Linkage maps from multiple genetic crosses and loci linked to growth-related virulent phenotype in
            <i>Plasmodium yoelii</i>

Li, Jian; Pattaradilokrat, Sittiporn; Zhu, Feng; Jiang, Hongying; Liu, Shengfa; Hong, Liu; Fu, Yong; Koo, Lily Y.; Xu, Wenyue; Pan, Weiqing; Carlton, Jane M.; Kaneko, O.; Carter, Richard; Wootton, John C.; Su, Xin-zhuan

doi:10.1073/pnas.1102261108

Cited by 50 publications

(104 citation statements)

References 43 publications

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“…We demonstrated that different innate pathways were stimulated when inbred mice were infected with the two isogenic parasite strains. In our previous study, we showed that out of 21 microsatellites, only one (Py2000 on chromosome 8) was polymorphic between the genomes of N67 and N67C parasites, and sequencing of the gene encoding PyEBL found only one nucleotide substitution leading to an amino acid change at position 741 (C to Y) (34). These results demonstrate that dramatic differences in disease phenotypes can be produced when mice are infected with different parasite strains, even with parasites of similar genomic backgrounds.…”

Section: Discussionmentioning

confidence: 85%

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Strain-specific innate immune signaling pathways determine malaria parasitemia dynamics and host mortality

Tian

Xiao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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143

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Malaria infection triggers vigorous host immune responses; however, the parasite ligands, host receptors, and the signaling pathways responsible for these reactions remain unknown or controversial. Malaria parasites primarily reside within RBCs, thereby hiding themselves from direct contact and recognition by host immune cells. Host responses to malaria infection are very different from those elicited by bacterial and viral infections and the host receptors recognizing parasite ligands have been elusive. Here we investigated mouse genome-wide transcriptional responses to infections with two strains of Plasmodium yoelii (N67 and N67C) and discovered differences in innate response pathways corresponding to strain-specific disease phenotypes. Using in vitro RNAi-based gene knockdown and KO mice, we demonstrated that a strong type I IFN (IFN-I) response triggered by RNA polymerase III and melanoma differentiation-associated protein 5, not Toll-like receptors (TLRs), binding of parasite DNA/RNA contributed to a decline of parasitemia in N67-infected mice. We showed that conventional dendritic cells were the major sources of early IFN-I, and that surface expression of phosphatidylserine on infected RBCs might promote their phagocytic uptake, leading to the release of parasite ligands and the IFN-I response in N67 infection. In contrast, an elevated inflammatory response mediated by CD14/TLR and p38 signaling played a role in disease severity and early host death in N67C-infected mice. In addition to identifying cytosolic DNA/RNA sensors and signaling pathways previously unrecognized in malaria infection, our study demonstrates the importance of parasite genetic backgrounds in malaria pathology and provides important information for studying human malaria pathogenesis.

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Section: Discussionmentioning

confidence: 85%

“…The parasite P. yoelii nigeriensis N67 (N67) and N67C were initially obtained from the Malaria Research and Reference Reagent Resource Center (MR4; www.mr4.org/) and was described previously (34). Freshly thawed parasites were injected into naïve C57BL/6 mice to initiate infection.…”

Section: Methodsmentioning

confidence: 99%

Strain-specific innate immune signaling pathways determine malaria parasitemia dynamics and host mortality

Tian

Xiao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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143

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“…For these and the remaining studies, mice were infected with P. yoelii nigeriensis (N67) (17) or with P. yoelii yoelii 17XNL (kindly provided by A. Rodriguez). Although these closely related subspecies differ in growth rate (N67's growth is fast; 17XNL's is slow) and lethality (N67 is lethal; 17XNL is nonlethal), infections with these subspecies yield peak parasitemias in inbred (C57BL/6) and outbred (CD-1, Kunming) mice by 11 days postinfection (49) and in CBA/J mice by 10 days postinfection. Neither parasite was lethal in CBA/J mice.…”

Section: Resultsmentioning

confidence: 99%

Malaria-Associatedl-Arginine Deficiency Induces Mast Cell-Associated Disruption to Intestinal Barrier Defenses against Nontyphoidal Salmonella Bacteremia

et al. 2013

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bCoinfection with malaria and nontyphoidal Salmonella serotypes (NTS) can cause life-threatening bacteremia in humans. Coinfection with malaria is a recognized risk factor for invasive NTS, suggesting that malaria impairs intestinal barrier function. Here, we investigated mechanisms and strategies for prevention of coinfection pathology in a mouse model. Our findings reveal that malarial-parasite-infected mice, like humans, develop L-arginine deficiency, which is associated with intestinal mastocytosis, elevated levels of histamine, and enhanced intestinal permeability. Prevention or reversal of L-arginine deficiency blunts mastocytosis in ileal villi as well as bacterial translocation, measured as numbers of mesenteric lymph node CFU of noninvasive Escherichia coli Nissle and Salmonella enterica serotype Typhimurium, the latter of which is naturally invasive in mice. Dietary supplementation of malarial-parasite-infected mice with L-arginine or L-citrulline reduced levels of ileal transcripts encoding interleukin-4 (IL-4), a key mediator of intestinal mastocytosis and macromolecular permeability. Supplementation with L-citrulline also enhanced epithelial adherens and tight junctions in the ilea of coinfected mice. These data suggest that increasing Larginine bioavailability via oral supplementation can ameliorate malaria-induced intestinal pathology, providing a basis for testing nutritional interventions to reduce malaria-associated mortality in humans. Half of the global population is at risk for malaria, which results in nearly 1 million deaths annually, 86% of which are of children (1). The majority of cases are in sub-Saharan Africa, where there is a high prevalence of coinfection with nontyphoidal Salmonella serotypes (NTS) during the rainy season (2-5). While infections with NTS are normally self-limiting in immunocompetent children, coinfection with malaria can predispose to the development of deadly NTS bacteremia (6-9). During malaria infection, sequestration of parasitized red blood cells (RBCs) and capillary blockage are prominent in intestinal villi (10) and are associated with ischemia, malabsorption, and increased gastrointestinal (GI) permeability (11,12). These phenomena are not restricted to severe malaria; up to 50% of Nigerian children with uncomplicated malaria have GI disturbances (13). The mechanisms that underlie malaria-associated GI pathology and enhance the risk of bacteremia are incompletely understood (14), although recent data indicate that malaria-induced heme oxygenase-1 (HO-1) contributes to impaired resistance to NTS by reducing the production of reactive oxygen species (15). Beyond these findings, knowledge is limited and therapeutic options for coinfection are few in the face of high antibiotic resistance in areas of malaria endemicity (16). To support the development of novel therapeutic interventions for invasive bacterial disease, we developed a murine model of coinfection with Plasmodium yoelii and the NTS strain Salmonella enterica serotype Typhimurium ATCC 14028. In this...

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“…Mice were challenged with homologous P. yoelii 17XNL strains unless otherwise described, in which case they were challenged with P. yoelii P265BY, which is genetically different from P. yoelii 17XNL [25], or with P. berghei ANKA [26].…”

Section: Tmp-smx Formulation and Dosementioning

confidence: 99%

Trimethoprim-Sulfamethoxazole Prophylaxis During Live Malaria Sporozoite Immunization Induces Long-Lived, Homologous, and Heterologous Protective Immunity Against Sporozoite Challenge

et al. 2016

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Linkage maps from multiple genetic crosses and loci linked to growth-related virulent phenotype in Plasmodium yoelii

Cited by 50 publications

References 43 publications

Strain-specific innate immune signaling pathways determine malaria parasitemia dynamics and host mortality

Strain-specific innate immune signaling pathways determine malaria parasitemia dynamics and host mortality

Malaria-Associatedl-Arginine Deficiency Induces Mast Cell-Associated Disruption to Intestinal Barrier Defenses against Nontyphoidal Salmonella Bacteremia

Trimethoprim-Sulfamethoxazole Prophylaxis During Live Malaria Sporozoite Immunization Induces Long-Lived, Homologous, and Heterologous Protective Immunity Against Sporozoite Challenge

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