Venomics and antivenomics profiles of North African Cerastes cerastes and C. vipera populations reveals a potentially important therapeutic weakness

Fahmi, Laila; Makran, Bouchra; Plá, Davinia; Sanz, Libia; Oukkache, Naoual; Lkhider, Mustapha; Harrison, Robert A.; Ghalim, Noreddine; Calvete, Juan J.

doi:10.1016/j.jprot.2012.02.021

Cited by 48 publications

(25 citation statements)

References 32 publications

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“…Gel electrophoresis analysis demonstrated several protein bands certainly responsible for almost all of the observed biological effects (6,19,20). Proteolytic activity, studied following the casein test, was low compared to other venoms reported in the literature (e.g.…”

Section: Discussionmentioning

confidence: 90%

General characterization of venom from the Moroccan snakes Macrovipera mauritanica and Cerastes cerastes

Oukkache¹,

Lalaoui²,

Ghalim³

2012

J. Venom. Anim. Toxins incl. Trop. Dis

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Abstract:Ophidian envenomation accidents constitute a serious public health problem in many countries around the globe. Over 5 million such accident cases occur each year causing more than 100,000 deaths. In Africa, more than 20,000 deaths per year are registered while 400,000 envenomation victims retain severe and permanent functional sequelae. In Morocco, snakebites are frequent and of greater severity in children. They occur mostly in rural areas. The incidence of these bites remains poorly understood and vastly underestimated. The epidemiological data are not well known due to the absence of a national registry, whereas a significant proportion of envenomations receive only traditional treatment methods in nonmedical intensive care. This prompted us to investigate the enzymatic and biological properties of venom biochemical constituents from two of the most dangerous snake venoms in Morocco: Cerastes cerastes (Cc) and Macrovipera mauritanica (Mm). Also, we studied the immune cross-reactivity of Cc and Mm venoms in comparison to that of another important dangerous Moroccan viper, Bitis arietans (Ba), to identify the best candidates (venom or a mixture of venoms) for producing the most efficient and protective antivenom. In the present study, we report a preliminary venom characterization of Cc and Mm and the cross-reactivity that may exist between their venoms and Ba. These venoms are known to be highly toxic and contain several proteins that differ by molecular weights. Interestingly, both Cc and Mm venoms are characterized by intense hemorrhagic and phospholipase A 2 activities and their ability to degrade the α and γ chains of fibrinogen. They display very low proteolysis through the casein test. After injection into mice, Cc and Mm induce myonecrosis in skeletal muscles, which most likely reflects direct action of myotoxins and indirect action of hemorrhagic molecules present in these venoms. In mice, this myonecrosis diminishes serum creatine phosphokinase (CPK) levels. As expected, Cc venom is immunogenic and induces highly protective antivenom against Mm and Ba venom antigens. This protective capacity is similar to that of the antivenom produced against the Mm venom.

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Section: Discussionmentioning

confidence: 90%

General characterization of venom from the Moroccan snakes Macrovipera mauritanica and Cerastes cerastes

Oukkache¹,

Lalaoui²,

Ghalim³

2012

J. Venom. Anim. Toxins incl. Trop. Dis

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show abstract

“…Therefore although some venom toxin genes have in the past been suggested to represent ancestral salivary proteins (notably CRISPs and Kallikrein-like serine proteases [ Fry 2005 ; Sunagar et al 2012] ), our analysis in fact shows that the majority of snake venom toxins are likely derived from pre-existing salivary proteins. Far from being an incredibly complex cocktail of proteins ( Kini 2002 ; Wagstaff et al 2006 ; Fox and Serrano 2008 ; Casewell et al 2013 ) recruited from multiple body tissues ( Fry 2005 ; Fry, Vidal, et al 2009 ; Warrell 2010 ; Casewell et al 2013 ), snake venom should instead be considered to be simply a modified form of saliva, where a relatively small number of gene families (typically 6–14) have expanded through gene duplication, often in a lineage-specific manner ( Kulkeaw et al 2007 ; Wagstaff et al 2009 ; Fahmi et al 2012 ; Vonk et al 2013 ).…”

Section: Resultsmentioning

confidence: 99%

Restriction and Recruitment—Gene Duplication and the Origin and Evolution of Snake Venom Toxins

Hargreaves

Swain

Hegarty

et al. 2014

Genome Biology and Evolution

139

113

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Snake venom has been hypothesized to have originated and diversified through a process that involves duplication of genes encoding body proteins with subsequent recruitment of the copy to the venom gland, where natural selection acts to develop or increase toxicity. However, gene duplication is known to be a rare event in vertebrate genomes, and the recruitment of duplicated genes to a novel expression domain (neofunctionalization) is an even rarer process that requires the evolution of novel combinations of transcription factor binding sites in upstream regulatory regions. Therefore, although this hypothesis concerning the evolution of snake venom is very unlikely and should be regarded with caution, it is nonetheless often assumed to be established fact, hindering research into the true origins of snake venom toxins. To critically evaluate this hypothesis, we have generated transcriptomic data for body tissues and salivary and venom glands from five species of venomous and nonvenomous reptiles. Our comparative transcriptomic analysis of these data reveals that snake venom does not evolve through the hypothesized process of duplication and recruitment of genes encoding body proteins. Indeed, our results show that many proposed venom toxins are in fact expressed in a wide variety of body tissues, including the salivary gland of nonvenomous reptiles and that these genes have therefore been restricted to the venom gland following duplication, not recruited. Thus, snake venom evolves through the duplication and subfunctionalization of genes encoding existing salivary proteins. These results highlight the danger of the elegant and intuitive “just-so story” in evolutionary biology.

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“…Therefore whilst some venom toxin genes have in the past been suggested to represent ancestral salivary proteins (notably cysteine-rich secretory proteins (CRISPs)) and Kallikreinlike serine proteases (Fry 2005;Sunagar et al 2012), our analysis in fact shows that the majority of snake venom toxins are likely derived from pre-existing salivary proteins. Far from being an incredibly complex cocktail of proteins (Kini 2002;Wagstaff et al 2006;Fox and Serrano 2008;Casewell et al 2013) recruited from multiple body tissues (Fry 2005;Fry et al 2009a;Warrell 2010;Casewell et al 2013), snake venom should instead be considered to be simply a modified form of saliva, where a relatively small number of gene families (typically 6-14) have expanded via gene duplication, often in a lineage-specific manner (Kulkeaw et al 2007;Wagstaff et al 2009;Fahmi et al 2012;Vonk et al 2013).…”

Section: Resultsmentioning

confidence: 99%

Restriction and recruitment - gene duplication and the origin and evolution of snake venom toxins

Hargreaves

Swain²,

Hegarty³

et al. 2014

Preprint

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The genetic and genomic mechanisms underlying evolutionary innovations are of fundamental importance to our understanding of animal evolution. Snake venom represents one such innovation and has been hypothesised to have originated and diversified via a process that involves duplication of genes encoding body proteins and subsequent recruitment of the copy to the venom gland where natural selection can act to develop or increase toxicity. However, gene duplication is known to be a rare event in vertebrate genomes and the recruitment of duplicated genes to a novel expression domain (neofunctionalisation) is an even rarer process that requires the evolution of novel combinations of transcription factor binding sites in upstream regulatory regions. This hypothesis concerning the evolution of snake venom is therefore very unlikely. Nonetheless, it is often assumed to be established fact and this has hampered research into the true origins of snake venom toxins. We have generated transcriptomic data for a diversity of body tissues and salivary and venom glands from venomous and non-venomous reptiles, which has allowed us to critically evaluate this hypothesis. Our comparative transcriptomic analysis of venom and salivary glands and body tissues in five species of reptile reveals that snake venom does not evolve via the hypothesised process of duplication and recruitment of body proteins. Indeed, our results show that many proposed venom toxins are in fact expressed in a wide variety of body tissues, including the salivary gland of non-venomous reptiles and have therefore been restricted to the venom gland following duplication, not recruited. Thus snake venom evolves via the duplication and subfunctionalisation of genes encoding existing salivary proteins. These results highlight the danger of the "just-so story" in evolutionary biology, where an elegant and intuitive idea is repeated so often that it assumes the mantle of established fact, to the detriment of the field as a whole.

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Venomics and antivenomics profiles of North African Cerastes cerastes and C. vipera populations reveals a potentially important therapeutic weakness

Cited by 48 publications

References 32 publications

General characterization of venom from the Moroccan snakes Macrovipera mauritanica and Cerastes cerastes

General characterization of venom from the Moroccan snakes Macrovipera mauritanica and Cerastes cerastes

Restriction and Recruitment—Gene Duplication and the Origin and Evolution of Snake Venom Toxins

Restriction and recruitment - gene duplication and the origin and evolution of snake venom toxins

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