The contribution of natural killer complex loci to the development of experimental cerebral malaria

• Published in: PloS one Vol. 9; no. 4; p. e93268
• Main Authors: Hansen, Diana S, Ryg-Cornejo, Victoria, Ioannidis, Lisa J, Chiu, Chris Y, Ly, Ann, Nie, Catherine Q, Scalzo, Anthony A, Schofield, Louis
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-04-2014; Public Library of Science (PLoS)
• Subjects: Alleles; Analysis; Animals; Biology and life sciences; Biomarkers; Brain; Brain research; Care and treatment; CD8 antigen; Chemokines; Chromosomes; Control methods; Cytokines; Cytotoxicity; Diagnosis; Disease; Disease Models, Animal; Distribution; Edema; Extracellular matrix; Gene expression; Gene Expression Regulation; Genes; Genetic Association Studies; Genetic Loci; Genetic Predisposition to Disease; Genomics; Genotype; Haplotypes; Immune response; Inbreeding; Infections; Interferon; Interferon-gamma - biosynthesis; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Lectins, C-Type - genetics; Ligands; Loci; Lymphocytes; Lymphocytes T; Malaria; Malaria, Cerebral - genetics; Malaria, Cerebral - immunology; Malaria, Cerebral - parasitology; Medical research; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Natural killer cells; Natural Killer T-Cells - immunology; Natural Killer T-Cells - metabolism; Parasites; Pathogenesis; Pathology; Plasmodium berghei; Plasmodium falciparum; Progeny; Receptor mechanisms; Receptors; Receptors, Cell Surface - genetics; Recruitment; Research and Analysis Methods; T cell receptors; T cells; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Tumor necrosis factor-TNF; Vector-borne diseases; Viral infections; γ-Interferon; Australia; Queensland Australia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0093268

The Natural Killer Complex (NKC) is a genetic region of highly linked genes encoding several receptors involved in the control of NK cell function. The NKC is highly polymorphic and allelic variability of various NKC loci has been demonstrated in inbred mice, providing evidence for NKC haplotypes. Using BALB.B6-Cmv1r congenic mice, in which NKC genes from C57BL/6 mice were introduced into the BALB/c background, we have previously shown that the NKC is a genetic determinant of malarial pathogenesis. C57BL/6 alleles are associated with increased disease-susceptibility as BALB.B6-Cmv1r congenic mice had increased cerebral pathology and death rates during P. berghei ANKA infection than cerebral malaria-resistant BALB/c controls.
To investigate which regions of the NKC are involved in susceptibility to experimental cerebral malaria (ECM), intra-NKC congenic mice generated by backcrossing recombinant F2 progeny from a (BALB/c x BALB.B6-Cmv1r) F1 intercross to BALB/c mice were infected with P. berghei ANKA.
Our results revealed that C57BL/6 alleles at two locations in the NKC contribute to the development of ECM. The increased severity to severe disease in intra-NKC congenic mice was not associated with higher parasite burdens but correlated with a significantly enhanced systemic IFN-γ response to infection and an increased recruitment of CD8+ T cells to the brain of infected animals.
Polymorphisms within the NKC modulate malarial pathogenesis and acquired immune responses to infection.