Sing to me, Oh wise muses, of foreskins, flaviviruses, saliva, blood, mosquitoes, monkeys, sylvan glens, and Dengue. Surasombatpattana et al’s article immersed me in this common (100,000,000 cases annually) – and serious — tropical disease. The Centers for Disease Control (CDC) summarizes clinical dengue, including the severe and frequently lethal hemorrhagic form.
Surasombatpattana et al describe cultured foreskin keratinocytes infected with dengue virus and treated with extracts of Aedes aegypti salivary glands; the extracts increased viral titers and decreased secretions by the innate defense system — molecules such as beta defensin 3 and LL-37 (cathelicidin).
Protective skin molecules may have evolved in response to a variety of organisms that attack through the skin. Dengue has a predominantly human reservoir and is spread by mosquitoes, most commonly Aedes aegypti poi and Aedes albopictus, from human to human, without any intermediate hosts. As in a war, the invading mosquito uses weapons against the skin’s innate defense mechanisms. The mosquito’s salivary glands synthesize a large set of proteins (the “sialome”), which allows for a good blood meal; it includes anticoagulants as well as proteins whose functions are unknown.
Mosquitoes are short-attention-span feeders; if they do not insert their proboscis into a blood vessel or a hemorrhagic pool within a minute, they “desist” their proboscis and move to another skin site. While probing, mosquitoes inject saliva in the skin; the saliva is not KY jelly for the proboscis, but it prevents blood coagulation and allows more time for vessel penetration. Unsuccessful attempts by the mosquito phlebotomist are common and have been studied in detail. The female mosquito frantically probes the skin, as a large blood meal is required for procreation. The rapid engorging of the stomach after a blood meal is graphically demonstrated online.
Extensive and prolonged manipulation of the proboscis results in viral deposition, as the mosquito’s salivary glands often contain large amounts of the Dengue virus. These early stages of flavivirus infection and the battleground for the lower epidermis and upper dermis can be exquisitely investigated with today’s methodologies.
Mosquitoes hold no special animosity toward humans, nor do they favor the flavivirus; by probing human skin, they are simply trying to ingest an important blood meal. Likewise, human skin has no special love or obvious need for the mosquito, and it has evolved molecules to make the mosquito’s job more difficult. Most evolutionary conundrums are like a cold crime scene: investigation is carried out thousands or millions of years after the key events have occurred, and often after the initial culprits have assumed disguises. This elegant tango between defense mechanism and host is an old one, and probably began in arboreal jungles where monkeys, virus and mosquitoes were, and still are, in close proximity. The sophisticated stealth approaches — such interfering with the host’s innate immune system — may have started in the forests of Southeast Asia and Central Africa. In these regions there are several species of monkeys that carry sylvan Dengue strains closely related to human Dengue strains. (Vasilakis et al, 2011). The sylvatic disease, when introduced into humans in rural areas, mimics the endogenous human disease and even presents in the hemorrhagic form.
There is a possibility that cross-species Dengue transmission is less than hundreds of years old. Tree harvesting, fires, drought and other climate changes, and human encroachment on forests can increase the spread of sylvatic dengue into human populations.
Understanding these defense and anti-defense mechanisms in detail holds more than heuristic interest; it may influence control of this disease, since vaccines and mosquito elimination may be only partially effective. The battle is eternal among man, vectors, and organisms, and it always deserves close attention, as the advantage can change rapidly among the species.
Surasombatpattana P, Patramool S, Luplertlop N, et al (2012) Aedes aegypti Saliva Enhances Dengue Virus Infection of Human Keratinocytes by Suppressing Innate Immune Responses. J Invest Dermatol doi:101038/jid.2012.76
Vasilakis N, Cardos J, Hanley K.A., et al (2011) Fever from the forest: prospects for the continued emergence of sylvatic dengue virus and its impact on public health. Nature Reviews Microbiology 9:532-542
Image credit: This image of Aedes aegypti feeding is from Wikipedia; it was taken by an employee of the USDA and is in the public domain.