the phylum apicomplexa includes a large group of protozoan parasites responsible for a wide range of animal and human diseases . among the human pathogens are plasmodium falciparum and plasmodium vivax , the major causative agents of human malaria , as well as cryptosporidium parvum and toxoplasma gondii , which are particularly pathogenic in immunocompromised patients .
apicomplexa are intracellular obligatory parasites that multiply in a so - called parasitophorous vacuole . although the alterations of the host cell harboring toxoplasma or plasmodium parasites have been extensively documented at the cellular level , still little is known about how the parasite manipulates the host cell at the molecular level , with the notable exception of plasmodium infection of host erythrocytes .
so far , most molecular studies on the host - parasite interface have focused on the role of parasite factors that are secreted by the invading parasite , as well as by the resident intracellular parasite , into the host cell .
these intracellular parasites are expected to profoundly reorganize the host cell for their own needs to ensure safe growth and persistence , and presumably to deploy the most sophisticated mechanisms to this end .
emerging evidence indicates that viruses and bacteria manipulate the microrna ( mirna ) pathways of the host cells they infect .
mirnas are the most abundant class of small , non - coding , single - stranded rnas and are involved in regulating gene expression at the post - transcriptional level . in silico target prediction
suggests that mirnas may control up to 30% of the translation of the human transcriptome . as such
, they govern a variety of fundamental cell functions , including cell proliferation and apoptosis , and are key regulators of cell metabolism . when homeostatic conditions are disrupted - for example , when cells encounter micro - organisms - these regulatory pathways might also contribute to host cell responses / defenses ( i.e. , the inflammatory response ) against the foreign bodies .
for example , cell infection by mammalian viruses might be counteracted by cellular mirnas that target either the virus itself , as in the case of the rhabdoviral vesicular stomatitis virus , or a host factor critical to the virus , as for the lentiviral hiv .
conversely , mirnas can also act in favor of the micro - organism , either when it is pathogen - encoded ( e.g. , mammalian virus - encoded mirnas ) or when the micro - organism subverts host mirnas to its own benefit .
effectors from the bacteria pseudomonas syringae have been recently shown to suppress transcriptional activation of some mirnas generated upon sensing of pamps ( pathogen - associated molecular patterns ) by arabidopsis .
recent data have begun to show how two apicomplexan parasites , cryptosporidium and toxoplasma , are able to target mirnas in the host cell to alter the cellular environment in ways that favor their intracellular development .
cryptosporidium is able to trigger the down - regulation of let-7i ( a mirna with complementarity to toll - like receptor ( tlr)-4 mrna ) in the host cell , leading to the up - regulation of tlr4 , a key pathogen recognition molecule that plays a central role in epithelial innate immunity to cryptosporidium infection .
various studies have further substantiated the ability of cryptosporidium to alter mirna expression in cholangiocytes [ 9 - 11 ] .
it is emerging from these studies that following cryptosporidium infection , specific mirna cluster genes are activated by the binding of the nf-b ( nuclear factor - kappa b ) p65 subunit to their promoter , and that inhibition of these mirnas increases parasite burden .
these results mirror those showing differential alterations in mature mirna expression profiles in primary human fibroblast cells following toxoplasma infection .
zeiner et al .   showed that toxoplasma infection specifically increased the transcription of the mir-17/92 loci by two- to three - fold in human fibroblasts .
the effect is apparently a specific response to toxoplasma infection since levels of the mature mir-17/92-derived mirnas remained unchanged upon infection by the closely related parasite neospora caninum .
microarray data comparing the mirna profiles of cells infected by toxoplasma or cryptosporidium or treated with lipopolysaccharide ( lps ) have revealed several important findings .
for example , mir-155/bic is up - regulated upon toxoplasma infection but remains unaffected or is down - regulated when exposed to cryptosporidium or lps , respectively . of note
, mir-155 has an important role in the mammalian immune system , regulating , at least in part , cytokine production .
two other mirnas , mir-198 and mir-320 , are both up - regulated upon toxoplasma infection whereas they are down - regulated after cryptosporidium infection and unaffected after lps stimulation .
these data point to specific modifications of host mirna profiles upon cell infection by apicomplexa parasites .
obviously , any change in the host cell mirna pattern might indicate either a defense mechanism by the cell or a subversion strategy by the parasite , two processes that can be differentiated by evaluating the consequences on parasite growth of disruption or over - expression of the target mirna pathway .
given the propensity of apicomplexan parasites to co - opt cellular pathways and activities for their benefit , it is perhaps not surprising that these parasites could also reshape their cellular environment by reprogramming the host s rna interference machinery .
specific host mirnas could either counteract the intracellular growth of parasites or facilitate it , the two possibilities being not mutually exclusive and depending on the physiological context .
these findings open an exciting opportunity to pursue a deep understanding of how the host proteome can be reprogrammed dynamically and reversibly upon apicomplexa infection .
an additional line of research should explore the upstream regulatory mechanisms , that is , how the parasites directly interfere with rna silencing pathways and , more specifically , the parasite effectors that are involved in the process . as discussed above , in response to cryptosporidium and toxoplasma infections , the expression of specific mirna genes is altered at the transcriptional level .
mirna are generated through the concerted action of multi - subunit complexes that promote the sequential cleavage , export , and loading of mirna into silencing complexes .
an increasing number of reports suggest that , beyond the transcriptional control of genes that code cluster mirnas , each of these steps serves as a potential point of regulation , and therefore adds additional complexity to mirna - dependent gene regulation
. could parasite regulators of host mirnas be ribonucleic acids ? unlike in cryptosporidium and plasmodium species , the toxoplasma genome encodes elaborate rna silencing machinery that generates endogenous small silencing rnas , including specific mirnas .
thus , an attractive hypothesis is that toxoplasma has the potential to secrete its own mirnas to hijack the host cell mirna defense pathway , similar to what some viruses are able to do .
it is known that apicomplexan parasites inject various molecules into the host cell resulting in extensive remodeling of the host cell gene expression profile and metabolic pathways [ 17 - 19 ] .
the expression of host mirnas can also be altered in response to parasite recognition by cell surface tlrs .
both intrinsic and extrinsic acting factors could then interfere with target host mirnas , at any point of the processing of the pri - mirnas and biogenesis of the mirnas - transcription , processing , or export .
 rna silencing plays an important role in development through the action of micrornas , which fine tune the expression of a large portion of the genome . 
 it is also very important in innate immune responses , especially in antiviral and antibacterial defenses in plants , insects , and animals . 
 two recent papers now indicate that apicomplexan parasites display the ability to interfere with host microrna populations . 