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Accidents caused by Loxosceles spiders, commonly known as brown spiders, are frequent in warm and temperate regions worldwide, with a higher prevalence in South America and the southern United States. In the venoms of species clinically associated with accidents, phospholipases D (PLDs) are the most expressed toxins. This classification is based on the toxins’ ability to cleave various phospholipids, with a preference for sphingomyelin. Studies using purified PLDs have demonstrated that these enzymes cleave phospholipids from cells, producing derivatives that can activate leukocytes. A dysregulated inflammatory response is the primary effect following envenomation, leading to dermonecrosis, which is histopathologically characterized by aseptic coagulative necrosis—a key feature of envenomation. Although advances in understanding the structure–function relationship of enzymes have been achieved through molecular biology, heterologous expression, site-directed mutations, crystallography, and bioinformatic analyses—describing PLDs in the venoms of various species and highlighting the conservation of amino acid residues involved in catalysis, substrate binding, and magnesium stabilization—little is known about the cellular biology of these PLDs. Studies have shown that the treatment of various cells with recombinant PLDs stimulates the formation of ectosomes and ectocytosis, events that initiate a cascade of intracellular signaling in PLD-binding cells and lead to the release of extracellular microvesicles. These microvesicles may act as signalosomes for other target cells, thereby triggering an inflammatory response and dermonecrosis. In this review, we will discuss the biochemical properties of PLDs, the target cells that bind to them, and the ectocytosis-dependent pathophysiology of envenoming.

The brown recluse is a fascinating spider very well adapted to dwelling in houses and other buildings. Because of this very quality and the ghastly reputation associated with the medical consequences of its bite, it has become infamous throughout North America. Although recluse spiders can cause serious skin injuries and, in very rare cases, death, the danger posed by this spider is often exaggerated as a result of arachnophobia and the misdiagnosis of non-spider-related conditions as brown recluse bites. These misdiagnoses often occur in areas of North America where the spider does not exist, making legitimate bites improbable. One of the greatest factors that keeps the myths alive is misidentification of common (and harmless) spiders as brown recluses. With this book, Richard S. Vetter hopes to educate readers regarding the biology of the spider and medical aspects of its bites, to reduce the incidence of misdiagnoses, and to quell misplaced anxiety. InThe Brown Recluse Spider, Vetter covers topics such as taxonomy, identification, misidentification, life history characteristics and biology, medical aspects of envenomations, medical conditions misdiagnosed as brown recluse bites, other spider species of medical consideration (several of which have been wrongly implicated as threats to human health), and the psychology behind the entrenched reasons why people believe so deeply in the presence of the spider in the face of strong, contradictory information. Vetter also makes recommendations for control of the spider for households in areas where the spiders are found and describes other species of recluse spiders in North America. AlthoughThe Brown Recluse Spider was written for a general audience, it is also a valuable source of information for arachnologists and medical personnel. The brown recluse is a fascinating spider very well adapted to dwelling in houses and other buildings. Because of this very quality and the ghastly reputation associated with the medical consequences of its bite, it has become infamous throughout North America. Although recluse spiders can cause serious skin injuries and, in very rare cases, death, the danger posed by this spider is often exaggerated as a result of arachnophobia and the misdiagnosis of non-spider-related conditions as brown recluse bites. These misdiagnoses often occur in areas of North America where the spider does not exist, making legitimate bites improbable. One of the greatest factors that keeps the myths alive is misidentification of common (and harmless) spiders as brown recluses. With this book, Richard S. Vetter hopes to educate readers regarding the biology of the spider and medical aspects of its bites, to reduce the incidence of misdiagnoses, and to quell misplaced anxiety.InThe Brown Recluse Spider, Vetter covers topics such as taxonomy, identification, misidentification, life history characteristics and biology, medical aspects of envenomations, medical conditions misdiagnosed as brown recluse bites, other spider species of medical consideration (several of which have been wrongly implicated as threats to human health), and the psychology behind the entrenched reasons why people believe so deeply in the presence of the spider in the face of strong, contradictory information. Vetter also makes recommendations for control of the spider for households in areas where the spiders are found and describes other species of recluse spiders in North America. Although The Brown Recluse Spider was written for a general audience, it is also a valuable source of information for arachnologists and medical personnel.

Hemoscorpius lepturus is the most medically important scorpion in Iran. The clinical signs of H. lepturus envenomation are remarkably similar to those reported for brown spiders, including dermonecrosis, hematuria, renal failure and even death. The lethality and toxicity of brown spiders’ venom have been attributed to its phospholipase D activity. This study aims to identify a phospholipase D with possible lethality and dermonecrotic activity in H. lepturus venom. In this study, a cDNA library of the venom glands was generated by Illumina RNA sequencing. Phospholipase D (PLD) from H. lepturus was characterized according to its significant similarity with PLDs from brown spiders. The main chain designated as Hl‐RecPLD1 (the first recombinant isoform of H. lepturus PLD) was cloned, expressed and purified. Sphingomyelinase, dermonecrotic and lethal activities were examined. Hl‐PLD1 showed remarkable sequence similarity and structural homology with PLDs of brown spiders. The conformation of Hl‐PLD1 was predicted as a “TIM beta/alpha‐barrel”. The lethal dose 50 (LD50) and dermonecrotic activities of Hl‐RecPLD1 were determined as 3.1 μg/mouse and 0.7 cm2 at 1 μg respectively. It is the first report indicating that a similar molecular evolutionary mechanism has occurred in both American brown spiders and this Iranian scorpion. In conclusion, Hl‐RecPLD1 is a highly active phospholipase D, which would be considered as the lethal dermonecrotic toxin in H. lepturus venom.

Spiders of the genus Loxosceles, popularly known as Brown spiders, are considered a serious public health issue, especially in regions of hot or temperate climates, such as parts of North and South America. Although the venoms of these arachnids are complex in molecular composition, often containing proteins with distinct biochemical characteristics, the literature has primarily described a family of toxins, the Phospholipases-D (PLDs), which are highly conserved in all Loxosceles species. PLDs trigger most of the major clinical symptoms of loxoscelism i.e., dermonecrosis, thrombocytopenia, hemolysis, and acute renal failure. The key role played by PLDs in the symptomatology of loxoscelism was first described 40 years ago, when researches purified a hemolytic toxin that cleaved sphingomyelin and generated choline, and was referred to as a Sphingomyelinase-D, which was subsequently changed to Phospholipase-D when it was demonstrated that the enzyme also cleaved other cellular phospholipids. In this review, we present the information gleaned over the last 40 years about PLDs from Loxosceles venoms especially with regard to the production and characterization of recombinant isoforms. The history of obtaining these toxins is discussed, as well as their molecular organization and mechanisms of interaction with their substrates. We will address cellular biology aspects of these toxins and how they can be used in the development of drugs to address inflammatory processes and loxoscelism. Present and future aspects of loxoscelism diagnosis will be discussed, as well as their biotechnological applications and actions expected for the future in this field.

The genus Loxosceles comprises 140 species widely distributed around the world. These spiders are nocturnal, sedentary and remarkably nonaggressive, although they cause accidents in humans with wide degrees of severity, generating signs and symptoms that define the clinical condition known as loxoscelism. Its local signs and symptoms were first reported in 1872, and over the years, a large medical literature has been accumulated; unfortunately, it is not always trustworthy. Assessing the reliability of such information, we reviewed 120 case reports of loxoscelism published in 84 articles over the past 20 years. This search allowed us to gather information on the clinical aspects, diagnosis and treatment of loxoscelism, showing that the severity of these accidents has multiple degrees and that it is influenced by many factors. Thus, coupled with epidemiological and species occurrence information, this study can be a useful tool for the clinical practice of loxoscelism. It may support and provide a multidisciplinary view that should be taken into consideration when establishing the therapeutic approach in cases of Loxosceles envenomation.

Bites of Loxosceles spiders can lead to a set of clinical manifestations called loxoscelism, and are considered a public health problem in many regions. The signs and symptoms of loxoscelism are divided into cutaneous and systemic forms. The former is more frequent and includes signs of envenoming at the bite site or neighboring regions. Systemic loxoscelism, although much less frequent, is associated with complications, and can even lead to death. It may include intravascular hemolysis, acute renal failure, and thrombocytopenia. Loxosceles venoms are enriched with phospholipases D (PLDs), which are a family of isoforms found at intra-species and inter-species levels. Under experimental conditions, these enzymes reproduce the main clinical signs of loxoscelism, including an exacerbated inflammatory response at the bite site and dermonecrosis, as well as thrombocytopenia, intravascular hemolysis, and acute renal failure. The role of PLDs in cutaneous loxoscelism was described over forty years ago, when studies identified and purified toxins featured as sphingomyelinase D. More recently, the production of recombinant PLDs and discoveries about their structure and mechanism has enabled a deeper characterization of these enzymes. In this review, we describe these biochemical and functional features of Loxosceles PLDs that determine their involvement in systemic loxoscelism.

Brown spider envenomation results in dermonecrosis, characterized by an intense inflammatory reaction. The principal toxins of brown spider venoms are phospholipase-D isoforms, which interact with different cellular membrane components, degrade phospholipids, and generate bioactive mediators leading to harmful effects. The Loxosceles intermedia phospholipase D, LiRecDT1, possesses a loop that modulates the accessibility to the active site and plays a crucial role in substrate. In vitro and in silico analyses were performed to determine aspects of this enzyme’s substrate preference. Sphingomyelin d18:1/6:0 was the preferred substrate of LiRecDT1 compared to other Sphingomyelins. Lysophosphatidylcholine 16:0/0:0 was preferred among other lysophosphatidylcholines, but much less than Sphingomyelin d18:1/6:0. In contrast, phosphatidylcholine d18:1/16:0 was not cleaved. Thus, the number of carbon atoms in the substrate plays a vital role in determining the optimal activity of this phospholipase-D. The presence of an amide group at C2 plays a key role in recognition and activity. In silico analyses indicated that a subsite containing the aromatic residues Y228 and W230 appears essential for choline recognition by cation-π interactions. These findings may help to explain why different cells, with different phospholipid fatty acid compositions exhibit distinct susceptibilities to brown spider venoms.

Spiders of Loxosceles genus are widely distributed and their venoms contain phospholipases D (PLDs), which degrade phospholipids and trigger inflammatory responses, dermonecrosis, hematological changes, and renal injuries. Biochemical, functional, and structural properties of three recombinant PLDs from L. intermedia, L. laeta, and L. gaucho, the principal species clinically relevant in South America, were analyzed. Sera against L. gaucho and L. laeta PLDs strongly cross-reacted with other PLDs, but sera against L. intermedia PLD mostly reacted with homologous molecules, suggesting underlying structural and functional differences. PLDs presented a similar secondary structure profile but distinct melting temperatures. Different methods demonstrated that all PLDs cleave sphingomyelin and lysophosphatidylcholine, but L. gaucho and L. laeta PLDs excelled. L. gaucho PLD showed greater “in vitro” hemolytic activity. L. gaucho and L. laeta PLDs were more lethal in assays with mice and crickets. Molecular dynamics simulations correlated their biochemical activities with differences in sequences and conformations of specific surface loops, which play roles in protein stability and in modulating interactions with the membrane. Despite the high similarity, PLDs from L. gaucho and L. laeta venoms are more active than L. intermedia PLD, requiring special attention from physicians when these two species prevail in endemic regions.