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Molecular dissection of cobra venom highlights heparinoids as an effective snakebite antidote

ABSTRACT: Snakebite affects ~1.8 million people annually. The current standard of care are antibody-based antivenoms, which are difficult to access and are not effective against local tissue injury, the primary cause of morbidity. Here we use a functional genomics approach to define human genes that genetically interact with spitting cobra venoms. Most genes that confer resistance to venom cytotoxicity control proteoglycan biosynthesis, suggesting heparinoids as possible inhibitors. Here we show that heparinoids prevent venom cytotoxicity by inhibiting three-finger cytotoxins. Critically, the FDA-approved heparinoid tinzaparin was found to reduce tissue damage in vivo when given via a medically relevant route and dose. Overall, our systematic molecular dissection of cobra venom mechanisms provides new insight into how we can treat cobra bites, information that can help improve the lives of millions of people worldwide.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262798 | GEO | 2025/04/06

REPOSITORIES: GEO

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Project description:Background The generalist dipteran pupal parasitoid Nasonia vitripennis injects 79 venom peptides into the host before egg laying. This venom induces several important changes in the host, including developmental arrest, immunosuppression, and alterations to normal metabolism. It is hoped that diverse and potent bioactivities of N. vitripennis venom provide an opportunity for the design of novel acting drugs. However, currently very little is known about the individual functions of N. vitripennis venom peptides and less than half can be bioinformatically annotated. The paucity of annotation information complicates the design of studies that seek to better understand the potential mechanisms underlying the envenomation response. Although the RNA interference system of N. vitripennis provides an opportunity to functionally characterise venom encoding genes, with 79 candidates this represents a daunting task. For this reason we were interested in determining the expression levels of venom encoding genes in the venom gland, such that this information could be used to rank candidate venoms. To do this we carried out deep sequencing of the transcriptome of the venom gland and neighbouring ovary tissue and used RNA-seq to measure expression from the 79 venom encoding genes. The generation of a specific venom gland transcriptome dataset also provides further opportunities to investigate novel features of this highly specialised organ. Results High throughput sequencing and RNA-seq revealed that the highest expressed venom encoding gene in the venom gland was a serine protease called Nasvi2EG007167, which has previously been implicated in the apoptotic activity of N. vitripennis venom. As expected the RNA-seq confirmed that the N. vitripennis venom encoding genes are almost exclusively expressed in the venom gland relative to the neighbouring ovary tissue. Novel peptides appear to perform key roles in N. vitripennis venom function as only four of the highest 15 expressed venom encoding genes are bioinformatically annotationed. The high throughput sequencing data also provided evidence for the existence of an additional 471 novel genes in the Nasonia genome that are expressed in the venom gland and ovary. Finally, metagenomic analysis of venom gland transcripts identified viral transcripts that may play an important part in the N. vitripennis venom function. Conclusions The expression level information provided here for the 79 venom encoding genes provides an unbiased dataset that can be used by the N. vitripennis community to identify high value candidates for further functional characterisation. These candidates represent bioactive peptides that have value in drug development pipelines.

Project description:The Mojave rattlesnake (Crotalus scutulatus scutulatus) is classified as the “highest medically important” snake in the risk categories in the United States. Although responsible for fewer snakebite envenomations and deaths compared to other species, Mojave rattlesnake venom is poorly characterized and shows significant geographical variability. The venom of Type A animals primarily contains the β-neurotoxin referred to as Mojave Toxin (MTX), which is responsible for the neurotoxic effects that make bites from this snake particularly feared. Previous studies have shown that β-neurotoxin from different snake species produced similar but complex effects by mechanisms that are not fully understood. We performed a genome-wide transcriptomic analysis of the neurocellular response to Mojave Type A rattlesnake venom using induced pluripotent stem cell (iPSC) -derived human neural stem cells (NSCs) to unveil the molecular mechanisms underlying the damage caused by this snake’s envenomation. Our results suggest that snake venom metalloproteases (svMPs), although have a limited repertoire in type A animal venom, facilitate venom spread by digesting tissue's extracellular matrix. The MTX, which is composed of heterodimers of basic and acidic phospholipase A2 (PLA2) and is the dominant constituent of this venom, co-opts the host arachidonic acid and Ca2+ second messenger mechanisms in a dose- and time-dependent escalating venom damage. The release of arachidonic acid and the rapid increase in intracellular Ca2+ caused by the PLA2 activity of MTX triggers multiple signaling cascades. The activation of MAPKs and NF-κB regulated proinflammatory cascades were the top enriched pathways in the shorter 4-hour NSC response to venom challenge and suggest a significant role of PKC-δ in the activation of MAPKs. The rapid increase in intercellular Ca2+ and resulting cellular depolarization plausibly have a role in neurotransmitter overload in the cholinergic and glutamatergic excitatory synapses and MTX-induced presynaptic blockade of nerve signals. The expression of the acetylcholinesterase gene (ACHE), which degrades acetylcholine, and the downregulation of GRIK1 and GRIK3 genes, which encode KA-iGluRs proteins suggest a cellular response to neurotransmitter overload in the excitatory synapses. Our results also show that the MTX/svPLA2 mediated dysregulation of Ca2+ homeostasis, particularly depletion from the endoplasmic reticulum (ER), causes ER stress and upregulation of unfolded protein response (UPR). The UPR and the oxidative stress caused by ROS generated in CYP1A1-mediated hydroxylation of arachidonic acid, contribute to mitochondrial membrane permeabilization. The activation of UPR, mitochondrial toxicity, and oxidative stress, constitute the degenerative phase of the venom challenge in NSCs and synergistically contribute to apoptotic and ferroptotic programmed cell death.

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Molecular dissection of cobra venom highlights heparinoids as an effective snakebite antidote

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