title: Expression of complement and toll-like receptor pathway genes is associated with malaria severity in Mali: a pilot case control study.
abstract: BACKGROUND
  The host response to infection by Plasmodium falciparum, the parasite most often responsible for severe malaria, ranges from asymptomatic parasitaemia to death. The clinical trajectory of malaria is influenced by host genetics and parasite load, but the factors determining why some infections produce uncomplicated malaria and some proceed to severe disease remain incompletely understood.
  
  
  METHODS
  To identify molecular markers of severe falciparum malaria, human gene expression patterns were compared between children aged 6 months to 5 years with severe and uncomplicated malaria who were enrolled in a case-control study in Bandiagara, Mali. Microarrays were used to obtain expression data on severe cases and uncomplicated controls at the time of acute disease presentation (five uncomplicated and five severe), 1 week after presentation (three uncomplicated and three severe) and treatment initiation, and in the subsequent dry season (late convalescence, four uncomplicated and four severe). This is a pilot study for the first use of microarray technology in Mali.
  
  
  RESULTS
  Complement and toll-like receptor (TLR) pathways were differentially expressed, with severe cases showing higher expression of the C1q, TLR2, TLR4, TLR8, and CR1 genes. Other genes previously associated with malaria pathogenesis, GZMB, FOS and HSPA6, were also higher among severe cases. TLR2, TLR4, TLR8, CR1, GZMB, FOS, and HSPA6 genes were expressed at lower levels in severe cases at late convalescence.
  
  
  CONCLUSIONS
  Overexpression of genes previously associated with uncomplicated malaria was associated with severe disease. Low baseline expression of these genes may represent candidate markers for severe malaria. Despite the small sample size, results of this pilot study offer promising targets for follow-up analyses.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA. rafal4484@gmail.com.|Department of Genetics, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA. rafal4484@gmail.com.
authors.forename: Rafal S
authors.initials: RS
authors.lastname: Sobota
authors.affiliation: Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, University of Sciences, Techniques and Technology of Bamako, Bamako, Mali. tonydara@gmail.com.|Division of Malaria Research, Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD, USA. tonydara@gmail.com.
authors.forename: Antoine
authors.initials: A
authors.lastname: Dara
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. jess.manning@gmail.com.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Manning
authors.affiliation: Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, University of Sciences, Techniques and Technology of Bamako, Bamako, Mali. abniangaly@gmail.com.
authors.forename: Amadou
authors.initials: A
authors.lastname: Niangaly
authors.affiliation: Division of Malaria Research, Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD, USA. Jbail006@umaryland.edu.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Bailey
authors.affiliation: Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, University of Sciences, Techniques and Technology of Bamako, Bamako, Mali. fankone@icermali.org.
authors.forename: Abdoulaye K
authors.initials: AK
authors.lastname: Kone
authors.affiliation: Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, University of Sciences, Techniques and Technology of Bamako, Bamako, Mali. mthera@icermali.org.
authors.forename: Mahamadou A
authors.initials: MA
authors.lastname: Thera
authors.affiliation: Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, University of Sciences, Techniques and Technology of Bamako, Bamako, Mali. adjimde@icermali.org.
authors.forename: Abdoulaye A
authors.initials: AA
authors.lastname: Djimdé
authors.affiliation: Pasteur Institute of Cameroon, Yaounde, Cameroon, Fondation Merieux, Lyon, France. vernet@pasteur-yaounde.org.
authors.forename: Guy
authors.initials: G
authors.lastname: Vernet
authors.affiliation: BioMerieux, Grenoble, France. philippe.leissner@biomerieux.com.
authors.forename: Philippe
authors.initials: P
authors.lastname: Leissner
authors.affiliation: Department of Genetics, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA. Scott.Williams@dartmouth.edu.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Williams
authors.affiliation: Division of Malaria Research, Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD, USA. cplowe@medicine.umaryland.edu.
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Plowe
authors.affiliation: Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, University of Sciences, Techniques and Technology of Bamako, Bamako, Mali. okd@icermali.org.
authors.forename: Ogobara K
authors.initials: OK
authors.lastname: Doumbo
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D002675:Child, Preschool; D016000:Cluster Analysis; D003165:Complement System Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008302:Mali; D017720:Molecular Epidemiology; D020411:Oligonucleotide Array Sequence Analysis; D010865:Pilot Projects; D010963:Plasmodium falciparum; D051193:Toll-Like Receptors / Q000235:genetics* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D051193:Toll-Like Receptors; D003165:Complement System Proteins