They are quarter-sized, like to hide, and feared by many: brown recluse spiders. Also known as "fiddleback," owing to a distinct violin-shaped marking on their backs, these tan, spindly spiders are notorious for causing bites that often go unnoticed but can result in extensive tissue damage. A research study led by University of Arizona researchers sheds new light on how recluse venom affects living tissue.

Brown recluses are common, but bites are rare 

Despite the fact that brown recluse spiders inhabit every continent except Antarctica, many people have never seen one. Matthew Cordes, associate professor emeritus in the University of Arizona Department of Chemistry and Biochemistry who led the study about the venom's molecular mechanism of action, said they have their name for a reason.

"They like to hide in wood piles, sheds, things like that," Cordes said. "They prefer dark, covered spaces. Recluse spiders are actually quite common and easy to find if you look for them." 

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Loxosceles reclusa, the species most commonly found in the U.S., has its main range in the central and southeastern states, while related species occur in in west Texas, New Mexico and Arizona, where Loxosceles arizonica is the most common.

Cordes said in the 22 years he has lived in his house in Tucson, he has only ever seen two of them, during winter, when colder temperatures may have driven them inside. Residents are much more likely to encounter black widows around their property than brown recluses, he added. While people are more likely to come across them less developed areas, recluses exist in urban environments, too.

"There is this myth that they're aggressive spiders, but they really are not," Cordes said. "They generally have a worse reputation than they deserve."

The spiders typically only bite when they are trapped, for example between clothing and the skin, and most people who get bitten never know it, according to Cordes.

"Your average bite either has no effect or causes some kind of fairly mild irritation," he said. "It's the maybe 10% or 20% of cases where you get something that's necrotic, and then some even smaller fraction of those develop into something that's really a spreading necrotic lesion."

When that happens, the tissue damage can get extensive, requiring skin grafts and leaving lasting scars.

Venom works like a 'molecular lawnmower'

Unlike the venom in most other spiders, which primarily acts as a neurotoxin that interferes with nerve function, the venom of spiders in the recluse family, known as Sicariids, is very effective at destroying tissue.

While bites from other spiders may cause necrotic lesions, too, the potential of severe, widespread tissue damage is the recluse's "calling card," according to Cordes. Scientist have known for a while that recluse venom contains toxins that disrupt cell membranes, but the precise mechanisms of action have not been well understood. In their recent paper, Cordes' research team reported their success catching the toxin "in the act." Using a technique called X-ray crystallography, the researchers resolved the atomic structure of the molecule – an enzyme known as Phospholipase D – and its active site interacting with the lipid molecules that form the building blocks of cell membranes.

"We believe a likely mode of operation for this thing is to attach itself to a cell and chew up its lipid molecules," Cordes said. "These enzymes are what we call processive: They don't just bite off one molecule's head and then go away again. More likely, they move from molecule to molecule, mowing them all down, in a lawnmower-like fashion."

The recluse's "lawnmower" toxin can account for as much as half the dry weight of the spider's venom, according to Cordes. Add the fact it acts a catalyst, unaffected by its destructive activity, and that means each toxin molecule can do a lot of damage, which may help explain the sometimes-extensive tissue defects that result from a bite. During this process, the toxin turns the cell's lipids into a product that – until this study – was not known to be found in nature, the researchers report.

"It makes a highly unusual, ring-shaped product called cyclic ceramide phosphate," Cordes said. "The interesting thing about that is that almost nothing is known about it, other than the fact it's unique to the venom of recluse spiders."

While all spiders carry genes encoding for the same enzyme family, they don't use them in their venom, but for some other unknown purpose in their bodies. Only recluses express these genes in their venom glands, where they make up the bulk of the venom, Cordes said.

"It appears they kind of took it and ran with it," he said. "In an interesting evolutionary twist, these phospholipases are also found in the venom of a scorpion species found in the deserts of Iran, and getting stung can cause a medically dangerous reaction, resulting in a necrotic wound similar to that of a recluse bite."

Think you know how to spot a brown recluse? Think again. 

According to a widely held belief, a violin-shaped marking on the spider's back, just behind the head, unequivocally identifies it as a brown recluse. Not so, according to Greta Binford, arachnologist and professor of biology at Lewis & Clark College in Portland, Oregon, who is the paper's second author. 

"Brown recluses are often confused with a whole range of other spiders," she said. "To identify a brown recluse beyond doubt, two things need to be present: the violin shape and three pairs of eyes. Most other spiders have eight eyes. Sicariids are the only family whose members have six." 

To make things murkier, The violin shape adorning the cephalothorax – the combined head and middle portion of the spider's body – can be more or less prominent, depending on the spider's sex or life stage, and there are other spiders that have a violin-like pattern.

Most bites attributed to brown recluses are something else

Because the spiders are so elusive and bites often go unnoticed, it is not uncommon even for medical professionals to blame unrelated medical conditions on them. According to Cordes, bacterial skin infections such as MRSA are particularly prone to being misdiagnosed as recluse bites.

"MRSA produces a sore that presents somewhat like a recluse spider lesion," he said. "One of the differences is that the recluse lesions don't really ooze pus the same way MRSA does. Doctors who are familiar with these types of lesions are more likely to make a correct diagnosis, but sometimes it's hard to tell."

Cordes said a correct diagnosis is more likely if following a perceived bite, a spider is found, and location is an important tip-off as well.

"If someone believes they were bitten, and they live outside the range where recluses occur, it's a red flag, and you almost certainly have a misdiagnosis."