Journal
GENES AND IMMUNITY
Volume 15, Issue 3, Pages 145-152Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gene.2013.74
Keywords
genetic mapping; cytokine; chemokine; inflammation; pathogenesis; virulence
Categories
Funding
- Intramural Research Program of the Division of Intramural Research
- National Institute of Allergy and Infectious Diseases
- National Institutes of Health
- Project 111
- State Bureau of Foreign Experts
- Ministry of Education of China [B06016]
- National Natural Science Foundation of China [81271858, 81201324, 81220108019]
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Both host and parasite factors contribute to disease severity of malaria infection; however, the molecular mechanisms responsible for the disease and the host-parasite interactions involved remain largely unresolved. To investigate the effects of parasite factors on host immune responses and pathogenesis, we measured levels of plasma cytokines/chemokines (CCs) and growth rates in mice infected with two Plasmodium yoelii strains having different virulence phenotypes and in progeny from a genetic cross of the two parasites. Quantitative trait loci (QTL) analysis linked levels of many CCs, particularly IL-1 beta, IP-10, IFN-gamma, MCP-1 and MIG, and early parasite growth rate to loci on multiple parasite chromosomes, including chromosomes 7, 9, 10, 12 and 13. Comparison of the genome sequences spanning the mapped loci revealed various candidate genes. The loci on chromosomes 7 and 13 had significant (P<0.005) additive effects on IL-1 beta, IL-5 and IP-10 responses, and the chromosome 9 and 12 loci had significant (P=0.017) interaction. Infection of knockout mice showed critical roles of MCP-1 and IL-10 in parasitemia control and host mortality. These results provide important information for a better understanding of malaria pathogenesis and can be used to examine the role of these factors in human malaria infection.
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