Plasmodium genetic loci linked to host cytokine and chemokine responses.
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-1β, IP-10, IFN-γ, 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-1β, 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.
1] Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA [2] Department of Biology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.
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Pattaradilokrat
1] Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA [2] State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, P. R. China.
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J
Li
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
J
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Wu
1] Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA [2] State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, P. R. China.
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Qi
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
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Eastman
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
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Zilversmit
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
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Nair
1] Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA [2] Advanced Bioscience Laboratories, Medical Center Drive, Rockville, MD, USA.
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Huaman
Bioinformatics and Computational Biosciences Branch, NIAID, NIH, Bethesda, MD, USA.
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M
Quinones
1] Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA [2] General Health Science, US Food and Drug Administration, Silver Spring, MD, USA.
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H
Jiang
MedImmune, Gaithersburg, MD, USA.
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Li
Genetics and Developmental Biology Center, NIH, Bethesda, MD, USA.
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J
Zhu
Systems Biology Center, National Heart Lung and Blood Institute, NIH, Bethesda, MD, USA.
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K
Zhao
Department of Protozoology, Institute of Tropical Medicine and the Global Center of Excellence Program, Nagasaki University, Nagasaki, Japan.
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Kaneko
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
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CA
Long
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
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D000818:Animals; D018932:Chemokine CCL2 / Q000097:blood / Q000378:metabolism; D018925:Chemokines / Q000097:blood / Q000378:metabolism; D003433:Crosses, Genetic; D016207:Cytokines / Q000097:blood / Q000378:metabolism*; D004195:Disease Models, Animal; D004843:Epistasis, Genetic; D005260:Female; D017125:Genes, Protozoan; D056426:Genetic Loci; D018503:Genome, Protozoan; D054884:Host-Pathogen Interactions; D008288:Malaria / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality; D051379:Mice; D018345:Mice, Knockout; D010961:Plasmodium / Q000235:genetics* / Q000276:immunology*; D010967:Plasmodium yoelii / Q000235:genetics / Q000276:immunology; D011110:Polymorphism, Genetic; D040641:Quantitative Trait Loci
D018932:Chemokine CCL2; D018925:Chemokines; D016207:Cytokines