Induction of an IL7-R+c-Kithi myelolymphoid progenitor critically dependent on IFN-γ signaling during acute malaria

Belyaev, Nikolai N.; Brown, Douglas; Díaz, Ana García; Rae, Aaron; Jarra, William; Thompson, Joanne; Langhorne, Jean; Potocnik, Alexandre J.

doi:10.1038/ni.1869

Cited by 128 publications

(165 citation statements)

References 47 publications

(51 reference statements)

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“…RBC production (46), it is possible that rag1 Ϫ/Ϫ mice have a different rate of reticulocyte production than WT mice and that reticulocytes are being infected rapidly after production, generating different infection dynamics in the two lines of mice. However, since a minimum of 2 days is required for a host to produce reticulocytes and since parasitemia is low in WT and rag1 Ϫ/Ϫ mice by day 4 of the 6-day infection, we do not expect that erythropoiesis has a large impact on the infection dynamics in this experiment.…”

Section: Discussionmentioning

confidence: 99%

Effect of Mature Blood-Stage Plasmodium Parasite Sequestration on Pathogen Biomass in Mathematical and In Vivo Models of Malaria

et al. 2014

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Parasite biomass and microvasculature obstruction are strongly associated with disease severity and death in Plasmodium falciparum-infected humans. This is related to sequestration of mature, blood-stage parasites (schizonts) in peripheral tissue. The prevailing view is that schizont sequestration leads to an increase in pathogen biomass, yet direct experimental data to support this are lacking. Here, we first studied parasite population dynamics in inbred wild-type (WT) mice infected with the rodent species of malaria, Plasmodium berghei ANKA. As is commonly reported, these mice became moribund due to large numbers of parasites in multiple tissues. We then studied infection dynamics in a genetically targeted line of mice, which displayed minimal tissue accumulation of parasites. We constructed a mathematical model of parasite biomass dynamics, incorporating schizontspecific host clearance, both with and without schizont sequestration. Combined use of mathematical and in vivo modeling indicated, first, that the slowing of parasite growth in the genetically targeted mice can be attributed to specific clearance of schizonts from the circulation and, second, that persistent parasite growth in WT mice can be explained solely as a result of schizont sequestration. Our work provides evidence that schizont sequestration could be a major biological process driving rapid, early increases in parasite biomass during blood-stage Plasmodium infection. Malaria caused approximately 1,238,000 deaths worldwide in 2010 (1). Of the five different Plasmodium species that infect humans, Plasmodium falciparum is associated with greatest morbidity (2, 3). Parasite biomass and microvasculature obstruction are among the most reliable prognostic indicators in P. falciparum-infected humans, with high levels of either indicator being strongly associated with severe disease and negative outcome (4-6). High P. falciparum biomass could in theory result from poor clearance of freely circulating parasites by the host's mononuclear phagocytic system (MPS), principally macrophages in the spleen and liver. Clinical studies, including ex vivo perfusion of human spleens and analyses of splenectomized malaria patients, argue that humans can clear at least a proportion of circulating P. falciparum parasites (7-11). Furthermore, increased rigidity of red blood cells (RBCs) infected with P. falciparum parasites, particularly mature-stage trophozoites and schizonts, appears to render them less capable of passage through the spleen than either uninfected RBCs or ring-stage P. falciparum-infected RBCs (P. falciparum-iRBCs) (12). Thus, the human MPS can clear circulating mature P. falciparum-iRBCs, but its competency at doing so in vivo remains unclear. A mechanism that could facilitate increases in parasite biomass is evasion of the host MPS by sequestration of P. falciparum-iRBCs in peripheral tissues. A large body of literature has clearly identified P. falciparum-expressed ligands, which mediate adherence of schizont-and late-stage trophozoite-iRBCs to ...

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Section: Discussionmentioning

confidence: 99%

Effect of Mature Blood-Stage Plasmodium Parasite Sequestration on Pathogen Biomass in Mathematical and In Vivo Models of Malaria

et al. 2014

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“…In some circumstances, particularly in response to infection, IFN-g-expanded hematopoietic cells might usefully contribute to production of differentiated myeloid cells. 25,27,73,74 However, under conditions of immune-mediated BM failure, in which activated FasL-bearing cytotoxic T cells expand in the local BM environment, IFN-g would be deleterious because it drives Fas upregulation on hematopoietic cell components in the BM and serves as a critical component of an aberrant immune response that prepares hematopoietic cells for destruction mediated by Fas/FasL and other signals.…”

Section: Cd48mentioning

confidence: 99%

IFN-γ-mediated hematopoietic cell destruction in murine models of immune-mediated bone marrow failure

Chen

Feng

Desierto

et al. 2015

Blood

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“…It should be noted that helminth parasites, such as S. mansoni, also trigger TLR/MyD88 signaling to induce an early Th1 response, which is subsequently converted to a dominant Th2 response [39,40]. Remarkably, CTL-suppressive CD11b Gr-1 1 cells during acute P. chabaudi infection critically depends on progenitor-intrinsic IFN-g-R1 signaling [24]. IFN-g-R1 is also absolutely required for splenic MDSC expansion observed in T. cruzi infection [22].…”

Section: Factors Mediating Mdsc Induction During Parasitic Infectionsmentioning

confidence: 99%

Myeloid‐derived suppressor cells in parasitic infections

et al. 2010

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BelgiumMyeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that share a common property of suppressing immune responses. Several helminth and protozoan parasite species have developed efficient strategies to increase the rate of medullary or extramedullary myelopoiesis and to induce the expansion and accumulation of immature myeloid cells such as MDSC. In this review, we examine current knowledge on the factors mediating enhanced myelopoiesis and MDSC induction and recruitment during parasitic infections and how the MDSC phenotype and mechanism of immune modulation and suppression depends on the factors they encounter within the host. Finally, we place MDSC expansion in the context of the critical balance between parasite elimination and pathogenicity to the host and suggest attractive avenues for future research.Key words: Myeloid-derived suppressor cells . Myelopoiesis . Parasitic infection .T-cell suppression IntroductionParasitic infections are notoriously associated with suppression of immune responses. Populations of mature myeloid cells, such as macrophages in various activation states, are capable of displaying immunosuppressive features, and as a result play important roles in the critical balance between parasite elimination and pathogenicity to host tissues [1][2][3]. Heterogeneous populations of immature myeloid cells, characterized by the surface expression of both Gr-1 and CD11b molecules in mice and a shared potent immune-suppressing activity in vitro and in vivo, have been recognized to arise as a conserved response to various insults, including cancer, bacterial and parasitic infections. Collectively, these cells have been termed myeloid-derived suppressor cells (MDSC) [4]. A number of factors complicate the analysis of MDSC biology. First, MDSC are a heterogeneous mixture of immature myeloid cells that are in various intermediate stages of myeloid cell differentiation (reflected by expression of various levels of macrophage and DC markers such as F4/80 and CD11c, respectively, as well as MHC class II, CD80/86) and murine MDSC consist of different subpopulations with varying levels of reactivity with the Gr-1 monoclonal antibody. This Gr-1 antibody binds a common epitope on the Ly6G and Ly6C antigens [5]. Using antibodies specifically recognizing Ly6C or Ly6G, MDSC have been shown to contain at least two main subfractions: the CD11b suppressive capacity in all tumor models [7,16]. The heterogeneity and plasticity of MDSC and the lack of markers to optimally distinguish MDSC from other, more mature myeloid cell types, render T-cell anti-proliferative activity to be the ultimate defining characteristic of MDSC. Despite the above-mentioned limitations, the impact of MDSC on immune responses has made MDSC the topic of intense research. To date, most of the attention has been focused on cancer-associated MDSC, whereas relatively few studies have reported the activation, phenotype and especially the role of MDSC during parasitic infections (Table 1). In thi...

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Induction of an IL7-R+c-Kithi myelolymphoid progenitor critically dependent on IFN-γ signaling during acute malaria

Cited by 128 publications

References 47 publications

Effect of Mature Blood-Stage Plasmodium Parasite Sequestration on Pathogen Biomass in Mathematical and In Vivo Models of Malaria

Effect of Mature Blood-Stage Plasmodium Parasite Sequestration on Pathogen Biomass in Mathematical and In Vivo Models of Malaria

IFN-γ-mediated hematopoietic cell destruction in murine models of immune-mediated bone marrow failure

Myeloid‐derived suppressor cells in parasitic infections

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