RNA Arms Race

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.

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.

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.

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.