Plasmodium genetic loci linked to host cytokine and chemokine responses

Abstract

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 effects of parasite factors on host immune responses and pathogenesis, we measured levels of plasma cytokines/chemokines (CC) 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 chromosome 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 better understanding of malaria pathogenesis and can be used to examine the role of these factors in human malaria infection.Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Genome-wide Analysis of Host-Plasmodium yoelii Interactions Reveals Regulators of the Type I Interferon Response

“…One example was the major peak on chromosome 8 (represented by marker Py20321) that was significantly linked to genes functioning in hematopoiesis or RBC surface molecules, including the gene encoding glycophorin A (Figure 4A and 4D). Examination of the MS marker inheritances among the progeny typed previously (Li et al, 2011; Pattaradilokrat et al, 2014) found two progeny (G001#4 and F117#2) having crossovers between MS marker Py2669 and Py20322 at the locus (~53.5 kb apart), which was responsible for the decline of LOD scores in the flanking regions (Figure 4E). The normalized log2 expression signal of glycophorin A for F117#2 was −0.44, similar to that of 17XNL (−0.08), whereas G001#4 was −3.81, more similar to that of N67 (−1.6) (Supplementary Table 2).…”

UTR introns, antisense RNA and differentially spliced transcripts between Plasmodium yoelii subspecies

“…Among the RMPs, P. yoelii has been used as an animal model for vaccine development and for studying the genetic basis of parasite invasion and virulence [ 7 – 9 ]. Recently, various genetic markers [ 10 – 12 ] and genetic crosses have been reported for mapping important traits, such as red blood cell (RBC) invasion, parasite growth, and host cytokine/chemokine levels in P. yoelii infection [ 8 , 13 , 14 ] using clonal P. yoelii lines that exhibit wide variation in disease genotypes [ 9 , 15 , 16 ]. However, genetic mapping can only link chromosome segments containing various candidate genes to a phenotype.…”

Genome-wide polymorphisms and development of a microarray platform to detect genetic variations in Plasmodium yoelii

“…There are three subspecies of Plasmodium yoelii ( P. yoelii yoelii , P. yoelii nigeriensis , and P. yoelii killicki ) and a number of strains and clonal lines (all lines used in this study are cloned parasite lines) that exhibit wide variation in disease phenotypes, from mild disease to lethal infection [8,9]. For example, P. y. yoelii strain 17XNL (17XNL), the most common laboratory strain and the genome reference strain of P. yoelii [10], is a non-virulent parasite that causes a mild infection, whereas P. y. yoelii strain YM (YM) and P. y. nigeriensis N67C (N67C) parasites are highly virulent and generally produce lethal diseases [8,9,11]. Characterization of the genetic differences between lethal and non-lethal parasite lines may lead to discovery of molecular markers of severe malaria phenotypes.…”

“…Characterization of the genetic differences between lethal and non-lethal parasite lines may lead to discovery of molecular markers of severe malaria phenotypes. Indeed, recent mapping studies have linked parasite growth-related virulence and host cytokine/chemokine levels to various chromosomal loci [9,11,12]. However, these mapping studies largely relied on typing individual genetic markers such microsatellites (MS) markers [9].…”