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RNA Arms Race

Mohamed-Ali Hakimi and Robert Ménard RNA Arms Race Do parasites use their own microRNAs to hijack host cell pathways? Red blood cells infected with the Plasmodium falciparum parasite. GARY D. GAUGLER / PHOTO RESEARCHERS, INC. RNA silencing, which fine tunes up to 30% of genome during development,1 also plays a major role in innate antiviral and antibacterial defenses in plants, insects, and animals. But

By | August 1, 2010

RNA Arms Race

Do parasites use their own microRNAs to hijack host cell pathways?

Red blood cells infected with the Plasmodium falciparum parasite.
GARY D. GAUGLER / PHOTO RESEARCHERS, INC.

RNA silencing, which fine tunes up to 30% of genome during development,1 also plays a major role in innate antiviral and antibacterial defenses in plants, insects, and animals. But the sword cuts both ways, with bacteria and viruses undermining the host’s microRNA (miRNA)-based defenses to allow their own successful replication. For example, the hepatitis C virus appears to control a host miRNA to promote its own replication,2 and in plants, the bacterium Pseudomonas syringae interferes with host processes that normally suppress bacterial replication by using a bacterial E3-ubiquitin ligase to degrade a host miRNA.3

New research is pointing to ways that the host cell mobilizes its miRNA machinery to fight intracellular eukaryotic parasites in addition to bacteria and viruses. The results offer the possibility that parasites may have developed tactics to use these defenses to their advantage, remarkably by using their own small RNA.

Infection responders

The causative agents of malaria ( Plasmodium falciparum), the diarrheal illness cryptosporidiosis ( Cryptosporidium parvum ), and toxoplasmosis ( Toxoplasma gondii ) which causes flu-like symptoms but can also induce miscarriage—are parasites of the phylum Apicomplexa. They can only survive and replicate inside host cells, and between them account for about 3 million deaths each year.

There’s growing evidence that the host uses miRNA to control the growth of these parasites.4 For example, in response to infection by Cryptosporidium, cells down-regulate miRNA let-7i, which increases a key pathogen recognition molecule, TLR4.5 Similarly, after Cryptosporidium infects epithelial cells, specific miRNA clusters of genes are activated by the transcription complex NF- κB, a component of a well-studied anti-pathogen pathway. The experimental inhibition of this group of miRNAs increases the parasite burden. MicroRNA expression is also altered in host cells following Toxoplasma infection, where the transcription of miRNA miR-17~92 is specifically increased, although it’s unclear whether the response is initiated by the host cell or the parasite. On the other hand, levels of this miRNA remained unchanged upon infection by the closely related parasite Neospora caninum.6 Cells therefore marshal their defenses to different parasites in very specific ways.

Parasites strike back

Hosts and their pathogens evolve together. As host cells developed miRNA strategies to defend against intracellular assault, the parasites may have also evolved methods to subvert those same defenses. The big question for the field now is which changes in the host cell miRNA pattern are due to host defense mechanisms, and which to the parasite’s subversion strategy? An answer might come from looking at the parasite’s own small RNAs.

The big question for the field now is which changes in the host cell miRNA pattern are due to host defense mechanisms, and which to the parasite’s subversion strategy?

Unlike Cryptosporidium and Plasmodium, Toxoplasma has an elaborate RNA silencing machinery that generates endogenous small, silencing RNAs.7 In fact, this machinery is functionally and phylogenetically related to that of plants and fungi, and produces an exceptionally diverse array of miRNAs. Additionally, the accumulation of microRNAs in Toxoplasma is sometimes extremely high and dynamic, rather like what is seen in animals. Therefore, it’s possible that Toxoplasma uses its own host-like miRNAs to hijack the target cell’s miRNA defense pathway, just as some viruses do.

Toxoplasma and other Apicomplexa offer a unique model system for studying the evolution and molecular mechanisms of RNA silencing among eukaryotes, presenting an exciting opportunity to deepen our understanding of how the host proteome can be reprogrammed dynamically and reversibly, and provide insights into the potential control of important parasites involved in human disease.

Mohamed-Ali Hakimi is from the Université Joseph Fourier Grenoble in France, and Faculty Member Robert Ménard is from the Pasteur Institute in France.

1. A. Grimson et al., “MicroRNA targeting specificity in mammals: determinants beyond seed pairing,” Mol Cell, 27:91–105, 2007.
2. C.L. Jopling et al., “Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA,” Science, 309:1577–81, 2005. F1000 Factor 6.4 http://bit.ly/miRNAmodHCV
3. L. Navarro et al., “Suppression of the microRNA pathway by bacterial effector proteins,” Science, 321:964–67, 2008. F1000 Factor 6.5 http://bit.ly/miRNAsuppr
4. C.G. Lüder et al., “Intracellular survival of apicomplexan parasites and host cell modification,” Int J Parasitol, 39:163–73, 2009.
5. X.M. Chen et al., “A cellular micro-RNA, let-7i, regulates Toll-like receptor 4 expression and contributes to cholangiocyte immune responses against Cryptosporidium parvum infection,” J Biol Chem, 282:28929–38, 2007.
6. G.M. Zeiner et al., “ Toxoplasma gondii infection specifically increases the levels of key host microRNAs,” PLoS One , 5:e8742, 2010.
7. L. Braun et al., “A complex small RNA repertoire is generated by a plant/fungal-like machinery and effected by a metazoan-like Argonaute in the single-cell human parasite Toxoplasma gondii,” PLoS Pathogens, 6:e1000920, 2010. F1000 Factor 3.0 http://bit.ly/miRNAtoxo

This article is an adaptation of an article published in F1000 Biology Reports, a publication of the Faculty of 1000. For the full-length version, click here. F1000 Biology consists of more than 2,000 leading biologists (Faculty Members) who select and review the most important published papers in their respective fields (Faculties). The next two pages describe recent selections from various Faculties.

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Comments

August 17, 2010

This is a great article on microRNAs (miRNAs) and the immune system which makes me think about the interplay between infection by a pathogen, miRNAs, and cancer. MiRNAs are well known to be over/under expressed in cancer tissues, and given the link between cancer and viruses (e.g. cervical cancer) it prompts me to think if perhaps miRNAs induced by viral infection could be an initiating factor in cancer. An interesting question would be: do cells that have an increased expression of miRNAs in response to a viral infection always return to normal after the virus is cleared? Also, are there also some common miRNAs that are increase in response to infection and in cancer cells?\n\nAnother interesting point is that viruses and other pathogens can also produce homologues to human miRNAs. This seems obvious in hind sight that viruses would produce miRNA that mimic human miRNAs as they are already known to produce many cytoknine mimics to thwart recognition by the immune system.\n\nwww.thescientistsperspective.com
Avatar of: Christopher Lee

Christopher Lee

Posts: 50

August 17, 2010

This short article (the full version isn't open access) is a bit frustrating. It doesn't say which of the parasites are specific for homo sapiens; this information may be a key indicator of competitive evolution. Apparantly human red cells have been quite badly messed up by the battle with plasmodium.\n\nNor does it refer to the presence of a plant-derived organelle in plasmodium.

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Mettler Toledo
BD Biosciences
BD Biosciences