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. 2020 Jul 25;7:100053. doi: 10.1016/j.toxcx.2020.100053

A brief review on the natural history, venomics and the medical importance of bushmaster (Lachesis) pit viper snakes

Rafaela Diniz-Sousa a,b,c,∗∗, Jeane do N Moraes a,b, Tainara M Rodrigues-da-Silva d, Cláudia S Oliveira a,b, Cleópatra A da S Caldeira a,b,∗
PMCID: PMC7408722  PMID: 32793880

Abstract

Snakes of the genus Lachesis, commonly known as bushmasters, are the largest venomous snakes in the Americas. Because these snakes have their habitats in areas of remote forests they are difficult to find, and consequently there are few studies of Lachesis taxa in their natural ecosystems. Bushmasters are distributed in tropical forest areas of South and Central America. In Brazil they can be found in the Amazon Rainforest and the Atlantic Forest. Despite the low incidence of cases, laquetic envenoming causes severe permanent sequelae due to the high amount of inoculated venom. These accidents are characterized by local pain, hemorrhage and myonecrosis that can be confused with bothropic envenomings. However, victims of Lachesis bites develop symptoms characteristic of Lachesis envenoming, known as vagal syndrome. An important message of this bibliographic synthesis exercise is that, despite having the proteomic profiles of all the taxa of the genus available, very few structure-function correlation studies have been carried out. Therefore the motivation for this review was to fill a gap in the literature on the genus Lachesis, about which there is no recent review. Here we discuss data scattered in a number of original articles published in specialized journals, spanning the evolutionary history and extant phylogeographic distribution of the bushmasters, their venom composition and diet, as well as the pathophysiology of their bites to humans and the biological activities and possible biotechnological applicability of their venom toxins.

Keywords: Snake venom, Genus lachesis, Bushmasters, Snakebite envenoming, Snake venom toxins

Highlights

  • •

    This review collects and discuss data of genus Lachesis scattered in the literature.

  • •

    Natural history, ecology and dietary habits of Lachesis taxa are reviewed.

  • •

    Bioactive components of Lachesis venom and their actions are reviewed.

  • •

    This review may help to put this genus of medically and ecologically relevant snakes in the spotlight of future studies.

1. Overview of genus Lachesis

Genus Lachesis (Daudin, 1803) (Viperidae: Crotalinae), commonly called in Brazil “Surucucu-pico-de-jaca” and in other countries “Bushmaster”. With the largest known specimens reaching 3.05–3.36 m (Bellairs, 1969), 3.35 m (Ditmars, 1937), 3.5 m (Abalos, 1977), 4.27 m (Dunn, 1951), and 4.5 m (Hoge and Lancini, 1962), bushmasters comprises the longest snakes in the Western Hemisphere, and the longest vipers (Viperidae: Crotalidae) in the world. Lachesis taxa are the only oviparous species (Fig. 1B) among New World vipers (Campbell and Lamar, 2004; McDiarmid et al., 1999). They lay up to 20 eggs to which the female provides parental care curling up in the eggs to protect them (Ditmars, 1910; Mole, 1924) (Fig. 1A). It has also been reported that females remain with eggs until hatching, and that males stay close to females for some time after mating (Emsley, 1977).

Fig. 1.

Fig. 1

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Lachesis sp in different behaviors. (A) Parental care of a L. stenophrys female along with the eggs (Corrales et al., 2014) (B) A neonate of L. acrochorda that just hatched (Daniel Fuentes and Corrales, 2016). Photos kindly provided by Greivin Corrales.

The four nominal species within Lachesis are nocturnal terrestrial venomous pit vipers found in primary and secondary forested areas of Central and South America and on the island of Trinidad (Campbell and Lamar, 2004; McDiarmid et al., 1999; Zamudio and Greene, 1997). The Central American bushmaster, L. stenophrys (Cope, 1975), is endemic to the Caribbean coast of Central America; the black-headed bushmaster, L. melanocephala (Solorzano and Cerdas, 1986) has an extremely limited distribution restricted to the Corcovado. National Park along the Pacific coast of southwestern Costa Rica, and possibly in the extreme western part of Panama. The Chocoan bushmaster L. acrochorda (Garcia, 1896) ranges in both the Atlantic and Pacific versants of western Panama and into northwestern Colombia, on the Atlantic coast where it extends southward into the Cauca and Magdalena river Valleys, and along the Pacific versant of Colombia into northwestern Ecuador. Among the two subspecies of L. muta (Linnaeus, 1766), the nominal subspecies, the South American bushmaster (L. muta muta), can be found in South America in the equatorial forests east of the Andes and the island of Trinidad, and the Atlantic Forest bushmaster, L. muta rhombeata (Wied-Neuwied, 1824) inhabits Coastal forests of southeastern Brazil, from southern Rio Grande do Norte to Rio de Janeiro (Fig. 2).

Fig. 2.

Fig. 2

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Geographic distribution of the genus Lachesis in Central and South America.L. muta muta (red: highest medical importance, and in orange: secondary medical importance) distributed in the following countries: Venezuela, Colombia, Trinidad and Tobago, Guyana, Suriname, French Guiana, Ecuador, Perú, Bolivia and Brazil (in the States: Goiânia, Mato-Grosso, Tocantis, Para, Amazonas, Rondônia, Acre, Amapá, Roraima and Maranhão). Photo: Paulo Sérgio Bernarde. L. m. rhombeata (blue), found in Coastal forest of southeastern Brazil (Ceara, Rio de Janeiro, Paraíba, Pernambuco, Bahia, Espirito Santo, Minas Gerais, Alagoas and Rio Grande do Norte). L. acrochorda (green) found in the countries: Panamá, Colombia e Ecuador. Photo: Jairo Maldonado. L. stenophrys (yellow) found in Costa Rica and Panamá. Photo: Instituto Clodomiro Picado. L. melanocephala (gray) found in Costa Rica. Photo: Jaime Culebras. Maps taken from (World Health Organization) (https://apps.who.int/bloodproducts/snakeantivenoms/database/).

The Central and South American forms diverged 18–6 Mya, perhaps due to the uplifting of the Andes, whereas the two Central American subspecies may have diverged 11–4 Mya with the uprising of the Cordillera de Talamanca that separates them today (Zamudio and Greene, 1997). The split between Central American L. melanocephala and L. stenophrys is estimated to have taken place 11–4 Mya, and differentiation among the South American lineages happened only 800,000 to 300,000 years ago (Fernandes et al., 2004; Zamudio and Greene, 1997) (Fig. 3).

Fig. 3.

Fig. 3

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Phylogenetic tree of genus Lachesis highlighting the estimated divergence time between the Central and South American taxa (Zamudio and Greene, 1997), the remarkably similar overall venom compositional profiles among the five species of Central and South American bushmasters (Pla et al., 2013; Sanz et al., 2008), and the ontogenetic changes in the venom composition of L. stenophrys (Madrigal et al., 2012). La, L. acrochorda; Lme, L. melanocephala; Lmm, L. muta muta; Lmr, L. m. rhombeata; Ls, L. stenophrys. Acronyms = VAP: BPP, bradykinin-potentiating peptide, and C-NP, type natriuretic peptide; D49-PLA2, Asp49 phospholipase A2; SP, snake venom serine proteinase; LAO, L-aminoacid oxidase; SVMP, snake venom metalloproteinase; CTL: Gal lectin, galactose-specific lectin; svVEGF, snake venom vascular endothelial growth factor; CRISP, cysteine-rich secretory protein. Phylogenetic scheme adapted from Fig. 5 (Calvete, 2017), kindly provided by Professor Juan Calvete.

Bushmaster can live long. There are records of a male of L. m. muta that lived for more than 16 years in captivity at the Fort Worth Zoo and a specimen of L. stenophrys that lasted 31 years and 7 months at the Atlanta Zoo (Slavens and Slavens, 2000). Campbell and Lamar (2004) also mention an L. stenophrys from Costa Rica, kept for almost 30 years in Europe. However, there are no data on longevity in its natural ecosystem.

Bushmasters prey primarily on small mammals, such as rodents and marsupials (Beebe, 1946; Cunha and Nascimento, 1993; Martins and Oliveira, 1998; Medem, 1969; Mole, 1924), but also hedgehog (Fountain, 1902), birds and amphibians (Carrillo de Espinoza, 1970). Although the specimens examined were adults, the prey was relatively small. Juvenile snakes (and some adults) maintain control when attacking prey, and an epicantic fold protects the eyes from possible damage during predation. Juvenile individuals may have the tip of the tail bright orange or yellow, but tail movements to attract prey ("tail luring") has not been reported (Ripa, 2001).

Lachesis, daughter of Erebus (Darkness) and Nyx (Night), is a goddess who in the Greek mythology assigned individual destinies to mortals at birth. This epithet given to the homonymous genus may refer to the feeling that during an encounter with these imposing snakes one's own fate is momentarily at the snake's will. However, human envenomings by Lachesis taxa are infrequent as these snakes do not exhibit aggressive behavior, inhabit shelters in fallen trees, burrows and excavations of rodents or in rocky caves of remote forest area (Fonseca, 1949), where contact with man is scarce (Souza, 2007). Lachesis have nocturnal habits, remaining throughout the day in a state of torpor. Only in the breeding season, males are on day alert and ready for combat. In addition, venom lethality is weak compared to those of some other vipers (Bolaños, 1972; da Silva et al., 2020). Brown (1973) quote the following LD50 values of L. m. muta venom for mice: 1.5 mg/kg (intravenous), 1.6–6.2 mg/kg (intraperitoneal) and 6.0 mg/kg (subcutaneous). Nevertheless, human envenomings can be rather severe due to the large venom yield (200–411 mg) (Brown, 1973; Málaque and França, 2003).

Venomics studies have been conducted on all species and subspecies within genus Lachesis (Madrigal et al., 2012; Pla et al., 2013; Sanz et al., 2008). Comparison of their venom proteomes provided an overview of the geographic and ontogenetic variation of the toxic arsenal across genus Lachesis. Hence, notwithstanding minor qualitative and quantitative differences, the venom arsenals of L. melanocephala and L. acrochorda are broadly similar between themselves and also closely mirror those of adult L. stenophrys and L. muta venoms. On the other hand, the toxin composition of L. stenophrys venom undergoes ontogenetic changes, which involve changes in the concentration of vasoactive peptides and serine proteinases, which steadily decrease from birth to adulthood, and age-dependent biosynthesis of Gal-lectin and snake venom metalloproteinases (SVMPs). The net result is a shift from a bradykinin-potentiating and C-type natriuretic peptide (BPP/C-NP)-rich and serine proteinase-rich venom in newborns and 2-years-old juveniles to a (PI > PIII) SVMP-rich venom in adults (Madrigal et al., 2012). The venom of newborn L. stenophrys has lower toxicity to mice than venom from older conspecific snakes (Gutiérrez et al., 1990). However, bites by a 10 to 14-day-old and a 2-month-old L. stenophrys specimens produced substantial toxicity to humans, which similar to an adult bite completely overwhelmed the 80 kg victim within 30 min (Ripa, 2003). The venomics analysis of neonate and juvenile L. stenophrys suggests that the high content of vasoactive peptides and serine proteinases may be responsible for the high toxicity of newborn venom in humans. On the other hand, the high similarity of their venom proteomes is mirrored by a high immunological conservation across the genus (Pla et al., 2013). A corollary of this fortunate circumstance is that antivenoms generated against venom mixtures containing any Lachesis spp. venom may exhibit paraspecific protection against (Daltry et al., 1996; Davies and Arbuckle, 2019) the toxic activities of venoms from any other congeneric species (Madrigal et al., 2017).

Adaptations result from selective pressures on both morphological and molecular phenotypic traits that maximize the organism's fitness in local environments, e.g., the snake foraging success on preferred prey. Venom is an intrinsically ecological trophic trait crucial for the foraging success of the organisms that produce it. Hence, functional evolution of venoms is intimately linked to the ecology and dietary habits of the venomous organisms. A still small but increasing number of studies support the idea that snake venom evolution is driven by diet-related selection pressures leading to local adaptations (Barlow et al., 2009; Barua and Mikheyev, 2019; Daltry et al., 1996; Davies and Arbuckle, 2019; Jackson et al., 2004; Smiley-Walters et al., 2019). Consequently, the changes in toxic characteristics of venom that ocurr during the development of L. stenophrys (Madrigal et al., 2012), should be rationalized in the context of its use by the venomous predator. Optimal foraging theory predicts that juvenile gape-limited predators should feed efficiently in order to compete with adults for food (Schoener, 1971) and to minimize their exposure to predators (Sih et al., 1985). Carrier (1996) predicted that juvenile animals should compensate for their small size by increasing their overall performance relative to adults (compensation hypothesis, e.g. decreased ingestion and/or handling times relative to body size compared with adults). In line with this view, concomitantly with age-dependent venom compositional changes, newborn L. stenophrys venom showed highest coagulant effect on human plasma, in line with its high serine proteinase content, whereas the venom lethal, proteolytic, hemorrhagic, edema-forming, myotoxic, and PLA2 activities raise as snakes aged (Gutiérrez et al., 1990). The different pharmacological effects of venom from neonate and adult individuals is mirrored by clinical reports indicating that human envenomings by juvenile specimens are often associated to prominent alterations and symptoms despite the low amount of venom that a small size specimens may inject in a bite (Chaves et al., 1992; Gutiérrez et al., 1980). Neonate L. stenophrys specimens produce substantial toxicity to humans, which similar to an adult bite completely overwhelmed an 80 kg victim within 30 min (Ripa, 2003). The proteomic analysis of ontogenetic changes in L. stenophrys venom suggests that the high content of vasoactive peptides and serine proteinases may be responsible for the high toxicity of newborn L. stenophrys venom in humans (Madrigal et al., 2012).

Age-related changes in venom composition, as it happens in L. stenophrys, have been reported in a number of New World pit viper species from different genera, i.e. Crotalus, Bothrops, Sistrurus, and Bothiechis (Alape-Girón et al., 2008; Calvete et al., 2011, 2010; Gibbs et al., 2011; Gonçalves-Machado et al., 2016; Guércio et al., 2006; Mackessy, 1988; Pla et al., 2017; Saldarriaga et al., 2003; Zelanis et al., 2010, 2008, 2011). A similar pattern was noted for the Brown Treesnake (Boiga irregularis), with juvenile venoms more toxic than adult venoms towards geckos (Mackessy et al., 2006), suggesting that this trend has not exclusively evolved in pit vipers. A shift in the feeding habits of juvenile versus adult snakes, from cold-blooded (arthropods, frogs and lizards) to warm-blooded (mammals) prey, has been invoked to explain the ontogenetic venom change in some pitviper species (Andrade and Abe, 1999). In concordance with this view, it has been documented that venoms from neonate snakes are more toxic to lizards and inbred mice than adult venoms (Mackessy, 1988). Young Bothrops snakes preferentially eat amphibians, lizards, birds, and shift to mammals when they become adults (Campbell and Lamar, 2004). However, Lachesis taxa feed from birth on vertebrates, primarily rodents (i.e., brown mice (Akodon), rice rats (Oryzomys), spiny rats (Proechimys)) and marsupials of the family Didelphidae (Campbell and Lamar, 2004). Similarly, the venom composition of the Central American rattlesnake, Crotalus simus, a species that feeds from its birth primarily on small rodents and lizards (Calvete et al., 2010), changes dramatically during development, from a neurotoxic to a hemorrhagic phenotype, and these ontogenetic changes appears to be post-transcriptionally modulated by miRNAs (Durban et al., 2013). Predator body size is one of the most important factors shaping predator–prey interactions (Jackson et al., 2004; Persson and Hansson, 1999; Peters, 1983), and dietary decisions define the trophic niche of the organism and have significant implications on the individual's energy budget. Ontogenetic venom composition shift resulting in a different pharmacological venom profile, may fulfill the requirements to subdue prey of different sizes and initiate its digestion may change with the size of both the predator and the prey. This is particularly important when a large prey (in relation to the snake's digestive apparatus size) is ingested. Biochemical features of venom that enhance trophic functions are likely very important for snakes. It has been hypothesized that tissue-degrading enhancement of venom may facilitate efficient prey digestion at suboptimal temperatures encountered in the field, thereby reducing the risk of prey putrefying before it can be digested (Thomas and Pough, 1979). Putrefaction forces a snake to regurgitate its prey, which had been swallowed whole, head first without mastication. Regurgitation can thus be a severe, and in some instances a life-threatening problem (Flannagan and Harwell, 1983). Injection of proteolytic venom may hasten the entrance of the acidic secretions of the snake's stomach into the prey's gut, reducing or eliminating the action the putrefactive bacteria (Thomas and Pough, 1979). It is therefore not unreasonable to suggest that he high amounts of histolytic enzymes contained in the venom of newborn L. stenophrys snakes may serve to breakdown the bolus, contributing to reduce the chances of putrefaction of the ingested prey.

2. Lachesis envenoming: epidemiology, symptoms and treatment

Snakebites by front-fanged snakes is an occupational disease that cause envenomings to at least 1.8–2.7 million people worldwide per year, with combined upper WHO estimates of mortality ranging from 81,000 to 138,000 deaths, and maims >400,000 people every year (Chippaux et al., 2019; Chippaux, 1998; Gutiérrez et al., 2017; Williams et al., 2019). The only scientific validated treatment of snakebite envenoming is the timely administration of an effective antivenoms (Gutiérrez, 2014; Gutiérrez et al., 2011a, 2011b). One of the greatest limitations for developing effective interventions for snakebite envenomation is the paucity of reliable information on incidence and mortality (Gutiérrez and Fan, 2018). A recent report on data gathered from Ministries of Health the specialized literature identified a total of 57,500 snakebite cases in the Americas, 370 of which resulted in death (Chippaux, 2017). However, due to the limitations of the information systems in many countries where snakebite reporting is not compulsory, these figures are likely to be underestimations.

In Brazil, snakebites are mainly associated with agricultural work and, in the Amazon region, also with extractive activities (Silva et al., 2020; Feitosa et al., 2015; Pierini et al., 1996; Waldez and Vogt, 2009). Approximately 29,000 cases of snakebite accidents are reported each year by the SINAN (Reporting Disease Information System), with an average of 129 yearly deaths (0.44% lethality) (Bernarde, 2014). According to data from the Ministry of Health, 939 laquetic accidents were reported in Brazil in the period 1990–1993. This figure is equivalent to 1.4% of the total envenomings caused by venomous snakes in Brazil (Brasil, 1996). Another study carried out from 2001 to 2015 reported 13,044 accidents (84 deaths) by the Lachesis taxa, i.e. approximately 869 accidents per year (Magalhães, 2017). In the Amazon region bites caused by Lachesis taxa in the period 2010–2015 were responsible for 5217 cases, only superated by envenomations caused by snakes of genus Bothrops (57,374 cases, 81.02%, including a high proportion of deaths (74.48%) and amputations (86.88%) among the victims) (Magalhães et al., 2018). In line with these data, a recent study by da Silva and coworkers (2020), conducted in the Alto Juruá, a region in the western Brazilian Amazonia, also reported low frequency of accidents caused by Lachesis snakebites. Despite these data, in the same study da Silva and coworkers (2020) investigated the ethnobiological perception of dangerousness of different snake species by the population of the rural areas of Alto Juruá. Interviews to 100 villagers active in the forests revealed that L. muta muta was considered the most dangerous venomous snake, and B. atrox appeared to be the most feared snake species. The authors interpreted that the high incidence, severity, and mortality of B. atrox bites and the severity and mortality of L. muta bites represented the factors that contributed to these species being perceived as the most feared and venomous snakes, respectively. This villagers' perception reflects the fact that although encounters with human are infrequent owing to their little aggressive behavior and elusive ecological habits, envenomings by Lachesis taxa are characterized by the high amounts of venom inoculated, (200–411 mg) (Brown, 1973; Málaque and França, 2003), which makes bite by bushmasters serious and result in high rates of permanent sequelae and mortality (Oliveira et al., 2002; Sánchez et al., 1992; Tanus Jorge et al., 1997).

The symptoms of envenomations caused by Lachesis taxa can be similar to those observed in bothropic envenomings, i.e. local pain, edema, hemorrhage and myonecrosis. Distinct features of bites by Lachesis taxa are agonizing burning-throbbing local pain and edema, within the first few minutes after the bite, followed within the next within 15–20 min by a “vagal symptomatology” characterized by profuse sweating, abdominal colic, nausea, recurrent vomiting, watery diarrhea, diastolic and systolic hypotension, sinus bradycardia, uncoordinated march, lapses of consciousness (Silva-Haad, 1982; Warrell, 2004). The vagal syndrome, may assists in the differential diagnosis between laquetic and bothropic accidents (de Lima and Junior, 2015; Tanus Jorge et al., 1997). Laquetic accidents are classified according to their clinical manifestations as i) Mild: mild or absent edema and mild or absent hemorrhagic manifestations. Absence of vagal manifestations; ii) Moderate: with evident edema and discrete hemorrhagic manifestations at a distance (gingivorrhagia, epistaxis). Absence of vagal manifestations; and iii) Severe: presence of severe edema and systemic manifestations such as profuse hemorrhage. Presence of vagal manifestations (diarrhea, bradycardia, hypotension or shock) (Souza et al., 2020) (Table 1). In Brazil, treatment of laquetic envenoming is based on the severity of the accident, administering when necessary the Brazilian Soro Antibotrópico-Laquético (SABL) intravenously (Brasil, 2001; Pardal et al., 2007). The antivenom, manufactured at Instituto Butantan (São Paulo, Brazil), is obtained from the plasma of horses hyperimmunized with a mixture of venoms from five species of snakes of genus Bothrops (B. jararaca (50%), B. jararacussu (12.5%), B. moojeni (12.5%), B. alternatus (12.5%) and B. neuwiedi (12.5%) and from the plasma of horses hyperimmunized with venom of L. muta. The final formulation consists of purified F(ab')2 fragments generated by digestion with pepsin of ammonium sulphate-precipitated IgG molecules. A vial of SABL (10 mL) nominally neutralizes at least 50.0 mg of B. jararaca venom (the reference venom for assessing the bothropic antivenom potency in Brazil) and no less than 30 mg of the L. muta reference venom (Brasil, 1996; Monaco, 2018; Raw et al., 1991).

Table 1.

Serotherapy and clinical manifestations of laquetic accidents.

ACTIVITY
 CLASSIFICATION AND INITIAL CLINICAL EVALUATION
Serotherapy No. of ampoules Moderate
 Severe
10 20
Route of administration Endovenous
Acute inflammatory Endothelial injury and necrosis at the bite site. Release of inflammatory mediators.
Coagulant Blood incoagulability
Hemorrhagic Bleeding in the bite region (ecchymosis) and at distance (gingival, hematuria).
Vagal neurotoxic Cholinergic stimulation (vomiting, abdominal pain, diarrhea, hypotension, shock).
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(Source: adapted from Brazil, 2019)

Key technical issues concerning the generation of an antidote for snakebite envenoming are i) the design of the immunization mixture in such a way that the resulting antivenoms results effective against most venoms of the medically-relevant snake species within the geographical range where these antivenoms is intended to be used, and ii) a reliable taxonomy. This purpose is not trivial given the well-documented occurrence of venom variability at all the taxonomic levels (genus, species, subspecies, population and individual) (Calvete et al., 2013) and the instability of the phylogeny of certain snake clades (Carrasco et al., 2016). In addition, the rational generation of polyvalent antivenoms of broad clinical spectrum require a deep understanding of the toxicovenomics profile of the target venoms (Gutiérrez et al., 2014). Toxicovenomics refers to the screening of individual venom fractions of a toxin-resolved chromatographic profile for specific toxic activities (Lauridsen et al., 2016; Lomonte and Calvete, 2017). Genus Lachesis meets these criteria for what we can consider it a prospective model system to define knowledge-based omics strategies (Calvete et al., 2018, 2014) for the production of next-generation pan-generic antivenoms.

3. Bioactive components of Lachesis venom

Lachesis m. muta venom gland transcriptomic analysis (Junqueira-de-Azevedo et al., 2006) and proteomic analyses of the venoms of all the nominal species and subspecies within genus Lachesis: L. m. muta, (Sanz et al., 2008); L. m. rhombeata (Pla et al., 2013); L. stenophrys, L. acrochorda, and L. melanocephala (Madrigal et al., 2012), have provided a genus-wide insight into the overall complexity of their toxic arsenals. Bushmaster venoms comprise a relatively conserved set of proteins and peptides, belonging to just a few major (i.e. relative abundances between 10 and 30% of the total venom proteome: bradykinin-potentiating peptides; snake venom serine proteinases; PIII- and PI-snake venom metalloproteinases; and PLA2) and minor (L-aminoacid oxidase; galactose-specific lectin; vascular endothelial growth factor; cysteine-rich secretory protein; phospholipase B; and hyaluronidase) toxin families (Fig. 2 and Fig. 4). Pairwise comparisons showed overall similarities of 33–51% across the different conspecific venom proteomes (Pla et al., 2013), with PLA2 showing the greatest interspecific variability (Sanz et al., 2008). Despite the wealth of low-resolution proteomics and biochemical information available (Table 2) (Bregge-Silva et al., 2012; Damico et al., 2005), the timing and relevance of individual venom proteins and overall venom proteome divergence in the mechanisms of adaptation to local ecosystems and speciation of the Bushmasters remains elusive.

Fig. 4.

Fig. 4

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Distribution of Lachesis venom toxin families from which individual toxins have been isolated and charaterized (Table 2). Toxin families are represented as gray bars and the different color lines refer to the species/subspecies. Discontinuous gray lines indicate absence of data on isolated toxins from the Lachesis taxa labeled with an asterisk.

Table 2.

Main components characterized in venoms of the genus Lachesis.

NAME SPECIE PROTEIN/PEPTIDE MOLECULAR
MASS (kDa)		 BIOLOGICAL PROPERTIES THERAPEUTIC POTENTIAL REFERENCES
LmrBPP9 L. m. rhombeata Bradykinin-potentiating peptides (BPP) 1.08 Inhibit ACE activity in vitro Hypotensive effect Pinheiro-Júnior et al. (2018)
Lmr-MP L. m. rhombeata Metalloproteinase 22.85 Proteolytic activity on synthetic substrate of human kallikrein – Cordeiro et al. (2018)
LmrSP-4 L. m. rhombeata Serine proteinase 28.19 Aα- fibrinogenolytic;
Proteolytic activity on synthetic substrate of human kallikrein		 – Wiezel et al. (2019)
LmrLEC-1 L. m. rhombeata C-type lectin ~14 – – Wiezel et al. (2019)
LmuTX L. m. muta PLA2 Lys-49 13.8 Cytotoxicity on C2C12 cells differentiated in myotubes Antibacterial activity against strains of MRSA and Pseudomonas aeruginosa Diniz-Sousa et al. (2018)
LmLAAO L. muta L-amino acid oxidase (LAAO) 60 Without myotoxic activities, hemorrhagic and edematogenic Cytotoxic activity on AGS and MCF-7 cells; L. braziliensis activity Bregge-Silva et al. (2012)
Stenoxobin L. stenophyrs Serine proteinase (thrombin-like) 37 α and β- fibrinogenolytic – Aragon-Ortiz and Gubensek (1993)
LsPA-1 L. stenophyrs PLA2 Asp49 13.87 – – De Assis et al. (2008)
LmTX-I L. m. muta Basic PLA2 Asp49 14.24 Phospholipase activity on synthetic substrates; edema; myotoxicity; neurotoxicity – (Damico et al., 2008, 2006, 2005)
LmTX-II L. m. muta Basic PLA2 Asp49 14.18 Phospholipase activity on synthetic substrates – Damico et al. (2005)
LmrTX L. m. rhombeata Basic PLA2 Asp49 14.27 Anticoagulant and antithrombotic activities – Damico et al. (2012)
Lmr-PLA2 L. m. rhombeata Acidic PLA2 Asp49 13.97 Inhibition of platelet aggregation – Cordeiro et al. (2015)
LV-Ka L. m. muta Serine proteinase (calicreína-símile) 33 Plasminogen activation – Felicori et al. (2003)
LM-PLA2-I L. muta Acidic PLA2 Asp49 – Myotoxicity – Fuly et al. (2000)
LM-PLA2-II L. muta Acidic PLA2 Asp49 18 Myotoxicity; inhibition of platelet aggregation; edematogenic activity. – (Fuly et al., 2003, 2002)
TLE-B L. m. muta Serine proteinase 44 α and β- fibrinogenolytic. – Magalhaes et al. (2003)
TLB-P L. m. muta Serine proteinase 43 α and β- fibrinogenolytic. – Magalhaes et al. (2003)
Mutalisin I (LHF-I) L. m. muta Metalloproteinase 100 α and β-fibrinogenolytic; high hemorrhagic activity; caseinolytic activity. – (Sanchez et al., 1995, 1987)
Mutalisin II (LHF-II) L. m. muta Metalloproteinase 22 Degradation of laminin, fibronectin and type IV collagen; edematogenic; low hemorrhagic activity. Thrombolytic effect (Agero et al., 2007; Rucavado et al., 1999; Sánchez et al., 1991)
Mut IIa L. m. muta Mutalisin isoform II ≈23 α and β- fibrinogenolytic; proteolytic activity on dimethylcasein. – Sánchez et al. (2003)
Mut IIb L. m. muta Mutalisin isoform II ≈23 α e β-fibrinogenolítica; proteolytic activity on dimethylcasein. – Sánchez et al. (2003)
Hyaluronidase L. m. rhombeata Hyaluronidase 60 – – Wiezel et al. (2015)
PLB L. m. rhombeata Phospholipase B – – – Wiezel et al. (2015)
LMR-47 L. m. rhombeata Serine proteinase (gyroxin) 47 α - fibrinogenolytic – Aguiar et al. (1996)
Protein similar to lectin L. stenophyrs Lectin 16.2 Hemagglutination – (Aragón-Ortiz et al., 1996; Aragón-Ortíz et al., 1989)
Lachesin L. muta Disintegrin – Inhibition of platelet aggregation; binding to integrin αIIbβ3 – Scarborough et al. (1993)
LSF L. stenophyrs Metalloproteinase 24 – – Leonardi et al. (1999)
Serine proteinase L. m. muta Serine proteinase 45 – – Magalhães et al. (1997)
Kininogenin L. muta Serine proteinase 29.7 Hypotensive effect Diniz et al. (1992)
Gyroxin L. m. muta Serine proteinase ≈60 High lethality – da Silva et al. (1989)
Thrombin-like L. m. muta Serine proteinase ≈41-47 Fibrinogenolytic – Silveira et al. (1989)
Serine proteinase L. m. muta Serine proteinase 40 α and β- fibrinogenolytic – Yarleque et al. (1989)
Arginine esterase L. muta – ≈30 Arginyl esterase activity – Silva et al. (1985)
BIP L. muta Bradykinin inhibitor 1.06 Inhibitory activity on bradykinin via B2 receptors – Graham et al. (2005)
βPLIs L. muta Beta-type inhibitors PLA2s 36.5 – – Lima et al. (2011)
LNF1 and LNF2 L. m. muta Gamma-type inhibitors
PLA2s		 ≈20 – – Fortes-Dias et al. (2003)
Thrombin-like/analogous to gyroxin L. m. muta Serine proteinase 25.6 – – Magalhaes et al. (1993)
LV-PA L. m. muta Serine proteinase 33 Plasminogen activation – (Sanchez et al., 2006, 2000)
Lm-BPP 1 to 5 and Lm-CNP L. muta BPPs and C-type natriuretic peptides 1 a 2.2 – – Soares et al. (2005)
Open in a new tab

Table 2 lists molecules characterized in Lachesis venoms. Most of these proteins are myotoxins, neurotoxins, anticoagulant and antithrombotic PLA2s, thrombin-like, gyroxin and kallikrein serine proteinases, and hemorrhagic PIII-metalloproteinases, including L. m. muta LHF-I and II and a new P-1 class metalloproteinase (Lmr-MP) isolated from the venom of L. m. rhombeata venom (Cordeiro et al., 2018). Other toxins, include serine proteinase (LmrSP-4), type C lectin (LmrLEC-1) (Wiezel et al., 2019) and bradykinin-potentiating peptides (Pinheiro-Júnior et al., 2018). However, little is known about the biological roles of these proteins and peptides in the mechanisms underlying Lachesis envenoming. Furthermore, there are few superficial investigations on the biotechnological potential of Lachesis venom components, with biological activities mainly restricted to hypotensive effect (Diniz et al., 1992; Pinheiro-Júnior et al., 2018), thrombolytic activity (Agero et al., 2007; Rucavado et al., 1999; Sánchez et al., 1991), antimicrobial activity against methicillin-resistant strains of Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (Diniz-Sousa et al., 2018), and antiparasitic activity against Leishmania braziliensis (Bregge-Silva et al., 2012).

4. Concluding remarks and perspectives

Bushmaster are important components of tropical ecosystems. However, our understanding of the details of their natural history, ecology and dietary habits of Lachesis taxa in the wild is scarce and limited to only some species of the genus (Campbell and Lamar, 2004; Ripa, 2001; Savage, 2002; Solórzano, 2004; Zamudio and Greene, 1997), and a good number of reports are derived from observations of specimens in captivity (Boyer et al., 2007; Chacón and Valverde, 2004; Corrales et al., 2014; Ripa, 1994; Souza, 2007). This is, in part, due to the challenge of observing these snakes in their natural habitats in remote tropical moist forested areas where, except during breeding activities, bushmasters are solitary crepuscular or nocturnal predators (Campbell and Lamar, 2004). The limited work conducted on bushmaster species suggests these snakes are dependent on several specific resources and are thus particularly susceptible to disturbance. Hence, due to habitat destruction, the population density of Lachesis taxa has decreased worryingly to the point that L. muta. ssp. rhombeata, which exhibits the broadest range in the Amazon region of Brazil and surrounding countries, is listed as vulnerable according to the IUCN Red List of Threatened Species criteria and considered endangered throughout its range (IUCN, 2000). Habitat loss, pollution and poaching are the main reasons for its decline. At the other extreme, the Atlantic bushmaster L. m. rhombeata, a species endemic to Brazil, has a very restricted distribution that is becoming increasingly fragmented through deforestation for using the cleared areas for agriculture and human settlements (Martins and Marques, 2000). Another species, the black-headed bushmaster L. melanocephala, inhabits also a very small geographic range, including tropical, premontane and montane humid, very humid, and pluvial forests. The limited work that has been conducted on this bushmaster species suggests that it is particularly susceptible to disturbance (Solórzano, 2004). Due to its restricted geographic range and habitat specificity, the severe and continued loss of lowland and mid-elevation forests throughout its range pose serious threats to the persistence of the endemic black-headed bushmaster in Costa Rica and Panamá (González-Maya et al., 2014). The paucity of information on L. melanocephala, which is due in large part to its cryptic nature spending much time underground and its occurrence at low densities, prevents any effective conservation actions for this species.

Omic technologies, including comparative genomics across the reptile phylogeny along with paleogeographic niche reconstruction, can provide important insights into the ecological factor and evolutionary pressures that shaped the explosive diversification of many species-rich clades, including caenophidian snakes, in the wake of the Cretaceous-Paleogene (K-Pg) Mass Extinction 66 Mya, when a massive asteroid struck the Earth, brought a calamitous end to the reign of dinosaurs, and account for the loss of 75 percent of known species (Alvarez et al., 1980; Gulick et al., 2019). The K-Pg global mass extinction event left numerous ecological niches vacant creating new ecological opportunities (Feng et al., 2017; Hsiang et al., 2015; Martill et al., 2015; Pyron and Burbrink, 2012; Skipwith et al., 2019). Although some aspects of the phylogeny of some clades within the medically important snake families Viperidae, Elapidae, and Colubridae are still under dispute, in general, their phylogenetic relationships and time of divergence between lineages are well supported from fossil and molecular (nuclear and mitochondrial gene) information (Alencar et al., 2016; Pyron et al., 2013; Reeder et al., 2015; Zaher et al., 2019). Venom emerged as a key evolutionary innovation that underpinned the explosive radiation of caenophidian snakes. A reliable phylogeny is key to establishing the evolutionary trends that have shaped the patterns of venom across the speciation of a clade of snakes.

An increasing trend in venom analysis is the identification of evolutionary trends across whole genera, taxonomic clades, and phylogenetic families. The overall picture, rather than the individual venom proteomes, provides hints for reconstructing the origin of evolutionary trends (Calvete, 2017, 2013). Lachesis represents one of the few snake genus for which the venom proteomes of all its species have been unveiled. Mapping the pattern of present-day venom variability into a phylogenetic and biogeographic framework may lay the foundation for understanding the evolutionary trends that have shaped the venomic landscape across the clade. In addition, the genome also encodes traces from both functionally-failed recombinations and those that passed the natural selection filter and contributed to the functional genome of the species (Kvon et al., 2016; Li et al., 2018; Lind et al., 2019; Pasquesi et al., 2018; Peng et al., 2020; Perry et al., 2018; Reyes-Velasco et al., 2020; Schield et al., 2019). The development of comparative genomics in the last 20 years has taught us that no lineage can be studied genomically in isolation from related lineages. However, despite the genomes of birds and nonavian reptiles will not only uncover a treasure trove of biological information to reconstruct the evolution of venomous reptiles and their venom genes, but are also critical for understanding genome evolution in mammals and amniotes generally (Janes et al., 2010; Tollis et al., 2018, 2014), snake genome sequencing is in its infancy. Squamates exhibit some of the most extreme and fascinating biological adaptations among vertebrates (Shaney et al., 2014). However, genomic resources are currently only available for a handful of squamous reptiles (Alföldi et al., 2011; Castoe et al., 2013; Giorgianni et al., 2020; Green et al., 2014; Kerkkamp et al., 2016; Li et al., 2018; Lind et al., 2019; Peng et al., 2020; Schield et al., 2019; Shibata et al., 2018; Suryamohan et al., 2020; Tollis et al., 2014; Ullate-Agote et al., 2014; Vonk et al., 2013; Yin et al., 2016). Comparative Squamata omics (genomics, transcriptomics, and proteomics) will play a fundamental role in filling this gap and addressing the connection between genome evolution and the present-day adaptive phenotype for fitness related traits (Cenik et al., 2015; Drukewitz and von Reumont, 2019; Eckalbar et al., 2013; Hajirasouliha and Tilgner, 2019).

The wide spectrum of pathological and pathophysiological manifestations of snake envenomings, due to the concerted actions of the unpredictable venom variability across the phylogeny and distribution range of extant snakes, represents a great challenge for the development, and preclinical evaluation of the efficacy of antivenoms. From a biotechnological stand point, this goal requires knowing the phylogeographical patterns of present-day snake venoms, identifying their most medically-important molecules in the context of a human envenoming, and assessing the specific and para-specific efficacy of current antivenoms against the different medically relevant snake venoms. For the case of genus Lachesis, the high conservation of the overall composition of Central and South American bushmaster venoms provides the ground for rationalizing the “Lachesis syndrome" documented in envenomings by different species of this wide-ranging genus. From an evolutionary ecology perspective legitimate human snake envenomings result from defensive bites inflicted by sympatric venomous snakes when snake and human have a fortuitous encounter in their shared natural environment that blows the snake's alarms. In this context, knowledge gained on the natural history and organismal physiology of medically important snakes, particularly those that prey on mammals, have conceptually applicability in clinical toxinology as in the ecological context, highlighting the mutually enlightening relationship between evolutionary and translational venomics (Calvete, 2019).

Clearly, we believe that it is not an exaggeration to conclude that our field, molecular toxinology, has a very exciting future ahead. We trust this short review on the bushmasters may help to put this genus of medically and ecologically relevant snakes in the spotlight of near future basic and applied developments.

Credit author statement

Rafaela Diniz-Sousa: Conceptualization, Writing, Data curation and Formal analysis, Editing, Jeane do N. Moraes: Writing, Data curation and Formal analysis, Tainara M. Rodrigues-da-Silva: Writing, Data curation and Formal analysis, Cláudia S. Oliveira: Writing, Cleópatra A. da S. Caldeira: Conceptualization, Writing, Data curation and Formal analysis, Editing.

Ethical statement

International ethical guidelines for scientific papers were followed in the preparation of this.

Funding

The authors wish to express their gratitude to Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq/MCTIC), Brazil; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/MEC), Brazil; Program for Technological Development in Tools for Health-PDTIS-FIOCRUZ, Brazil for the use of its facilities and Fundação Rondônia de Amparo ao Desenvolvimento das Ações Cientificas e Tecnológicas de Pesquisa do Estado de Rondônia (FAPERO), Brazil for financial support.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

The authors wish to gratefully acknowledge the collaboration and great assistance of Dr. Juan J. Calvete and Dr. Andreimar Martins Soares for reviewing the manuscript. Authors gratefully thank Dr. Paulo Sérgio Bernarde for the kind donation of the pictures of Lachesis muta and Professor Greivin Corrales for permission to include in this review pictures of L. stenophrys and L. acrochorda.

Contributor Information

Rafaela Diniz-Sousa, Email: raf.dinizs@gmail.com.

Jeane do N. Moraes, Email: jeanemoraes2009@gmail.com.

Tainara M. Rodrigues-da-Silva, Email: tainara.maiane.tm@gmail.com.

Cláudia S. Oliveira, Email: claudiasiqueira.cebio@gmail.com.

Cleópatra A. da S. Caldeira, Email: cleobiol@gmail.com.

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