SummaryA major part of virulence for Plasmodium falciparum malaria infection, the most lethal parasitic disease of humans, results from increased rigidity and adhesiveness of infected host red cells. These changes are caused by parasite proteins exported to the erythrocyte using novel trafficking machinery assembled in the host cell. To understand these unique modifications, we used a large-scale gene knockout strategy combined with functional screens to identify proteins exported into parasite-infected erythrocytes and involved in remodeling these cells. Eight genes were identified encoding proteins required for export of the parasite adhesin PfEMP1 and assembly of knobs that function as physical platforms to anchor the adhesin. Additionally, we show that multiple proteins play a role in generating increased rigidity of infected erythrocytes. Collectively these proteins function as a pathogen secretion system, similar to bacteria and may provide targets for antivirulence based therapies to a disease responsible for millions of deaths annually.

Commitment to and completion of sexual development are essential for malaria parasites (protists of the genus Plasmodium) to be transmitted through mosquitoes1. The molecular mechanism(s) responsible for commitment have been hitherto unknown. Here we show that PBAP2-G, a conserved member of the ApiAP2 family of transcription factors, is essential for the commitment of asexually replicating forms to sexual development in P. berghei, a malaria parasite of rodents. PBAP2-G was identified from mutations in its encoding gene, PBANKA_143750, which account for the loss of sexual development frequently observed in parasites transmitted artificially by blood passage. Systematic gene deletion of conserved ApiAP2 genes in Plasmodium confirmed the role of PBAP2-G and revealed a second ApiAP2 member (PBANKA_103430, termed PBAP2-G2) that significantly modulates but does not abolish gametocytogenesis indicating that a cascade of ApiAP2 proteins are involved in commitment to the production and maturation of gametocytes. The data suggest a mechanism of commitment to gametocytogenesis in Plasmodium consistent with a positive feedback loop involving PBAP2G which might be exploited to prevent the transmission of this pernicious parasite.

SummarySerratia sp. ATCC 39006 (39006) uses a complex hierarchical regulatory network allowing multiple inputs to be assessed before genes involved in secondary metabolite biosynthesis are expressed. This taxonomically ill-defined Serratia sp. produces a carbapenem antibiotic (Car; a b b b b -lactam) and a red pigmented antibiotic, prodigiosin (Pig; a tripyrrole), which are controlled by the smaIR quorum sensing (QS) locus. SmaR is a repressor of Pig and Car when levels of Nacyl-L -homoserine lactones, produced by SmaI, are low. In this study, we demonstrate direct DNA binding of purified SmaR to the promoter of the Car biosynthetic genes and abolition of this binding by the QS ligand. We have also identified multiple new secondary metabolite regulators. QS controls production of secondary metabolites, at least in part, by modulating transcription of three genes encoding regulatory proteins, including a putative response regulator of the GacAS two-component signalling system family, a novel putative adenylate cyclase and Rap ( r egulator of a ntibiotic and p igment). Mutations in another gene encoding a novel predicted global regulator, pigP , are highly pleiotropic; PigP has a significant 'master' regulatory role in 39006 where it controls the transcription of six other regulators. The PigP protein and its homologues define a new family of regulators and are predicted to bind DNA via a helix-turn-helix domain. There are regulatory overlaps between the QS and PigP regulons that enable the information from different physiological cues to be funnelled into the control of secondary metabolite production.