Translocation of Sickle Cell Erythrocyte MicroRNAs into Plasmodium falciparum Inhibits Parasite Translation and Contributes to Malaria Resistance
TL;DR: Sickle cell erythrocytes exhibit cell-intrinsic resistance to malaria in part through an atypical miRNA activity, which may represent a unique host defense strategy against complex eukaryotic pathogens.
About: This article is published in Cell Host & Microbe.The article was published on 2012-08-16 and is currently open access. It has received 266 citations till now. The article focuses on the topics: Plasmodium falciparum.
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TL;DR: It is shown that host Arabidopsis cells secrete exosome-like extracellular vesicles to deliver sRNAs into fungal pathogen Botrytis cinerea, which induce silencing of fungal genes critical for pathogenicity.
Abstract: Some pathogens and pests deliver small RNAs (sRNAs) into host cells to suppress host immunity. Conversely, hosts also transfer sRNAs into pathogens and pests to inhibit their virulence. Although sRNA trafficking has been observed in a wide variety of interactions, how sRNAs are transferred, especially from hosts to pathogens and pests, is still unknown. Here, we show that host Arabidopsis cells secrete exosome-like extracellular vesicles to deliver sRNAs into fungal pathogen Botrytis cinerea . These sRNA-containing vesicles accumulate at the infection sites and are taken up by the fungal cells. Transferred host sRNAs induce silencing of fungal genes critical for pathogenicity. Thus, Arabidopsis has adapted exosome-mediated cross-kingdom RNA interference as part of its immune responses during the evolutionary arms race with the pathogen.
616 citations
TL;DR: RMVs demonstrate potent immunomodulatory properties on human primary macrophages and neutrophils and stimulate production of transmission stage parasites in a dose-dependent manner, which mediate cellular communication within the parasite population and with the host innate immune system.
346 citations
Cites background from "Translocation of Sickle Cell Erythr..."
...It has recently been demonstrated that parasite-infected sickle cell RBCs produce miRNAs that can translocate into the parasite where they interfere with protein translation and induce formation of gametocytes (LaMonte et al., 2012)....
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TL;DR: This review highlights the current studies that focus on the identification of circulating miRNA-based diagnostic and prognostic markers, for the most prevalent types of cancer.
270 citations
TL;DR: This work has shown that RNA-binding proteins and noncoding RNAs have roles in the development and function of the immune system and in pathogen life cycles, and they represent an important aspect of intracellular immunity.
Abstract: The rapid changes in gene expression that accompany developmental transitions, stress responses and proliferation are controlled by signal-mediated coordination of transcriptional and post-transcriptional mechanisms. In recent years, understanding of the mechanics of these processes and the contexts in which they are employed during hematopoiesis and immune challenge has increased. An important aspect of this progress is recognition of the importance of RNA-binding proteins and noncoding RNAs. These have roles in the development and function of the immune system and in pathogen life cycles, and they represent an important aspect of intracellular immunity.
166 citations
TL;DR: The genetic theory of infectious diseases is presented and illustrated by highlighting inborn errors of immunity underlying eight life-threatening infectious diseases of children and young adults, and the far-reaching biological and clinical implications of the ongoing human genetic dissection of severe infectious diseases are considered.
Abstract: Until the mid-nineteenth century, life expectancy at birth averaged 20 years worldwide, owing mostly to childhood fevers. The germ theory of diseases then gradually overcame the belief that diseases were intrinsic. However, around the turn of the twentieth century, asymptomatic infection was discovered to be much more common than clinical disease. Paradoxically, this observation barely challenged the newly developed notion that infectious diseases were fundamentally extrinsic. Moreover, interindividual variability in the course of infection was typically explained by the emerging immunological (or somatic) theory of infectious diseases, best illustrated by the impact of vaccination. This powerful explanation is, however, best applicable to reactivation and secondary infections, particularly in adults; it can less easily account for interindividual variability in the course of primary infection during childhood. Population and clinical geneticists soon proposed a complementary hypothesis, a germline genetic theory of infectious diseases. Over the past century, this idea has gained some support, particularly among clinicians and geneticists, but has also encountered resistance, particularly among microbiologists and immunologists. We present here the genetic theory of infectious diseases and briefly discuss its history and the challenges encountered during its emergence in the context of the apparently competing but actually complementary microbiological and immunological theories. We also illustrate its recent achievements by highlighting inborn errors of immunity underlying eight life-threatening infectious diseases of children and young adults. Finally, we consider the far-reaching biological and clinical implications of the ongoing human genetic dissection of severe infectious diseases.
141 citations
References
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TL;DR: Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.
32,946 citations
"Translocation of Sickle Cell Erythr..." refers background in this paper
...Human miRNAs Form Chimeric Fusion RNAs with P. falciparum mRNA Mammalian miRNAs typically regulate their target mRNAs through partial base pairing with the 30 untranslated region, Cell Hos mediated by a ribonucleoprotein complex composed of Dicer/ Ago proteins (Bartel, 2004)....
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...Cell Hos mediated by a ribonucleoprotein complex composed of Dicer/ Ago proteins (Bartel, 2004)....
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TL;DR: MicroRNA (miRNA) control has emerged as a critical regulatory principle in the mammalian immune system and severely compromises immune development and response and can lead to immune disorders like autoimmunity and cancer.
1,016 citations
"Translocation of Sickle Cell Erythr..." refers background in this paper
...Host immune responses have been widely reported to be regulated by small RNAs, including miRNAs (Lodish et al., 2008; Xiao and Rajewsky, 2009)....
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...Mutation of components of the miRNA machinery or loss of specific miRNAs have been shown to profoundly compromise immune cell development and both innate and adaptive immunity, indicating that miRNA biology plays diverse roles in mammalian immune responses (Lodish et al., 2008; Xiao and Rajewsky, 2009)....
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...…of components of the miRNA machinery or loss of specific miRNAs have been shown to profoundly compromise immune cell development and both innate and adaptive immunity, indicating that miRNA biology plays diverse roles in mammalian immune responses (Lodish et al., 2008; Xiao and Rajewsky, 2009)....
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TL;DR: It is shown that a cellular microRNA effectively restricts the accumulation of the retrovirus primate foamy virus type 1 (PFV-1) in human cells and has direct antiviral effects in addition to their regulatory functions.
Abstract: In eukaryotes, 21- to 24-nucleotide-long RNAs engage in sequence-specific interactions that inhibit gene expression by RNA silencing. This process has regulatory roles involving microRNAs and, in plants and insects, it also forms the basis of a defense mechanism directed by small interfering RNAs that derive from replicative or integrated viral genomes. We show that a cellular microRNA effectively restricts the accumulation of the retrovirus primate foamy virus type 1 (PFV-1) in human cells. PFV-1 also encodes a protein, Tas, that suppresses microRNA-directed functions in mammalian cells and displays cross-kingdom antisilencing activities. Therefore, through fortuitous recognition of foreign nucleic acids, cellular microRNAs have direct antiviral effects in addition to their regulatory functions.
943 citations
"Translocation of Sickle Cell Erythr..." refers background in this paper
...Host miRNAs have also been shown to directly target sequences in viral RNA genomes to suppress virus replication (Lecellier et al., 2005)....
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TL;DR: It is observed posttranscriptional gene silencing through translational repression of messenger RNA during sexual development, and a 47-base 3′ untranslated region motif is implicated in this process.
Abstract: Plasmodium berghei and Plasmodium chabaudi are widely used model malaria species. Comparison of their genomes, integrated with proteomic and microarray data, with the genomes of Plasmodium falciparum and Plasmodium yoelii revealed a conserved core of 4500 Plasmodium genes in the central regions of the 14 chromosomes and highlighted genes evolving rapidly because of stage-specific selective pressures. Four strategies for gene expression are apparent during the parasites' life cycle: (i) housekeeping; (ii) host-related; (iii) strategy-specific related to invasion, asexual replication, and sexual development; and (iv) stage-specific. We observed posttranscriptional gene silencing through translational repression of messenger RNA during sexual development, and a 47-base 3' untranslated region motif is implicated in this process.
815 citations
"Translocation of Sickle Cell Erythr..." refers background in this paper
...falciparum lacks orthologs for Dicer/Ago (Baum et al., 2009; Hall et al., 2005), it is unclear how human miRNAs might affect parasites....
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...Since P. falciparum lacks orthologs for Dicer/Ago (Baum et al., 2009; Hall et al., 2005), it is unclear how human miRNAs might affect parasites....
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TL;DR: A large-scale, high-accuracy mass spectrometric proteome analysis of selected stages of the human malaria parasite Plasmodium falciparum revealed 1,289 proteins that contain domains that indicate a role in cell–cell interactions, and therefore can be evaluated as potential components of a malaria vaccine formulation.
Abstract: The annotated genomes of organisms define a 'blueprint' of their possible gene products. Post-genome analyses attempt to confirm and modify the annotation and impose a sense of the spatial, temporal and developmental usage of genetic information by the organism. Here we describe a large-scale, high-accuracy (average deviation less than 0.02 Da at 1,000 Da) mass spectrometric proteome analysis of selected stages of the human malaria parasite Plasmodium falciparum. The analysis revealed 1,289 proteins of which 714 proteins were identified in asexual blood stages, 931 in gametocytes and 645 in gametes. The last two groups provide insights into the biology of the sexual stages of the parasite, and include conserved, stage-specific, secreted and membrane-associated proteins. A subset of these proteins contain domains that indicate a role in cell-cell interactions, and therefore can be evaluated as potential components of a malaria vaccine formulation. We also report a set of peptides with significant matches in the parasite genome but not in the protein set predicted by computational methods.
667 citations
"Translocation of Sickle Cell Erythr..." refers background in this paper
...Moreover, multiple mass spectrometry studies of PKA-R during a variety of Plasmodium life-cycle stages show peptide hits only from exon 2 and beyond, suggesting that the shorter transcript may be the dominantly translated form (Lasonder et al., 2002; Lasonder et al., 2008)....
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