Intracellular pathogens promote their survival by targeting host signaling pathways that either turn off antimicrobial activities or activate events that support their replication and/or survival of the host cell. The parasite Toxoplasma gondii introduces an array of proteins from specialized organelles (rhoptries and dense granules) into infected cells, and a small number of these proteins have been shown to modify host signaling, including STAT and NF-κB pathways.

In this issue, Ma et al. identify a novel role for GRA6 (a dense granule protein) in activating the transcription factor NFAT4 in the host cell. This activity is mediated through the interaction of the C-terminal domain of GRA6 with the host protein calcium modulating ligand (CAMLG). The authors show that the parasite needs GRA6 for full virulence in mice, as shown by parasite burdens measured by luminescence imaging (pictured). At the local site of infection, GRA6 activation of NFAT4 is required for chemokine production and recruitment of monocytes and neutrophils which, when infected, promote parasite dissemination.

These findings may explain why certain T. gondii strains with polymorphisms in the C terminus of GRA6 are less virulent in mice. As T. gondii infects a wide variety of hosts, these polymorphisms could reflect specialization of different parasite strains for different hosts.

Ma et al. link T. gondii virulence to NFAT for the first time and add GRA6 to the small number of rhoptry and dense granule proteins known to modulate host signal transduction. However, there are hundreds of parasite proteins introduced into host cells whose functions are not known. With the new technical advances in parasite and host genetics, it should now be possible to systematically delete each of these secreted proteins in multiple parasite strains and use these mutants to define their impact on different host responses.

J. S.
, et al
J. Exp. Med.