Biology subjects

Moyer, C. L.

Publications and source records attributed to Moyer, C. L..

3 recordsLinked to original sources

bioRxiv2018

Human antibody cocktail deploys multiple functions to confer pan-ebolavirus protection

During the unprecedented 2013-2016 Ebola virus disease (EVD) epidemic in Western Africa and in its aftermath, the passive administration of monoclonal antibodies (mAbs) emerged as a promising treatment approach1-7. However, all antibody-based therapeutics currently in advanced development are specific for a single member of the Ebolavirus genus, Ebola virus (EBOV), and ineffective against divergent outbreak-causing ebolaviruses, including Bundibugyo virus (BDBV) and Sudan virus (SUDV)2,3,5,7. Here we advance MBP134, a cocktail of two broadly neutralizing human mAbs targeting the filovirus surface glycoprotein, GP, as a candidate pan-ebolavirus therapeutic. One component of this cocktail is a pan-ebolavirus neutralizing mAb, ADI-15878, isolated from a human EVD survivor8,9. The second, ADI-23774, was derived by affinity maturation of a human mAb8,9 via yeast display to enhance its potency against SUDV. MBP134 afforded exceptionally potent pan-ebolavirus neutralization in vitro and demonstrated greater protective efficacy than ADI-15878 alone in the guinea pig model of lethal EBOV challenge. A second-generation cocktail, MBP134AF, engineered to effectively harness natural killer (NK) cells afforded additional, unprecedented improvements in protective efficacy against EBOV and SUDV in guinea pigs relative to both its precursor and to any mAbs or mAb cocktails tested previously. MBP134AF is a best-in-class mAb cocktail suitable for evaluation as a pan-ebolavirus therapeutic in nonhuman primates.

microbiology↗

bioRxiv2018

Structural Basis of Broad Ebolavirus Neutralization by a Human Survivor Antibody

The structural features that govern broad-spectrum activity of broadly neutralizing, anti-ebolavirus antibodies (Abs) are currently unknown. Here we describe the first structure of a broadly neutralizing human Ab, ADI-15946, in complex with cleaved Ebola virus glycoprotein (EBOV GPCL). We find that ADI-15946 employs structural mimicry of a conserved interaction between the GP core and the glycan cap {beta}17-{beta}18 loop to inhibit infection. Both endosomal proteolysis of EBOV GP and binding of monoclonal Ab (mAb) FVM09 displace this loop, increase exposure of ADI-15946s conserved epitope and potentiate neutralization. Our work also illuminated the determinants of ADI-15946s reduced activity against Sudan virus (SUDV), and enabled rational, structure-guided engineering to enhance binding and neutralization against SUDV while retaining the parental breadth of activity.\n\nOne Sentence SummaryThe first crystal structure of a broadly active antibody against surface glycoproteins of ebolaviruses identifies a highly conserved epitope beneath the glycan cap and highlights the molecular requirements for broad ebolavirus neutralization.

immunology↗

bioRxiv2016

In situ estimates of iron-oxidation and accretion rates for iron-oxidizing bacterial mats at Loihi Seamount.

It is increasingly recognized that diffuse, hydrothermal venting is an important source of iron to the deep-sea that can influence oceanic iron dynamics and abundance. Lithotrophic Fe-oxidizing bacteria (FeOB) are dominant at diffuse hydrothermal vent sites, producing microbial iron mats that are often centimeters or more thick. At present, little is known about in situ Fe-oxidation rates, or accretion rates for iron mats. An in situ productivity chamber was developed that took advantage of the unique mineral morphotypes produced by FeOB to estimate rates of Fe-oxidation and accretion. Chambers were placed at two diffuse vents (1179 and 1300 mbsl) at L[o]ihi Seamount where they were colonized by FeOB for different amounts of time. From this analysis, it was estimated that Fe-oxidation rates could range from 8.2-51.9 x 10-6 mol {middle dot} hr-1, and that iron mats could accrete at around 2.2 cm {middle dot} yr-1. Molecular analysis indicated that the relative abundance of Zetaproteobacteria, a group of known FeOB, accounted for 80-90% of the bacteria colonizing the chambers. There was a distinct difference between populations at the 1179m site (Pohaku), and the 1300m site (North Hiolo Ridge). Microscope slides placed within the productivity chambers were colonized by different morphotypes of FeOB. The cells responsible for one common morphotype that produces a Y-shaped filament were identified as Zetaproteobacteria by use of a small subunit rRNA probe. This work confirms the importance of FeOB in the formation of chemosynthetic iron mats, and provides the first estimates for in situ Fe-oxidation rates and mat accretion rates.\n\nHighlightsO_LIAn in-situ productivity chamber was developed to estimate rates of Fe-oxidation and understand colonization patterns at chemosynthetic iron mats at L[o]ihi Seamount.\nC_LIO_LIFe-oxidation rates ranged from 8.2-51.9 x 10-6 mol {dot} hr-1, and it was estimated that the iron mats could accrete at around 2.2 cm {dot} yr-1.\nC_LIO_LIThe iron mat community was dominated by Zetaproteobacteria, whose relative abundance accounted for up to 89% of the microbial community.\nC_LIO_LIThe community membership that grew during short-term incubations reflected the community composition of nearby microbial mats.\nC_LI

microbiology↗