Systemic Loxoscelism, Less Frequent but More Deadly: The Involvement of Phospholipases D in the Pathophysiology of Envenomation

Abstract

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.

Arthropods and the skin

“…Recluse spiders including the brown recluse (Loxosceles reclusa) can cause necrotic skin lesions and systemic loxoscelism due to their venom containing sphingomyelinase D, and as more recently described, phospholipase D. 26,27 These lesions often heal slowly over weeks to months and may require surgical debridement. Management of cutaneous lesions has remained primarily focused on adequate wound care, tetanus prophylaxis, analgesics, and observation.…”

“…28 Systemic loxoscelism is more rare but also far more severe, presenting most commonly with symptoms such as hemolysis, acute renal failure, and thrombocytopenia as well as a recently described case of toxin-associated myocarditis. 27,29 Management of systemic loxoscelism includes addressing complications as they arise, such as in a recently described case involving hemolysis refractory to transfusions and steroids that responded after plasma exchange. 30 Early vaccine protocols have been developed targeting phospholipases D from three loxosceles species in South America, and preliminary findings have shown the ability to inhibit cutaneous manifestations after venom inoculation in rabbits.…”

“…A recent prospective observational study in Brazil found that early medical attention and antivenom administration could decrease rates of necrosis secondary to Loxosceles spider bites 28 . Systemic loxoscelism is more rare but also far more severe, presenting most commonly with symptoms such as hemolysis, acute renal failure, and thrombocytopenia as well as a recently described case of toxin‐associated myocarditis 27,29 . Management of systemic loxoscelism includes addressing complications as they arise, such as in a recently described case involving hemolysis refractory to transfusions and steroids that responded after plasma exchange 30 .…”