapping) gene
modules associated with invasiveness
S Some of the genes were previously associated with
invasiveness, while other still need to be studied
S No gene modules were found associated with colonization
S Module definition needs perfection to allow for a module-
wise interpretation of function.
S Apply same strategy with the metabolic and transcriptional
networks
Enzimology group: The Boss: Francisco Pinto research grant PTDC/EBB-EBI/113824/2009 PTDC/BIA-MIC/101375/2008