Biology subjects

Rasmussen, S. A.

Publications and source records attributed to Rasmussen, S. A..

4 recordsLinked to original sources

bioRxiv2023

Dermonecrosis caused by spitting cobra snakebite is the result of toxin potentiation and is prevented by the repurposed drug varespladib

Snakebite envenoming is a neglected tropical disease that causes substantial mortality and morbidity globally. The venom of African spitting cobras often causes permanent injury via tissue-destructive dermonecrosis at the bite site, which is ineffectively treated by current antivenoms. To address this therapeutic gap, we identified the aetiological venom toxins responsible for causing local dermonecrosis. While cytotoxic three-finger toxins were primarily responsible for causing spitting cobra cytotoxicity in cultured keratinocytes, their potentiation by phospholipases A2 toxins was essential to cause dermonecrosis in vivo. This evidence of probable toxin synergism suggests that a single toxin-family inhibiting drug could prevent local envenoming. We show that local injection with the repurposed phospholipase A2-inhibiting drug varespladib significantly prevents local tissue damage caused by several spitting cobra venoms in murine models of envenoming. Our findings therefore provide a new therapeutic strategy to more effectively prevent life-changing morbidity caused by snakebite in rural Africa. Significance StatementSpitting cobra venoms cause extensive local tissue damage surrounding the site of a snakebite. This damage cannot be effectively prevented with current antivenom treatments, and patients are often left with life-changing wounds. In this study we used cellular and mouse experiments to determine which toxins in African spitting cobra venom are responsible for causing tissue damage, revealing that a combination of two different types of toxins are required to cause pathology in vivo. We then showed that the repurposed drug, varespladib, which targets one of these toxin types, effectively prevents skin and muscle damage in mouse models of envenoming. Collectively these findings suggest that varespladib could be an effective new type of therapy for preventing snakebite morbidity in Africa.

pharmacology and toxicology↗

bioRxiv2022

Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms

Morbidity from snakebite envenoming affects approximately 400,000 people annually. Tissue damage at the bite-site often leaves victims with catastrophic life-long injuries and is largely untreatable by currently available antivenoms. Repurposing small molecule drugs that inhibit specific snake venom toxins offers a potential new treatment strategy for tackling this neglected tropical disease. Using human skin cell assays as an initial model for snakebite-induced dermonecrosis, we show that the repurposed drugs 2,3-dimercapto-1-propanesulfonic acid (DMPS), marimastat, and varespladib, alone or in combination, reduce the cytotoxic potency of a broad range of medically important snake venoms up to 5.7-fold. Thereafter, using a preclinical murine model of dermonecrosis, we demonstrate that the dual therapeutic combinations of DMPS or marimastat with varespladib potently inhibit the dermonecrotic activity of three geographically distinct and medically important snake venoms. These findings strongly support the future translation of repurposed drug combinations as broad-spectrum therapeutics for preventing morbidity caused by snakebite.

pharmacology and toxicology↗

bioRxiv2018

Phylogenetic distribution of roseobacticides in the Roseobacter group and their effect on microalgae

The Roseobacter-group species Phaeobacter inhibens produces the antibacterial tropodithietic acid (TDA) and the algaecidal roseobacticides with both compound classes sharing part of the same biosynthetic pathway. The purpose of this study was to investigate the production of roseobacticides more broadly in TDA-producing roseobacters and to compare the effect of producers and non-producers on microalgae. Of 33 roseobacters analyzed, roseobacticide production was a unique feature of TDA-producing P. inhibens, P. gallaeciensis and P. piscinae strains. One TDA-producing Phaeobacter strain, 27-4, was unable to produce roseobacticides, possibly due to a transposable element. TDA-producing Ruegeria mobilis and Pseudovibrio did not produce roseobacticides. Addition of roseobacticide-containing bacterial extracts affected the growth of the microalgae Rhodomonas salina, Thalassiosira pseudonana and Emiliania huxleyi, while growth of Tetraselmis suecica was unaffected. During co-cultivation, growth of E. huxleyi was initially stimulated by the roseobacticide producer DSM 17395, while the subsequent decline in algal cell numbers during senescence was enhanced. Strain 27-4 that does not produce roseobacticides had no effect on algal growth. Both bacterial strains, DSM 17395 and 27-4, grew during co-cultivation presumably utilizing algal exudates. Furthermore, TDA-producing roseobacters have potential as probiotics in marine larviculture and it is promising that the live feed Tetraselmis was unaffected by roseobacticides-containing extracts.\n\nOriginality-significance statementSome Roseobacter-group bacteria produce the antibacterial compound tropodithetic acid (TDA) and have potential as probiotics in marine aquaculture. However, a few of these strains additionally produce algaecidal compounds, the roseobacticides, which would restrict their use in marine larviculture where algae are used as live feed for fish larvae. We herein found that roseobacticides are limited to TDA-producing Phaeobacter strains and were not biosynthesized by TDA-producers outside this genus. Roseobacticides affected several strains of microalgae, but not the chlorophyte that is used as live feed in the aquaculture industry. Thus, the application of Roseobacter strains as probiotics is not hampered. Furthermore, these results demonstrate how Roseobacter-group strains act as gardeners of microalgae and thereby would be involved in environmental processes on a larger scale.

microbiology↗

bioRxiv2017

Evolutionary and functional data power search for obsessive-compulsive disorder genes

Obsessive-compulsive disorder (OCD) is a severe psychiatric disorder linked to abnormalities in the cortico-striatal circuit and in glutamate signaling. We sequenced coding and regulatory elements for 608 genes implicated in OCD from humans and two animal models (mouse and dog). Using a new method, PolyStrat, which prioritizes variants disrupting evolutionarily conserved, functional regions, we found four strongly associated genes when comparing 592 cases to 560 controls. These results were validated in a second, larger cohort. NRXN1 and HTR2A are enriched for coding variants altering postsynaptic protein-binding domains, while CTTNBP2 (synapse maintenance) and REEP3 (vesicle trafficking) are enriched for regulatory variants. The rare coding variant burden in NRXN1 achieves genomewide significance (p=6.37x10-11) when we include public data for 33,370 controls. Of 17 regulatory variants identified in CTTNBP2 and REEP3, we show that at least six alter transcription factor-DNA binding in human neuroblastoma cells. Our findings suggest synaptic adhesion as a key function in compulsive behaviors across three species, and demonstrate how combining targeted sequencing with functional annotations can identify potentially causative variants in both coding and noncoding regions, even when genomic data is limited.

genomics↗