Interleukin-3-Deficient Mice Have Increased Resistance to Blood-Stage Malaria

Auclair, Sarah; Roth, Kenneth; Saunders, Bryan; Ogborn, Kathryn M.; Sheikh, Abdalla; Naples, Julianne; Young, Ann; Boisen, Dorottya; Tavangar, Amelia; Welch, Jane; Lantz, Chris S.

doi:10.1128/iai.01140-13

Cited by 19 publications

(22 citation statements)

References 41 publications

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“…Differential analysis of individual transcriptomics, metabolomics, and lipidomics datasets showed significant alterations of transcriptional and metabolic programs related to inflammation and immune regulation during acute infections that are consistent with a number of reported observations (Auclair et al, 2014; Haque et al, 2001; Sarangi et al, 2014; Sinha et al, 2010; Zago et al, 2012). Altered pathways were related to two axes of immune regulation: those modulating cell proliferation through the cell cycle and those controlling immune function (including cellular immunity).…”

Section: Discussionsupporting

confidence: 89%

Multi-omics Integrative Analysis of Acute and Relapsing Malaria in a Non-Human Primate Model ofP. vivaxinfection

Tang

Joyner

Cordy

et al. 2019

Preprint

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SummarySystems-scale analysis of multiple layers of molecular and cellular data has significant potential for providing novel insights into malaria pathology and immunity. We present here a unique longitudinal multi-omics dataset encompassing Macaca mulatta blood and bone marrow responses to infection by Plasmodium cynomolgi, a non-human primate (NHP) parasite species used to model P. vivax malaria acute and relapsing infections in humans. We analyzed relationships across multiple biological layers using a mutual information-based machine learning approach to integrate heterogeneous longitudinal datasets and constructed an atlas of multi-omics relatedness networks (MORNs). Using this technique, we were able to detect signatures that defined both acute and relapsing infections. Importantly, relapse infections could be distinguished from both acutely-infected and uninfected NHP, suggesting that the host-parasite interactions during relapses are unique compared to acute Plasmodium infections. To our knowledge, this is the first report of large-scale, longitudinal multi-omics analysis of malaria in any system. This dataset, along with the method used to analyze it, provides a unique resource for the malaria research community and demonstrates the power of longitudinal infection study designs, NHP model systems and integrative multi-omics analyses.

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Section: Discussionsupporting

confidence: 89%

Multi-omics Integrative Analysis of Acute and Relapsing Malaria in a Non-Human Primate Model ofP. vivaxinfection

Tang

Joyner

Cordy

et al. 2019

Preprint

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“…Instead, these mice were found to have defects in delayed-type hypersensitivity (3) and in immunity to parasites (4). More recent studies have shown that IL-3 has a detrimental role in experimental autoimmune encephalitis and myocarditis (2, 5), lupus nephritis (6), sepsis (7), and blood-stage malaria (8) and a beneficial role in anti-tick immunity (9).…”

Section: Introductionmentioning

confidence: 99%

Generation of IL-3–Secreting CD4+ T Cells by Microbial Challenge at Skin and Mucosal Barriers

et al. 2019

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During Ag priming, naive CD4 + T cells differentiate into subsets with distinct patterns of cytokine expression that dictate to a major extent their functional roles in immune responses. We identified a subset of CD4 + T cells defined by secretion of IL-3 that was induced by Ag stimulation under conditions different from those associated with previously defined functional subsets. Using mouse models of bacterial and viral infections, we showed that IL-3-secreting CD4 + T cells were generated by infection at the skin and mucosa but not by infections introduced directly into the blood. Most IL-3-producing T cells coexpressed GM-CSF and other cytokines that define multifunctionality. Generation of IL-3-secreting T cells in vitro was dependent on IL-1 family cytokines and was inhibited by cytokines that induce canonical Th1 or Th2 cells. Our results identify IL-3-secreting CD4 + T cells as a potential functional subset that arises during priming of naive T cells in specific tissue locations. ImmunoHorizons, 2019, 3: 161-171.

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“…Similarly to bacterial sepsis, in which IRA B cells are reported to either promote (via IL-3) or protect (via GM-CSF) the host, a lack of GM-CSF or IL-3 has opposite outcomes during malaria infection, with GM-CSF-deficient mice exhibiting lower resistance to chronic P. chabaudi infection (19), while IL-3-deficient mice resisted better P. bergheiinduced experimental cerebral malaria (ECM) (20). IRA B cell-derived GM-CSF increases resistance to bacterial sepsis through secreted IgM and subsequent activation of innate myeloid cell phagocytic capacity and bacterial clearance.…”

Section: Discussionmentioning

confidence: 99%

“…We found that the production of GM-CSF by the B1 B cell plasmablasts is partially dependent on both cell-extrinsic type I (IFN-␣/␤) and cell-intrinsic type II (IFN-␥) interferon signaling but is independent of MyD88 signaling, a key cytosolic adaptor of most TLR signaling. Given that GM-CSF and IL-3 are reported to play opposite roles in malaria infection outcomes in mouse models (19,20), we speculate that GM-CSF and IL-3 from these subsets of B1 B cell plasmablasts could represent important contributors to clinical malaria in humans.…”

mentioning

confidence: 90%

“…Further evidence using mice genetically deficient for GM-CSF infected with chronic Plasmodium chabaudi suggested that GM-CSF contributes to the control of parasite growth and rebounds (19). Interestingly, mice lacking IL-3 better resisted Plasmodium berghei-induced cerebral malaria, suggesting that IL-3 may impair mechanisms of protective immunity in this model (20). GM-CSF and IL-3 exhibit pleiotropic functions at steady state, as well as during inflammatory processes and immune defenses, which include promoting monocyte/ neutrophil and megakaryocyte/mast cell/basophil production and activation (18,21).…”

mentioning

confidence: 94%

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Splenic Innate B1 B Cell Plasmablasts Produce Sustained Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-3 Cytokines during Murine Malaria Infections

et al. 2019

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The physiopathology of malaria, one of the most deadly human parasitic diseases worldwide, is complex, as it is a systemic disease involving multiple parasitic stages and hosts and leads to the activation of numerous immune cells and release of inflammatory mediators. While some cytokines increased in the blood of patients infected with Plasmodium falciparum have been extensively studied, others, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), have not received much attention. GM-CSF and IL-3 belong to the β common (βc/CD131) chain family of cytokines, which exhibit pleiotropic functions, including the regulation of myeloid cell growth, differentiation, and activation. GM-CSF can be secreted by multiple cell types, whereas IL-3 is mostly restricted to T cells, yet innate response activator (IRA) B cells, a subset of innate B1 B cells, also produce significant amounts of these cytokines during bacterial sepsis via Toll-like receptor 4 (TLR4)/MyD88 sensing of lipopolysaccharides. Herein, using murine models of malaria, we report a sustained production of GM-CSF and IL-3 from IgM+ and IgM−/IgG+ CD138+ Blimp-1+ innate B1b B cell plasmablasts. IgM+ B1b B cells include IRA-like and non-IRA B cells and express higher levels of both cytokines than do their IgG+ counterparts. Interestingly, as infection progresses, the relative proportion of IgM+ B1 B cells decreases while that of IgG+ plasmablasts increases, correlating with potential isotype switching of GM-CSF- and IL-3-producing IgM+ B1 B cells. GM-CSF/IL-3+ B1 B cells originate in the spleen of infected mice and are partially dependent on type I and type II interferon signaling to produce both cytokines. These data reveal that GM-CSF and IL-3 are produced during malaria infections, initially from IgM+ and then from IgG+ B1b B cell plasmablasts, which may represent important emergency cellular sources of these cytokines. These results further highlight the phenotypic heterogeneity of innate B1 B cell subsets and of their possible fates in a relevant murine model of parasitic infection in vivo.

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Interleukin-3-Deficient Mice Have Increased Resistance to Blood-Stage Malaria

Cited by 19 publications

References 41 publications

Multi-omics Integrative Analysis of Acute and Relapsing Malaria in a Non-Human Primate Model ofP. vivaxinfection

Multi-omics Integrative Analysis of Acute and Relapsing Malaria in a Non-Human Primate Model ofP. vivaxinfection

Generation of IL-3–Secreting CD4+ T Cells by Microbial Challenge at Skin and Mucosal Barriers

Splenic Innate B1 B Cell Plasmablasts Produce Sustained Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-3 Cytokines during Murine Malaria Infections

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