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The Wellcome Trust is a global charitable foundation dedicated to achieving improvements in human and animal health. The company supports biomedical research and the medical humanities, including public engagement, education and the application of research to improve health. Funding focuses on supporting outstanding research, accelerating the application of research and exploring medicine in historical and cultural contexts.

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Sep 21, 2023
Abstract Following endocytosis, enveloped viruses employ the changing environment of maturing endosomes as cues to promote endosomal escape, a process often mediated by viral glycoproteins. We previously showed that both high [K+] and low pH promote entry of Bunyamwera virus (BUNV), the prototypical bunyavirus. Here, we use sub-tomogram averaging and AlphaFold, to generate a pseudo-atomic model of the whole BUNV glycoprotein envelope. We unambiguously locate the Gc fusion domain and its chaperone Gn within the floor domain of the spike. Furthermore, viral incubation at low pH and high [K+], reminiscent of endocytic conditions, results in a dramatic rearrangement of the BUNV envelope. Structural and biochemical assays indicate that pH 6.3/K+ in the absence of a target membrane elicits a fusion-capable triggered intermediate state of BUNV GPs; but the same conditions induce fusion when target membranes are present. Taken together, we provide mechanistic understanding of the requirements for bunyavirus entry. Introduction The Bunyavirales constitute the largest order of enveloped negative-sense RNA viruses with over 500 named isolates. Within this group, members of the Hantaviridae, Nairoviridae, Phenuiviridae and Peribunyaviridae families possess tri-segmented genomes 1 that minimally encode an RNA-dependent RNA-polymerase (L), a nucleocapsid (N) protein that encapsidates the genomic segments forming ribonucleoproteins (vRNPs), and two viral glycoproteins (GPs) Gn and Gc, which form spikes projecting from the viral envelope 2 . Several members of these families are serious human pathogens, including La Crosse virus (LACV) (Peribunyaviridae family) which causes severe neurological encephalitis and Crimean-Congo haemorrhagic fever virus (Nairoviridae family) which carries a 30% fatality rate. However, no vaccines or antiviral therapies to prevent their associated disease in humans have been approved 3 , 4 . Bunyaviruses enter cells through the endocytic system, releasing their genomes following fusion between their envelope and vesicular membranes, mediated by the Gn-Gc spikes, which together comprise the fusion machinery. For the prototypic model peribunyavirus, Bunyamwera virus (BUNV), a low-resolution subtomogram average (STA) of the BUNV Gn-Gc ( ~ 30 Å) previously revealed an unusual tripod-like structure of the GPs, forming a local lattice-like arrangement of trimers on the virus surface 5 . Three regions of the GP tripod were termed the head (apex of the tripod; viral membrane-distal), stalk (connects head-floor) and the floor region (membrane-proximal). More recently, it was identified that the head and stalk regions are formed by the first half of the Gc ectodomain by solving the crystal structures of the head domains from the peribunyaviruses BUNV, Oropouche virus (OROV) and LACV, and the head/stalk domains from Schmallenberg virus (SBV) 6 . The membrane-proximal floor region is therefore predicted to contain the remaining half of the Gc ectodomain, which includes the fusion domain, and the entire Gn ectodomain. While there are no published structures of Gn, an AlphaFold model of LACV Gn alone was previously generated 7 , however without a complete structure of Gn-Gc or a higher resolution map the interpretation of this model is limited. In structures of related bunyavirus Gn-Gc complexes (Phenuiviridae: Rift Valley fever virus (RVFV) and Hantaviridae: Tula virus (TULV) and Andes virus (ANDV)) the fusogenic protein Gc adopts a class II fusion fold, and Gn acts as the shielding subunit typically overtopping Gc 8 , 9 . Thus Gn is likely involved in protecting the fusion loops and mediating initial contact with the target cells 10 , 11 . Compared to these orthologous systems, peribunyaviruses possess a relatively small Gn ( ~ half the size; 186 residue ectodomain for BUNV) and a Gc around twice the size (910 residue ectodomain for BUNV) (Fig. 1a ) 10 , 11 . This suggests that the functions of these proteins may not be identical across bunyavirus families, which coupled with the scarcity of peribunyavirus structures available has limited our structural understanding. Fig. 1: BUNV GPs exhibit a trimeric tripod-like architecture. a Schematic of the M segment polyprotein constituted by Gn, NSm (non-structural protein) and Gc. The Gc protein is comprised of three sections: the head (blue), stalk (green) and floor (gold) regions. The fusion loop (fl; orange) resides in the floor region. Arrowheads indicate cleavage sites, black bars the predicted TMDs, numbers the amino acid residues, and ‘Y’ the glycans N60 (Gn, ♦) and N624 (Gc, *) 6 , 31 , 32 , 34 . b Cryo-ET tilt series were collected of BUNV virions (buffer: pH 7.3/no K+), then 3D tomographic reconstructions were calculated (14 tomograms). Slices through tomograms of two virions are shown (representative of 71 virions, full tomogram section in Supplementary Fig. 5d ). c, d STA of over 20,000 GP spikes aligned through iterative refinements, generating a ~ 16 Å average (GS-FSC). Panels are sections through the electron density averages, showing a trimeric spike on top of the viral lipid bilayer (M; membrane). e, f Isosurface rendering of the GP trimer, identifying the three regions; head (light blue), stalk (light green) and floor (gold; where Gn also resides) on top of the viral membrane (grey). White arrowheads indicate a previously unresolved region in the floor. g, h The previously solved X-ray structures of the BUNV head (pdb: 6H3V; light blue) and SBV stalk (pdb: 6H3S; light green) domains 6 were fitted into our model. The glycosylation site N624 is indicated (purple circle). i, j A model of the local lattice arrangement of BUNV GPs, emphasizing the two C3 symmetry axes; one forming a tripod, and one in the floor region where three neighbouring tripods connect. Scale bars: b = 100 nm, d = 5 nm; e, i = 2 nm. The cues that trigger fusion often result from endosomal maturation, which might involve a gradual drop in intraluminal pH, changes in concentrations of other ions, or alterations to the lipid and protein composition of endosomal membranes 12 , dictating when and where fusion occurs. This prevents premature fusion in inappropriate compartments, which would jeopardize virus entry and infection 13 . For bunyaviruses, the events that lead to spike fusogenesis are incompletely characterised and indeed the structural steps in membrane fusion are often inferred from pre-fusion and post-fusion structures, and from what is known for class II fusion proteins of alphaviruses 7 , 11 . Many bunyaviruses require low pH to induce a fusogenic state and, for some, a high H+ concentration has been reported to be sufficient to establish post-fusion conformations in vitro and trigger interactions with liposomes 14 , 15 , 16 . Working with the model peribunyavirus BUNV, and the model nairovirus, Hazara virus (HAZV), we recently showed the current description of bunyavirus entry is over-simplistic. We showed that the concentration of K+ ions ([K+]) in endosomes, which is controlled by cellular K+ channels and increases as endosomes mature 17 , peaking in late endosomes, is an important cue for BUNV and HAZV entry. By blocking K+ channels pharmacologically, we showed that disruption of endosomal K+ accumulation impeded BUNV infection by preventing endosomal release, and instead, viruses were trafficked to lysosomes, where they were degraded 18 , 19 , 20 . For HAZV, we further showed that elevated K+ alone (at pH 7.3) triggered conformational changes in the GP spikes and induced interactions with co-purified vesicles 21 . Additionally, it has recently been shown that disruption of the cellular K+ gradient using KCl or the K+ ionophore valinomycin inhibits infection by the peribunyaviruses LACV, Keystone virus and Germiston virus; and of the phenuivirus RVFV 22 , 23 , suggesting that K+ is broadly required during bunyavirus entry. Here, we used cryo-electron tomography (cryo-ET) to unravel the structure of the envelope of BUNV and to identify changes in the virion architecture at endosomal pH and [K+]. STA was performed to generate an average of the BUNV GPs that allowed us to fit published atomic models of specific regions of Gc 6 , and modelling both GPs (Gn and Gc) using AlphaFold 24 allowed us to generate a full pseudo-atomic model of the BUNV GP envelope. Furthermore, STA of pH 6.3/K+ treated virions revealed drastic changes in the GPs, including an uncoupling of Gn-Gc hetero-hexamers. Consistent with these structural data, biochemical assays confirmed that the structural changes elicited by K+ are localised to the floor region of the GP spikes. pH 6.3/K+ treated viruses also interacted more readily with target membranes, suggesting these conditions prompt exposure of the fusion loops, and when treatment occurs in the presence of a target membrane, it can trigger fusion. Results An improved STA of the BUNV GP permits modelling of the Gc and Gn hetero-hexameric arrangement To determine the arrangement of Gn and Gc in the BUNV spike by cryo-EM, WT BUNV was concentrated and purified as previously described 5 , 25 (Supplementary Fig. 1 ). Purified virions (in a pH 7.3/no K+ buffer) were then vitrified on cryo-EM grids. Cryo-ET tilt series were collected and 3D tomograms were reconstructed, revealing roughly spherical virions ( ~ 100 nm) in which the lipid bilayer with tripod-like spikes was clearly identifiable surrounding a core of tightly packed ribonucleoproteins (Fig. 1b ), as previously described 5 . STA was used to align and average ~20,000 spikes, which confirmed their tripodal arrangement, resolved at ~16 Å (by gold-standard (GS)-FSC Supplementary Fig. 2a and Supplementary Table 1 ). In this average, both leaflets of the viral membrane (‘M’) were clearly defined at the base, with a GP spike projecting ~16 nm from the surface (Fig. 1c, d ). Our STA showed distinguishable head, stalk and floor regions (Fig. 1e, f ), and a previously unidentified density protruding from the floor but shielded by the tripod head (Fig. 1e white arrowheads). Fitting of the previously determined X-ray structures of the head (BUNV) and stalk (SBV) domains into our model (Fig. 1g, h ) revealed a tight fit corresponding to cross-correlation values of 0.70 and 0.82 for the head and stalk domains, respectively. The fit of the head trimer allowed us to confirm the handedness of the average (Supplementary Fig. 2b, c ). By exclusion, the floor domain must contain the conserved class II fusion domain of Gc and Gn, however, specific arrangements could not be obtained from this average (Fig. 1g, h and Supplementary Movie 1 ). To further our understanding of the architecture of this floor domain, STA was performed focused on the floor region (Fig. 1i, j ) and resulted in an average at a slightly improved resolution of ~13 Å, as determined by GS-FSC (Supplementary Fig. 2a ). This average is thought to represent a hetero-hexameric assembly of a trimer of Gn and a trimer of the Gc floor region, which includes the fusion domains. In the floor domain, details were identified that were not resolved in the previously published STA 5 , highlighting the interconnected organisation of the fusion domains (Fig. 2a–d ). Three stalk domains were also resolved, which identify the connections to three independent tripods. A post-fusion structure of the fusion domain for the related peribunyavirus LACV has been recently solved (pdb: 7A57) 26 . LACV Gc exhibits a class II fusion domain and shares ~49% amino acid identity and ~69% amino acid similarity with the fusion domain of BUNV Gc. We therefore modelled a LACV pre-fusion domain, based on the differences between the pre-fusion and post-fusion conformations observed for other bunyavirus class II fusion domains, which in broad terms involve the rigid-body rearrangement of domain III (Supplementary Fig. 3 ) 9 , 14 , 27 , 28 . In addition, there was unoccupied density remaining in the floor region that could accommodate a trimer of Gn in the centre, allowing it to contact the Gc fusion domains and the viral membrane (Fig. 2e, f ). Fig. 2: STA of the floor region allows modelling of the BUNV fusion domain. STA was performed as in Fig. 1 , however aligning the floor region trimer (as opposed to the tripod). Over 16,000 subtomograms were aligned resulting in a ~ 13 Å resolution average (GS-FSC). a, b Sections through the electron density of the floor region average atop the viral membrane (M). c, d Isosurface rendering of the electron density (c side view, d top view) of the floor region (gold) atop the viral membrane (grey). Translucent tripods of the head-stalk (blue-green) regions have been added for orientation. e, f Modelling of the LACV fusion domain (residues 949–1344; domain I red, domain II yellow, domain III blue) in C3 symmetry within the BUNV floor region, revealing the location of the fusion loops (fl; orange) and remaining density that could be occupied by Gn (Gn? ; pink arrow) (post-fusion structure pdb: 7A57). The location of the head (light blue) and stalk (light green) domains are indicated in (e) for orientation. Scale bars: a, b = 5 nm; c, d = 2 nm. Discussion We previously demonstrated that for BUNV low pH and K+ treatment, and for HAZV neutral pH and K+ treatment expedite infection 19 , 21 . However, mechanistic insight was limited owing to the low resolution of the HAZV STA and lack of complete GP structures available for BUNV and HAZV. Here, we utilised BUNV to investigate the mechanistic and structural consequences of endosomal pH and K+ during BUNV entry using cryo-ET and STA. First, we improved the average of the BUNV spike, allowing us to fit structures of the BUNV head and SBV stalk, confirming previous predictions that the fusion domain resides in the floor region (Figs. 1 , 2 ) 5 , 6 . Our improved resolution of the floor region, coupled with an AlphaFold model of the complete BUNV Gn-Gc dimer, allowed us to model the whole viral ectodomain and demonstrates the hetero-hexameric 3x(Gn/Gc) assembly (Fig. 3g, h ). Additionally, the fitting of Gc in our subtomogram average shows by exclusion that Gn resides at the centre of the floor domain, connecting the stalks from three tripods, likely stabilising this region. This assembly resembles the organization of the Alphavirus envelope, in which three protomers of the class II fusion protein E1 laterally surround a trimeric core of its chaperone E2 36 . A similar assembly, with different stoichiometry, is also found in the hetero-octameric 4x(Gn-Gc) complex of the orthohantavirus envelope (Fig. 4e, h ) 9 . In contrast to other bunyaviruses however, our model of the BUNV envelope illustrates that the orthobunyavirus Gn cannot completely cover the Gc fusion domain (Fig. 4g ). The capping loop found at the tip of BUNV Gn is also shorter than that of hantaviruses, although it still partially shields the fusion loops (Fig. 4a, b ). Additionally, a strictly conserved N-linked glycan on the capping loop (residue N60) is likely maintained to allow direct interaction with the fusion loops on Gc, as described for hantaviruses 9 (Figs. 3 a, f and 4a ). This BUNV Gn glycan was previously shown to be essential for correct GP folding and successful virus rescue, suggesting an important function in the regulation of the pre/post-fusion switch 32 . The unique N-terminal half of the larger orthobunyavirus Gc appears to compensate for the small size of its Gn, being well positioned for receptor scavenging and indirectly shielding the fusion machinery (Figs. 3 , 4 and Supplementary Movie 1 ). These head and stalk domains of BUNV Gc are however dispensable for infection in vitro and are not involved in cell fusion or Golgi trafficking, indicating no role in other stages of infection 33 , 34 . Furthermore, our results show that the head and stalk domains are not required for virus triggering by pH 6.3/K+, indicating an effect of this condition on the floor region (Supplementary Fig. 7e–g ). With the shielding of the fusion loops, disassembly is required during fusion, similar to the glycoprotein rearrangement required for exposure of the fusion loops of RVFV, HTNV and ANDV 8 , 9 , 37 , 38 . As is established for class II fusion proteins 13 , this pre-fusion conformation disassembly is initiated by a biochemical trigger during entry which would elicit structural changes in the GPs to expose the fusion loops, permitting their interaction with endosomal membranes. This is what we observed upon pH 6.3/K+ treatment, where pH 6.3/K+ triggers the disassembly of the organised hetero-hexameric arrangement, generating an intermediate state that likely involves exposure of the fusion loops to target membranes. This is consistent with the K+ effects previously shown for HAZV, where K+ treatment triggered large structural changes in the GPs at neutral pH, causing elongation of the GP spikes and their association with co-purified membranes 21 . At a more acidic pH 5.0, loss of the ordered tetrameric arrangement is also observed for TULV (hantavirus) GPs 38 , and the elongation and membrane interaction of GP spikes of UUKV (phenuivirus) 39 . However, the requirement of K+ for TULV and UUKV entry has not been explored. For BUNV, if virions are pH 6.3/K+ treated when a target membrane is present, fusion can occur, as is shown with the acid-bypass (plasma membrane; Fig. 6b , lane 4) and liposome-virus fusion (Fig. 6e–h ) assays. These conditions are therefore sufficient to induce the subsequent structural rearrangements necessary for fusion (Fig. 7a ), suggesting that no other host factors are required. In the absence of a target membrane (in vitro pre-treatment), disassembly of the ordered GP arrangement (Fig. 5f–j ) establishes a conformation with enhanced binding to the cell post-treatment (Supplementary Fig. 8b, d ), however does not lead to an irreversible post-fusion conformation, as these viruses are still fusion-capable and infectious post-treatment. In addition, our previous work determined that endosomal H+ and K+ are still required post-in vitro-treatment at pH 6.3/K+ but to a lesser extent 19 , suggesting low pH and K+ are required for further structural changes in the fusion process beyond the initial disassembly (Fig. 7b , dotted line). Interestingly, previous studies on the BUNV GP suggested the occurrence of uncoupling at pH 5.1 in the absence of K+ 5 , later shown to render BUNV non-infectious 19 , therefore likely representing a post-fusion conformation. Fusion events have also been observed at pH 5.3 (no K+) using cell-cell fusion assays with BUNV GPs expressed on the surface of BHK cells 34 , 40 . Although in our 2 min acid-bypass assay pH 5.3/no K+ did not elicit fusion (Fig. 6a–c ), likely due to the short incubation time, the 2 hr liposome fusion assay did suggest that this condition can actually induce fusion (Supplementary Fig. 9a ). We also demonstrated that although pH 6.3/K+ was the pre-eminent condition at inducing fusion, pH 6.3/no K+ can also induce fusion in acid-bypass and liposome assays, suggesting the H+ alone can induce fusion (Fig. 6a–c and Supplementary Fig. 9a ). Compared to pH 6.3/K+, similar structural changes in BUNV may also be elicited at low pH alone (pH 6.3/no K+), which allows interactions with other virions (Fig. 5b ). However, the lack of virus-virus interactions in the presence of K+ at pH 6.3 suggests that K+ limits the effects of pH and prevents full exposure of the fusion domains. Interestingly, a post-fusion X-ray structure of HTNV Gc at pH 6.5 in the presence of KCl coordinates a K+ ion within domain II, at tyrosine residue Y105, which then forms different interactions and a more unstable arrangement 41 . A similar scenario may be true for the pH 6.3/K+ BUNV Gc, in which a K+ ion coordination may affect exposure or stability of the fusion loops, thereby preventing virion aggregation as the fusion loops cannot interact with one another. The fact that we cannot resolve a stable conformation of the pH 6.3/K+ GP spike is also suggestive of an unstable, flexible conformation (Fig. 5f–j ). Of note, for the orthobunyavirus Germiston virus, fusion can be induced at pH 6.0 and the endocytic switch from Na+ to K+ was also shown to be important for entry 23 . Although the effects of pH 6.0 with K+ on Germiston virus fusion were not investigated, this represents an interesting comparison and suggests a shared mechanism. In summary, we have determined the molecular arrangement of the Gc fusion domain and Gn within the floor domain of the BUNV spike, and additionally resolved drastic structural changes in the GP architecture in response to pH 6.3/K+, which in the presence of a target membrane can induce fusion. The ability of pharmacological K+ channel inhibitors to disrupt infection by a number of bunyaviruses from different families 18 , 21 , 22 , 42 , alongside the structural changes elicited by K+ on both BUNV and HAZV, which is potentially shared by other bunyaviruses, suggests a shared mechanism that could be exploited therapeutically. Methods Cells and viruses A549 (human alveolar carcinoma epithelial; 86012804), SW13 (human adrenal cortex carcinoma; 87031801) and BHK-21 (baby hamster kidney; 85011433) cells were obtained from the European Collection of Cell Cultures (ECACC). Cell lines were authenticated by ECACC and were routinely tested for mycoplasma. Cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM, Sigma) supplemented with 10% foetal bovine serum (FBS), 100 U/ml penicillin, and 100 µg/ml streptomycin, and maintained in a humidified incubator at 37 °C, with 5% CO2. Wild-type BUNV stocks (provided by Professor Richard Elliott, Glasgow Centre for Virus Research (CVR)) were generated from infected cell supernatants and titre estimated by plaque assay 18 , 19 . For infection assays, A549 cells were infected at an MOI = 0.1 unless otherwise specified. GFP-BUNV stocks were provided by Dr Xiaohong Shi (Glasgow CVR) and encoded an eGFP tag replacing residues 478-827 of the BUNV M segment (the Gc head and stalk regions) 33 . Wild-type human respiratory syncytial virus A2 strain (HRSV) was obtained from the National Collection of Pathogenic Viruses (NCPV; Public Health England) 43 . Virus purification BHK-21 cells were seeded into T175 flasks and infected with BUNV for 3 hr in FBS-free DMEM (MOI of 0.1). Media was replaced with 2% FBS DMEM and incubated until 44 hpi at 32 °C. Virus-containing supernatants were clarified by centrifugation and filtration (0.22 µm filter), and then virions were pelleted by ultracentrifugation (150,000 x g, 3 hr, 4 °C) through a 30% sucrose cushion 25 . Virions were resuspended in 0.1x phosphate-buffered saline (PBS, 0.1x to dilute the salts) by gentle rocking at 4 °C overnight. BUNV titres were determined by plaque assay, and purity was determined by silver staining and negative stain EM. Plaque assays Plaque assays were performed in SW13 cells as previously described 19 . Viral stocks were serially diluted from 10−1 to 10−6, and SW13 cells were infected for 1 hr at 37 °C. Infected cells were overlayed with 1.6% carboxy-methyl cellulose diluted equally in complete DMEM. After 6 days the overlay was removed, cells were fixed in 4% paraformaldehyde for 15 mins at 4 °C, stained with 1% crystal violet and the number of plaques counted to estimate viral titre. Silver staining During the BUNV purification 10 µl samples were collected of the pre-ultracentrifugation viral supernatant (snt), the post-ultracentrifugation snt, snt-sucrose interface, and sucrose. Samples were resolved by SDS-PAGE alongside 0.5 µl of purified BUNV and 1:100 diluted protein ladder, then fixed and stained following the silver staining kit (GE Healthcare) manufacturer’s instructions. Western blot At the indicated time points cells were lysed (25 mM glycerol phosphate, 20 mM tris, 150 mM NaCl, 1 mM EDTA, 1% triton X-100, 10% glycerol, 50 mM NaF, 5 mM Na4O7P2, pH 7.4), and western blotting was performed 19 , 43 . Proteins were resolved by SDS-PAGE and transferred onto polyvinylidene difluoride (PVDF; Millipore) membranes. After blocking in 10% (w/v) milk in TBS-T, the appropriate primary antibodies were added at 4 °C overnight: sheep α-BUNV-N (1:5000) produced by J N Barr, University of Leeds (antibody-containing serum was obtained from a sheep inoculated with BUNV-N protein previously expressed in E. coli and purified by affinity and size-exclusion chromatography detailed in Ariza et al. (2013) 44 ; and used extensively in previous publications 18 ); goat α-HRSV (1:1000; Abcam ab20745); mouse α-GAPDH (1:2000, Santa Cruz sc47724); or mouse α-GFP (1:1000; Santa Cruz sc-9996). This was followed by the corresponding HRP-conjugated secondary antibodies (Merck α-sheep A3415; α-goat A8919; α-mouse A4416) for 1 hr. Labelling was detected using enhanced chemiluminescence (Advansta) and a G:Box processor. Densitometry was performed using ImageJ, showing standard deviation error bars and statistical significance determined using a one-way ANOVA where P < 0.05. Full uncropped blots and densitometry data can be found in the Source Data file. Immunofluorescence staining After the indicated infection times, cells were washed with PBS and then fixed for 15 mins at 4 °C with 4% paraformaldehyde. Fixed cells were permeabilised with 50% methanol/acetone, blocked in 1% bovine serum albumin (in PBS) for 30 mins and labelled using α-BUNV-N primary antibodies (1:5000) for 1 hr, followed by α-sheep Alexa-fluor-594 or -488 fluorescent secondary antibodies added 1:500 for 1 hr (Thermo Scientific A11016 and A11015 respectively). As specified, fluorescence was imaged using the IncuCyte ZOOM imaging system, or coverslips were mounted onto glass slides (ProLong Gold Anti-Fade reagent; Invitrogen) and imaged using a Zeiss Confocal LSM880 upright microscope (40x magnification). In vitro acid pre-treatment assays BUNV acid pre-treatment assays were previously optimised, including assessment of a range of time points, ionic buffers and physiological KCl concentrations 19 . Therefore, these in vitro treatment assays are from established protocols and were performed as previously described. Any adaptations are highlighted. BUNV was incubated pre-infection at 37 °C for 2 hrs in a range of buffers: pH 7.3 (20 mM tris), pH 6.3 (30 mM bis-tris) or pH 5.3 (50 mM sodium citrate) supplemented with 10 mM NaCl (to maintain osmolarity), with or without 140 mM KCl (‘K+’ vs ‘no K+’). Buffer was diluted out with DMEM prior to infection of A549 cells at a MOI of 0.1 for the indicated times (hpi), after which cells were lysed and BUNV infection assessed by western blot. Cell lysis at 18 hpi represents the exponential phase of BUNV infection (where pH 6.3/K+ expedited entry at BUNV-N expression begins earlier than WT and there is therefore more N) and 24 hpi during the plateau post-exponential phase (pH 6.3/K+ treated virions and WT BUNV-N expression is equal) 19 . For the GFP-BUNV, virus was treated with buffers as with WT BUNV, and infection was assessed at 18 hpi. For the cell binding assays, after the pre-infection in vitro treatment (pH 6.3/no K+, pH 6.3/K+, or a pH 7.3 control), buffers were diluted out with cold DMEM and virions added to cells at 4 °C for 1.5 hrs; to allow binding but prevent internalisation 19 . Cells were washed 3x 30 secs with 0.1x PBS or left unwashed, and infection was allowed to proceed until 24 hpi (see Supplementary Fig. 8b ). Infection was assessed by western blot of cells lysed at 24 hpi. In the immunofluorescence binding test, purified virions were in vitro treated (pH 7.3/no K+ or pH 6.3/K+), bound to cells at 4 °C for 1.5 hrs, and then washed as above. Cells were fixed (0 hpi) and immunofluorescently stained for BUNV-N. Purified BUNV of a high titre ( ~ 1 × 109 PFU/ml) was used in order to bind viral particles an MOI of ~10 to the cells, to improve virion detection by this method. Images were taken by confocal microscopy. In the initial wash test assay (Supplementary Fig. 8a ), A549 cells were infected at 4 °C with BUNV (MOI = 0.1) and left unwashed or washed 3x 30 seconds with 0.1x PBS or 0.1% trypsin. Infection was assessed at 24 hpi by western blot. For the neutralisation assays, BUNV was treated at pH 7.3/no K+ (control), pH 6.3/no K+ or pH 6.3/K+ as above, then buffer was diluted and virions were neutralised with mAb-742 anti-BUNV-Gc monoclonal antibody (1:10,000; produced in the Professor Richard Elliott laboratory, CVR, University of Glasgow and provided by Dr Xiaohong Shi 31 ) or a dH2O control for 1 hr with gentle rocking. A549 cells were then infected at an MOI 0.1 for 18 hrs, at which point cells were fixed for immunofluorescence or lysed for western blot. Fixed cells were immunofluorescently stained for BUNV-N and images taken using an IncuCyte ZOOM as previously utilised 19 , 43 . HRSV control experiments were performed as with WT BUNV, however infections were performed at an MOI = 1 for 24 hrs, and analysed by western blot. Acid-bypass assay To induce fusion at the plasma membrane, and thus bypass endosomal entry (see Fig. 6a ), a protocol was adapted from the procedure previously outlined by Stauffer et al. (2014) 35 . BUNV (MOI 0.1) was bound to A549 cells by addition at 4 °C for 1 hr, and unbound virus was then removed with the media. Virions bound to the cell membrane were subjected to acidic buffers (‘acid-bypass’) by adding warm fusion buffers to cells for a 2 min pulse at 37 °C: pH 6.3/no K+, pH 6.3/K+, pH 5.3/no K+, or a DMEM-added infection control (Inf. ctl) (instead of the 2 hrs used for acid pre-treatments). The fusion buffers used were the same as those used for the acid-treatments in the above experiments, but additionally containing 0.1x PBS to maintain cell osmolarity. Conditions were performed in duplicate and to one of each buffer condition, fusion buffers were gently removed and replaced with DMEM (no harsh washing steps to avoid removing weakly bound virions). Thus, endocytic entry, as well as plasma membrane fusion, will proceed (labelled: endocytosed+fused). To the duplicate well for each fusion buffer condition, cells were subsequently washed with cold DMEM and treated with or without drugs to prevent endocytic entry: the reducing agent tris(2-carboxyethyl)phosphine (TCEP; 10 mM, Sigma) was added to cells for the + drugs wells for 5 mins at 37 °C to inactivate surface-bound virions 20 , which was then removed and replaced with an acid-bypass stop buffer (DMEM containing 50 mM HEPES (pH 7.3), and 20 mM ammonium chloride (NH4Cl); Sigma) to prevent endosomal acidification and hence entry by endocytosis 19 . As such, only virions that bypass the endocytic network and fuse at the plasma membrane would result in a productive infection 19 , 20 (labelled: fused at p.m. (drugs)). Cells were incubated at 37 °C for 24 hrs, then lysed and infection assessed by western blot. Liposome preparation Liposomes consisting of phosphatidic acid, phosphatidylcholine, and rhodamine-labelled phosphatidylethanolamine (ratio 10:10:1) with 10% cholesterol were purified as previously described 45 . Briefly, lipids in chloroform were dried in a film with argon and rehydrated in 10 mM NaCl, 10 mM Hepes pH 7.5. The rehydrated lipids were initially extruded through a mini-extruder (Avanti Polar Lipids) using a 400 nm pore-size membrane (Whatman) and further extruded using a 100 nm pore-size membrane (Whatman). Liposomes were pelleted by ultracentrifugation at 140,100 xg (20 °C) for 20 minutes using a SW55 rotor. A comparison of the rhodamine fluorescence in the liposome preparation and samples of rehydrated lipids with known lipid concentrations was used to estimate the lipid concentration of the liposomes. Electron microscopy Negative stain EM was used to assess the purification of BUNV prior to cryo-EM 21 . Briefly, purified BUNV was loaded onto glow-discharged carbon-coated grids and allowed to stand for 30 secs. Grids were washed three times with dH2O and stained with 1% aqueous uranyl acetate for 10 secs. Images were collected on a FEI Tecnai T12 electron microscope at 120 kV, using a Gatan Ultrascan 4000 charge-coupled device camera and operated between -1 µm and -5 µm nominal defocus. For cryo-EM and cryo-ET, 2 µl purified BUNV virions ( ~ 6.8 x 106 particles) were diluted in 2 µl (1:1) of a range of acidic buffers (components outlined in ‘acid pre-treatment’ section above, however, adjusted to equate the same final concentrations: pH 7.3/no K+, pH 6.3/no K+, pH 6.3/K+; final concentration 127.5 mM KCl) for 2 hr at 37 °C matching the acid-treatment experiments used previously 19 . Virions were then mixed with 2 µl of Protein A conjugated with 10-nm colloidal gold (Aurion) as a fiducial marker for tomogram alignment, and 3 µl of the mixture was immediately loaded onto glow-discharged lacey-carbon EM grids, with an ultra-thin 2 nm carbon support film (Agar scientific). Grids were blotted for 3 secs and vitrified using a Leica EM GP automatic plunge freezer. Cryo-EM micrographs were collected for each condition on an FEI Titan Krios using a Falcon E3C direct electron detector, operated at 300 KeV and at −0.5 to −3.5 µm defocus. For the liposome fusion assay, 2 µl purified BUNV ( ~ 2.25 × 106 particles) were combined with 1 µl liposomes and 3 µl buffer (buffer pH 7.3/no K+, pH 6.3/no K+, pH 6.3 or pH 5.3/no K+ as for cryo-EM of virions) for 2 hr at 37 °C, conditions known to elicit changes in the BUNV GPs. Samples were then cooled at 4 °C until 3 µl colloidal gold was added and immediately vitrified on cryo-EM grids, as above. Cryo-EM grid screening micrographs were collected as above. Cryo-ET and image processing Grids for cryo-ET were prepared as described above and tilt series were collected using a FEI Titan Krios using an energy-filtered (20 eV slit) Gatan K2 XP summit direct electron detector in counting mode (300 KeV), and a Volta phase plate. Tomography 4 (FEI) and EPU v2.8.1 software were used to collect single-axis tilt series from −60° to +60°, at 2° increments. A defocus of -1 µm was used, at x53,000 magnification, corresponding to a pixel size of 2.72 Å, and an electron dose of ~1.8 e− per image (total dose per tilt series ~108 e-/Å2). Tilt-series projections were pre-processed by motion correction using Relion 3.0, and contrast transfer function (CTF) calculated using Relion 3.0 (gctf) and then corrected using CTF phase-flip 46 , 47 . The IMOD package eTOMO was used to align the projections using the gold fiducials and calculate the 3D reconstructions by weighted back projection 48 , with a final pixel size of 5.44 Å after binning by a factor of two. For STA, unbinned tomograms (2.72 Å pixel size) were also generated using only the −30˚ to +30˚ tilt angles (to improve the signal-to-noise of the resulting tomograms). Representative images were Gaussian Blur 3D filtered using ImageJ. Cryo-ET tilt series were collected for the liposome-virus fusion assays for the pH 7.3/no K+ and pH 6.3/K+ conditions, using similar parameters to those above (−60˚ to +60˚, at 2˚ increments) on a FEI Titan Krios with a Falcon 4i detector in counting mode (300 KeV). TOMO software was used to set up data collections, and a dose of ~2.4 e− per image was used (total dose 148 e−/Å2). Projections were motion corrected as above and 3D reconstructions also generated using eTOMO (IMOD). Tomograms were binned by a factor of 4, yielding a final pixel size of 9.6 Å, and representative images ( > 6 tomograms per condition) were Gaussian blur filtered in ImageJ. Segmentation of representative tomograms was performed using AmiraEM software (Thermo Scientific). Subtomogram averaging PEET (IMOD package) was used for STA 49 and Bsoft for basic image processing 50 . Briefly, for both conditions ~200 tripodal spikes were initially selected and the spikeInit programme used to calculate initial orientations perpendicular to the viral membrane. These initial orientations were employed to generate an initial ‘tripod’ reference used for subsequent particle selection. For the pH 7.3/no K+ tripod STA, the seedSpikes and spikeInit programmes were used to automatically estimate all spike positions and orientations on the viral membranes (71 virions used, ~9000 subtomograms), which were then iteratively refined following PEET guidelines using the previously generated initial reference. A summary of the processing stages and EM maps obtained can be found in Supplementary Table 1 . Duplicate particles were removed at each stage, and a spherical mask around the tripod was used to focus alignments. After the initial refinements C3 symmetry was evident, therefore in later stages pseudo-particles representing the 3 possible orientations of each tripod were calculated, thereby tripling the number of subtomograms. Additionally, re-creating unbinned tomograms using -30˚ to +30˚ tilt angles, to remove the projections from high tilt angles, improved the resolution achievable in STA. For the whole tripod, this resulted in 20,282 subtomograms with a calculated FSC resolution of ~9.1 Å, using the calcFSC PEET programme and a 0.5 cutoff. The subtomogram average of the floor region was generated as above, but by re-centring the average on this region instead of the tripod (using the modifyMotiveList programme to translate the position of the original spikes before tripod refinement) and then iteratively refining the locations and orientations of the subtomograms. This similarly resulted in 16,096 subtomograms, but an improved resolution of ~6.6 Å (0.5 FSC cutoff) of this region using the full dataset. For accurate structural determination and resolution calculations GS-FSC was also performed on half split datasets. For GS-FSC resolution estimation, all automatically selected particles were passed through an initial iteration to remove duplicate particles. The remaining particles were split into half datasets and independently aligned and averaged following identical steps to that outlined above. The half datasets were then aligned to bring the two averages into a common position and orientation, following PEET guidelines. The FSC between the two half maps was computed using the calcUnbiasedFSC programme (PEET), the result of which was used to filter the resolution of the full dataset. This resulted in an unbiased FSC calculation (using a 0.143 cutoff) for the tripod was ~16 Å and ~13 Å for the floor STA. For the pH 6.3/K+ treated virus STA, automatic selection of spikes using seedSpikes, did not result in a coherent average. Subtomograms were therefore manually selected ( ~ 20,000) from 89 virions and alignment was refined iteratively using the initial reference, obtained as for the control. No symmetry was evident and therefore was not applied (Supplementary Table 1 ). Additionally, the density at the top of the spikes could not be well refined suggesting multiple conformations. To address this, principal components analysis (pca) and clusterPca programmes were used to identify clusters of separate conformations. Three clusters were identified however the top of the spikes remained unresolved for all (this was also the case for all the clustering options explored) and therefore suggested a highly dynamic structure. The largest cluster (9,987 subtomograms) was taken forward for further refinements utilising a loosely fitted mask to improve the more structured regions and resulted in ~16 Å resolution. This was determined using the calcFSC (0.5 cutoff) PEET programme (not GS-FSC), owing to the high flexibility and low resolution of the average. Subtomograms were visualised using Chimera and ChimeraX 51 , 52 . Fitting of the BUNV head domain (pdb: 6H3V), SBV stalk (pdb: 6H3S) 6 and the LACV fusion domains (pre-fusion modelled from pdb: 7A57) was also performed in ChimeraX; using fitmap, which provides cross-correlation scores. Comparison of the RMSD values between the individual domain structures of the BUNV, SBV & LACV Gc with the AlphaFold Gc was obtained using the matchmaker command in ChimeraX. RMSD values (Å) for the pruned atom pairs are shown (Supplementary Fig. 4e ). A local install of AlphaFold_Multimer v2.1.0 (as described at https://github.com/deepmind/alphafold ) was used to generate the multimer structure of the BUNV Gn/Gc complex, using the M segment sequences for Gn and Gc from uniprot: P04505 (Gn residues 17-302, Gc residues 478−1433) 24 , 29 . At the time of model generation, only the Gc head and stalk domains were available for orthobunyaviruses; no Gc fusion domain nor Gn structures were available for training the model. For fitting into the tripod STA, the output model was rotated (ChimeraX and Coot) using rigid-body fitting about the flexible inter-domain region (which also had low model confidence) between the stalk and fusion domains I (see Supplementary Fig. 4a, d ). Reporting summary Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article. Data availability The data that support this study are available from the corresponding author upon request. The cryo-ET STA averages have been deposited in EMBD under accession codes EMD-15557 (STA of the pH 7.3/no K+ BUNV tripod in Fig. 1 ); EMD-15569 (STA of the floor region in Fig. 2 ); and EMD-15579 (STA of the pH 6.3/K+ GPs in Fig. 5 ). The AlphaFold model (Fig. 3 ), lacking the TMDs (which are not supported by the STA data) can be found in Supplementary Data 1 . The previously published X-ray crystal structures can be obtained from PDB using accession codes 6H3V [ https://doi.org/10.2210/pdb6H3V/pdb ] (BUNV Gc head domain); 6H3S [ https://doi.org/10.2210/pdb6H3S/pdb ] (SBV Gc head/stalk domains); and 7A57 [ https://doi.org/10.2210/pdb7A57/pdb ] (LACV Gc fusion domains in the post-fusion conformation). The source data underlying Fig. 6b, c ; and Supplementary Figs. 4a , 6a , 7b –d, 7f , g and 8a – c are provided as a Source Data file. Source data are provided with this paper. References Briese, T., Calisher, C. H. & Higgs, S. Viruses of the family Bunyaviridae: are all available isolates reassortants? Virology 446, 207–216 (2013). Elliott, R. M. Orthobunyaviruses: Recent genetic and structural insights. Nat. Rev. Microbiol. 12, 673–685 (2014). Hellert, J. et al. Orthobunyavirus spike architecture and recognition by neutralizing antibodies. Nat. Commun. 10, 879 (2019). Guardado-Calvo, P. & Rey, F. A. The viral class II membrane fusion machinery: divergent evolution from an ancestral heterodimer. Viruses 13, 2368 (2021). Halldorsson, S. et al. Shielding and activation of a viral membrane fusion protein. Nat. Commun. 9, 349 (2018). Guardado-Calvo, P. & Rey, F. A. The Envelope Proteins of the Bunyavirales. Adv. Virus Res. 98, 83–118 (2017). Hulswit R. J. G., Paesen G. C., Bowden T. A., Shi X. Recent advances in bunyavirus glycoprotein research: Precursor processing, receptor binding and structure. Viruses 13, 353 (2021). Huotari, J. & Helenius, A. Endosome maturation. EMBO J. 30, 3481–3500 (2011). Sandler Z. J. et al. Novel ionophores active against La Crosse virus identified through rapid antiviral screening. Antimicrob. Agents Chemother. 64, e00086–20 (2020). Windhaber, S. et al. The orthobunyavirus Germiston enters host cells from late endosomes. J. Virol. 96, e0214621 (2022). Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021). Hopkins F. R. et al. The native orthobunyavirus ribonucleoprotein possesses a helical architecture. mBio. 13, e0140522 (2022). Hellert, J. et al. Structure, function, and evolution of the Orthobunyavirus membrane fusion glycoprotein. Cell Rep. 42, 112142 (2023). Lee, K. K. Architecture of a nascent viral fusion pore. EMBO J. 29, 1299–1311 (2010). Zhang, K. Gctf: Real-time CTF determination and correction. J. Struct. Biol. 193, 1–12 (2016). Acknowledgements Thanks to the Astbury Biostructure Laboratory electron microscopy facility and the bioimaging facility for support in using the microscopes, and a particular thanks to Dr. Emma Hesketh, Dr. Rebecca Thompson, Dr. Yehuda Halfon and Dr. Louie Aspinall (University of Leeds) for the cryo-electron tomography data collection setups. Thanks to Professor Félix Rey (Institut Pasteur, Paris) for kindly providing the structure of the LACV post-fusion Gc prior to publication and for useful comments on the manuscript. Thanks also to Dr Xiaohong Shi, Professor Richard Elliott and Professor Alain Kohl from the Glasgow Centre for Virus Research (CVR, University of Glasgow), and Dr Cheryl Walter (University of Hull) for providing reagents. Finally, thanks to Dr. Samuel Haysom, Dr. Katherine Fenn and Jonathan Machin for their help with AlphaFold. J.F. was funded by the University of Leeds (University Academic Fellow scheme). This work was funded by the Human Frontiers Science Program (RGP0040/2019) awarded to J.F., the Academy of Medical Sciences and the Wellcome Trust (Springboard Award, SBF002\1029) awarded to J.F., the Rosetrees Trust (A1618) awarded to J.F., and the MRC (MR/T016159/1) awarded to J.M., J.N.B. and J.F. Electron Microscopy was performed at the Astbury Biostructure Laboratory (University of Leeds), which was funded by the University of Leeds and the Wellcome Trust (108466/Z/15/Z, 090932/Z/09/Z, 221524/Z/20/Z). The IncuCyte ZOOM live imaging system was funded by the BBSRC (BB/P001459/1), and awarded to Professor Nicola Stonehouse (University of Leeds). The Zeiss LSM 880 upright Confocal microscope was funded by the Wellcome Trust (WT104918MA) and awarded to the University of Leeds BioImaging facility. Author information Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ .
Wellcome Trust Investments
155 Investments
Wellcome Trust has made 155 investments. Their latest investment was in Generate Capital as part of their Private Equity on July 7, 2021.

Wellcome Trust Investments Activity

Date | Round | Company | Amount | New? | Co-Investors | Sources |
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7/19/2021 | Private Equity | Generate Capital | $2,000M | Yes | 17 | |
4/21/2021 | Grant - VIII | Oxitec | $6.8M | Yes | 8 | |
7/27/2020 | Seed VC | Transformative AI | $1.7M | Yes | 10 | |
6/3/2020 | Private Equity | |||||
4/23/2020 | Grant |
Date | 7/19/2021 | 4/21/2021 | 7/27/2020 | 6/3/2020 | 4/23/2020 |
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Round | Private Equity | Grant - VIII | Seed VC | Private Equity | Grant |
Company | Generate Capital | Oxitec | Transformative AI | ||
Amount | $2,000M | $6.8M | $1.7M | ||
New? | Yes | Yes | Yes | ||
Co-Investors | |||||
Sources | 17 | 8 | 10 |
Wellcome Trust Portfolio Exits
46 Portfolio Exits
Wellcome Trust has 46 portfolio exits. Their latest portfolio exit was Instacart on September 19, 2023.
Date | Exit | Companies | Valuation Valuations are submitted by companies, mined from state filings or news, provided by VentureSource, or based on a comparables valuation model. | Acquirer | Sources |
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9/19/2023 | IPO | Public | 13 | ||
12/19/2022 | Reverse Merger | 3 | |||
4/5/2022 | Shareholder Liquidity | Point A Hotels | 1 | ||
Date | 9/19/2023 | 12/19/2022 | 4/5/2022 | ||
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Exit | IPO | Reverse Merger | Shareholder Liquidity | ||
Companies | Point A Hotels | ||||
Valuation | |||||
Acquirer | Public | ||||
Sources | 13 | 3 | 1 |
Wellcome Trust Acquisitions
2 Acquisitions
Wellcome Trust acquired 2 companies. Their latest acquisition was Urban & Civic on October 28, 2021.
Date | Investment Stage | Companies | Valuation Valuations are submitted by companies, mined from state filings or news, provided by VentureSource, or based on a comparables valuation model. | Total Funding | Note | Sources |
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10/28/2021 | Growth Equity | Take Private | 3 | |||
5/13/2015 |
Date | 10/28/2021 | 5/13/2015 |
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Investment Stage | Growth Equity | |
Companies | ||
Valuation | ||
Total Funding | ||
Note | Take Private | |
Sources | 3 |
Wellcome Trust Fund History
2 Fund Histories
Wellcome Trust has 2 funds, including Health Innovation Challenge Fund.
Closing Date | Fund | Fund Type | Status | Amount | Sources |
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7/29/2014 | Health Innovation Challenge Fund | 1 | |||
Wellcome Trust Leap Fund |
Closing Date | 7/29/2014 | |
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Fund | Health Innovation Challenge Fund | Wellcome Trust Leap Fund |
Fund Type | ||
Status | ||
Amount | ||
Sources | 1 |
Wellcome Trust Partners & Customers
10 Partners and customers
Wellcome Trust has 10 strategic partners and customers. Wellcome Trust recently partnered with ripeta on September 9, 2020.
Date | Type | Business Partner | Country | News Snippet | Sources |
---|---|---|---|---|---|
9/8/2020 | Partner | Wellcome and Ripeta partner to assess dataset availability in funded research - Digital Science Wellcome Trust and Ripeta partner to assess dataset availability in funded research . | 1 | ||
6/24/2020 | Partner | United States | This release contains forward-looking information about the launch of the Surveillance Partnership to Improve Data for Action on Antimicrobial Resistance , a new multi-year , public-private research collaboration with the governments of Ghana , Kenya , Malawi and Uganda to track resistance patterns and better understand the burden of antimicrobial resistance on patients living in low - and middle-income countries , including its potential benefits , that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements . | 4 | |
12/2/2019 | Partner | Germany | Wellcome Trust establishes first Translational Partnership in Germany - with the BIH and Charité The overarching aim of the translational partnership between the Wellcome Trust and the Berlin Institute of Health is to effect a change in research culture , thus maximizing the possibilities for translational medicine to benefit patients and society at large . | 1 | |
11/25/2019 | Partner | ||||
7/8/2019 | Partner |
Date | 9/8/2020 | 6/24/2020 | 12/2/2019 | 11/25/2019 | 7/8/2019 |
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Type | Partner | Partner | Partner | Partner | Partner |
Business Partner | |||||
Country | United States | Germany | |||
News Snippet | Wellcome and Ripeta partner to assess dataset availability in funded research - Digital Science Wellcome Trust and Ripeta partner to assess dataset availability in funded research . | This release contains forward-looking information about the launch of the Surveillance Partnership to Improve Data for Action on Antimicrobial Resistance , a new multi-year , public-private research collaboration with the governments of Ghana , Kenya , Malawi and Uganda to track resistance patterns and better understand the burden of antimicrobial resistance on patients living in low - and middle-income countries , including its potential benefits , that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements . | Wellcome Trust establishes first Translational Partnership in Germany - with the BIH and Charité The overarching aim of the translational partnership between the Wellcome Trust and the Berlin Institute of Health is to effect a change in research culture , thus maximizing the possibilities for translational medicine to benefit patients and society at large . | ||
Sources | 1 | 4 | 1 |
Wellcome Trust Team
4 Team Members
Wellcome Trust has 4 team members, including , .
Name | Work History | Title | Status |
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Stewart Newton | Founder | Current | |
Name | Stewart Newton | |||
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Work History | ||||
Title | Founder | |||
Status | Current |