Aedes aegypti. (1)

It may not seem like it during this part of the year (in the northern hemisphere anyway), but most of the time, mosquitoes don't drink blood. Males and females both drink nectar for their own survival, so what they actually need your blood for is the propagation of the species. Female mosquitoes sometimes need to take a hot blood meal in order to get the required proteins and iron for making eggs. While necessary for reproduction, drinking mammalian blood has a lot of unique physiological challenges, not the least of which is the large temperature difference between your blood and a mosquito's body.

At room temperature, the average human's body temperature is about 15 °C (almost 30 °F) warmer than that of the average mosquito, and when a female takes a blood meal, her body temperature spikes 10 °C in just one minute! While ectotherms like mosquitoes are used to having their body temperatures fluctuate based on environmental conditions (such as the day/night cycle), these changes are usually gradual, allowing the mosquito ample time to acclimate their physiology in order to function properly in the different temperature. Hot blood meals impose the unique physiological problem of rapidly increasing the mosquito's body temperature without much time to adjust, which can lead to enzymatic dysfunction and disrupt physiological pathways such as digestion, reproduction, and metabolism.

Obviously mosquitoes are not dying out from heat stress, so how are they getting around this problem? Researchers in Dave Denlinger's lab group in the Department of Evolution, Ecology, and Organismal Biology at the Ohio State University have tackled this question and came up with the answer: Heat shock proteins! Heat shock proteins can act as enzymatic "chaperones", making sure that the enzyme proteins stay folded in the proper conformation during times of physiological stress (which includes not just heat but also extreme cold, lack of oxygen, infection, or exposure to toxins, among other things). Enzymes are a key player in digestion: they aid in the breakdown of proteins, fats, and carbohydrates, and the absorption of certain nutrients, so the mosquitoes definitely want to conserve the function of their digestive enzymes right after taking a meal.

It turns out that female mosquitoes experience an 8-fold spike in the expression of heat shock proteins in their midgut following a hot blood meal. If mosquitoes are prevented from being able to express HSP70 (the heat shock protein active in these mosquitoes), the blood proteins from their meal stay in the midgut longer, suggesting that the digestion of blood proteins is somehow impaired when heat shock proteins are not present to preserve the function of digestive enzymes during heat stress. It is unclear whether the delayed gastric emptying is due to a deficiency in enzymatic break-down of the proteins or due to slower uptake (aided by enzymes) of proteins and nutrients from the midgut, but the result is the same: the proteins are staying in the midgut longer instead of going into the body and aiding in egg formation.

While heat shock proteins are not preferentially expressed in the ovaries after a hot blood meal, when mosquitoes are prevented from expressing HSP70, they make fewer eggs than control mosquitoes, which provides further evidence that the delay of protein digestion and nutrient absorption is interfering with egg production. Since mosquitoes are vectors for many human diseases, the manipulation of heat shock proteins can be used in initiatives to potentially limit the fecundity of mosquitoes (i.e., how rapidly they reproduce) and reduce the rate of human infection with diseases like yellow fever, malaria, and dengue fever.

Mosquitoes may be pest animals and disease carriers, but there are other bloodsucking animals that might actually help save your life. One such animal is responsible for the discovery of a new plasminogen activator, a type of drug used to break up blood clots, which is currently undergoing clinical trials. The drug, desmoteplase, is modeled after a protein found in vampire bat saliva that prevents clots and platelet aggregation, which keeps the blood flowing while the bat is feeding. Plasminogen activators like desmoteplase are used to break down problematic blood clots that have lodged in a blood vessel and are blocking blood flow to vital organs such as the heart, lungs, or brain.

http://www.youtube.com/watch?v=gO29knhmjGA

Anatomy of a heart attack. (2)

To understand why bats have this protein in their saliva and why it may be medically useful, we first need to understand how clots form. Whenever a blood vessel is damaged, collagen fibers are exposed under the severed lining of the vessel. Platelets, one of the several blood cell types, will begin to stick to the collagen fibers and to one another until the damaged area is covered. This creates a platelet "plug" that stops immediate blood loss. Once the platelet plug is in place, a cascade of clotting factors (a vital one being a chemical called fibrin) will build a clot "seal" over the platelet plug, which forms a more permanent barrier to blood loss while the vessel heals.

After the vessel heals and the clot is no longer needed, a chemical called plasminogen is activated and becomes plasmin. Plasmin then breaks down the clot by solubilizing fibrin (remember that fibrin was a clotting factor). This is a safe way to get rid of the clot so that it doesn't come off in one piece and then lodge itself into a small vessel, where it can cut off circulation to parts of the body. However, sometimes clots are not broken down properly and can cut off blood flow to the brain (stroke) or heart (heart attack). When this happens, we need to manually turn plasminogen into plasmin using plasminogen activators, so that plasmin can break down the clot and restore blood flow.

Vampire bat, Desmodus rotundus. (3)

The plasminogen activators in vampire bat saliva were first described by Dr. Christine Hawkey in a letter to Nature in the 1960s. In addition to plasminogen activators, Hawkey later went on to describe platelet aggregation inhibitors (which stop platelets from forming the initial plug) in vampire bat saliva as well. Vampire bats do not directly suck blood as mosquitoes do; instead they puncture the skin with their teeth and lap the blood with their tongues as it seeps through the wound. This strategy requires the inhibition of platelet plugs and clots that would otherwise stop the blood from continuing to flow during the bat's meal.

Desmoteplase, which is derived from the plasminogen activators in vampire bat saliva originally described by Hawkey, seems to have some advantages over currently used plasminogen activators (which are often based on chemicals in humans). Current drugs are only approved for use up to 3 hours after symptom onset, and Dr. Michel Torbey at the Ohio State University Medical Center is hopeful that desmoteplase will demonstrate efficacy up to 9 hours after symptom onset, which could drastically reduce the number of deaths.

"Prompt medical care within three hours is very important for recovery from a stroke, but attempts to find drugs that extend the treatment window have not been successful," added Torbey. "If the study findings back up our hopes and expectations, desmoteplase could be a real game changer in our ability to help patients."

In addition to expanding the treatment window, desmoteplase is more potent and specific than current drugs. One current plasminogen activator is even linked to neurotoxicity in some patients, so there is high demand for newer and better drugs to treat problematic clots. If approved, this drug could reduce the risk of death in stroke patients who live in remote areas and may not be able to make it to the emergency room within the three hour window.


Referenced:

Benoit, J., Lopez-Martinez, G., Patrick, K., Phillips, Z., Krause, T., & Denlinger, D. (2011). Drinking a hot blood meal elicits a protective heat shock response in mosquitoes Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1105195108

HAWKEY, C. (1966). Plasminogen Activator in Saliva of the Vampire Bat Desmodus rotundus Nature, 211 (5047), 434-435 DOI: 10.1038/211434c0

Hawkey, C. (1967). Inhibitor of Platelet Aggregation Present in Saliva of the Vampire Bat Desmodus rotundus British Journal of Haematology, 13 (6), 1014-1020 DOI: 10.1111/j.1365-2141.1967.tb08870.x

Schleuning, W. (2001). Vampire Bat Plasminogen Activator DSPA-Alpha-1 (Desmoteplase): A Thrombolytic Drug Optimized by Natural Selection Pathophysiology of Haemostasis and Thrombosis, 31 (3-6), 118-122 DOI: 10.1159/000048054

Photo credit:

(1) Flickr user Sanofi Pasteur

(2) Flickr user gandhiji40

(3) Flickr user Robertsphotos1Site Meter