Summary Protein secretion in eukaryotes and prokaryotes involves a universally conserved protein translocation channel formed by the Sec61 complex. Unrelated small-molecule natural products and synthetic compounds inhibit Sec61 with differential effects for different substrates or for Sec61 from different organisms, making this a promising target for therapeutic intervention. To understand the mode of inhibition and provide insight into the molecular mechanism of this dynamic translocon, we determined the structure of mammalian Sec61 inhibited by the Mycobacterium ulcerans exotoxin mycolactone via electron cryo-microscopy. Unexpectedly, the conformation of inhibited Sec61 is optimal for substrate engagement, with mycolactone wedging open the cytosolic side of the lateral gate. The inability of mycolactone-inhibited Sec61 to effectively transport substrate proteins implies that signal peptides and transmembrane domains pass through the site occupied by mycolactone. This provides a foundation for understanding the molecular mechanism of Sec61 inhibitors and reveals novel features of translocon function and dynamics.

Despite ongoing efforts, a highly effective vaccine against Plasmodium falciparum remains elusive. Vaccines targeting the pre-erythrocytic stages of the P. falciparum life cycle are the most advanced to date, affording moderate levels of efficacy in field trials. However, the discovery that the members of the merozoite PfRH5-PfCyRPA-PfRipr (RCR) complex are capable of inducing strain-transcendent neutralizing antibodies has renewed enthusiasm for the possibility of preventing disease by targeting the parasite during the blood stage of infection. With Phase I/II clinical trials now underway using firstgeneration vaccines against PfRH5, and more on the horizon for PfCyRPA and PfRipr, this review explores the rationale and future potential of the RCR complex as a P. falciparum vaccine target. Malaria Vaccine StatusGlobal malaria mortality and morbidity has declined sharply in recent decades. Still, in 2018 there were 228 million infections resulting in 405 000 deaths, disproportionately shouldered by the developing world [1]. Despite progress, malaria continues to be an intractable global health threat. Improved access to insecticide-impregnated bed nets, vector control, and the availability of effective antimalarial medications have been the cornerstones of global malaria control efforts and will continue to play indispensable roles. However, even optimal deployment of current tools will still leave elimination in high-transmission settings unattainable [2].A highly effective malaria vaccine would be one way to achieve further reductions in the global malaria burden. The observation that passive immunoglobulin (Ig) transfer confers immunity against malaria suggests that a malaria vaccine is conceivable [3]. One malaria vaccine candidate from GlaxoSmithKline, RTS,S/AS01, targets the circumsporozoite protein (CSP) and has now progressed beyond Phase III and into pilot implementation trials. This is a milestone for the malaria vaccine field and provides an important proof-of-principle for this approach; however, improvement is still required given that RTS,S/AS01 affords only partial protection of modest duration [4]. Nonetheless, this partial success gives strong impetus for continued effort and investment to develop a more effective next-generation malaria vaccine.Currently, the field awaits proof-of-concept for a substantially improved CSP-based vaccine, while whole-sporozoite strategies still face challenges with regard to scalability, immunogenicity in African infants, and breadth of protection [5,6]. An alternative and complementary approach would be to include a vaccine targeting the subsequent pathogenic blood stage of infection; this would have the potential to protect against malaria death, disease, and transmission. This review focuses on the recently described PfRH5-PfCyRPA-PfRipr (RCR) complex, an elongated protein trimer formed on the P. falciparum merozoite surface that binds to erythrocyte basigin, as a new and highly promising next-generation blood-stage vaccine (see Glossary) candidate (Figure 1A). I...

Supplementary data are available at Bioinformatics online.

The IL-33-ST2 pathway is an important initiator of type 2 immune responses. We previously characterised the HpARI protein secreted by the model intestinal nematode Heligmosomoides polygyrus, which binds and blocks IL-33. Here, we identify H. polygyrus Binds Alarmin Receptor and Inhibits (HpBARI) and HpBARI_Hom2, both of which consist of complement control protein (CCP) domains, similarly to the immunomodulatory HpARI and Hp-TGM proteins. HpBARI binds murine ST2, inhibiting cell surface detection of ST2, preventing IL-33-ST2 interactions, and inhibiting IL-33 responses in vitro and in an in vivo mouse model of asthma. In H. polygyrus infection, ST2 detection is abrogated in the peritoneal cavity and lung, consistent with systemic effects of HpBARI. HpBARI_Hom2 also binds human ST2 with high affinity, and effectively blocks human PBMC responses to IL-33. Thus, we show that H. polygyrus blocks the IL-33 pathway via both HpARI which blocks the cytokine, and also HpBARI which blocks the receptor.

Persistent pathogens have evolved to avoid elimination by the mammalian immune system including mechanisms to evade complement. Infections with African trypanosomes can persist for years and cause human and animal disease throughout sub-Saharan Africa. It is not known how trypanosomes limit the action of the alternative complement pathway. Here we identify an African trypanosome receptor for mammalian factor H, a negative regulator of the alternative pathway. Structural studies show how the receptor binds ligand, leaving inhibitory domains of factor H free to inactivate complement C3b deposited on the trypanosome surface. Receptor expression is highest in developmental stages transmitted to the tsetse fly vector and those exposed to blood meals in the tsetse gut. Receptor gene deletion reduced tsetse infection, identifying this receptor as a virulence factor for transmission. This demonstrates how a pathogen evolved a molecular mechanism to increase transmission to an insect vector by exploitation of a mammalian complement regulator.