Onchocerca volvulus

Onchocerca volvulus has, for many years, been regarded as the causative agent of River Blindness. Reports in 2002 indicate that the bacterium Wolbachia, which is associated with the nematodes and which may be required for their growth and reproduction, has a major role in the pathology of the disease. Wolbachia incites a severe inflammatory response, leading to blindness and serious skin disorders.

The immune response of the host is also involved in the disease. Mice lacking an immune cell receptor molecule called TLR4 showed fewer signs of eye inflammation when exposed to Wolbachia-laden worm extract (Hoerauf and Volkmann, 2002).

Biology and Epidemiology

Distribution

Human onchocerciasis is found in both the Old and New World but about 96% of all cases are in Africa and mostly in Western Africa. Of the 36 countries where the disease is endemic, 30 are in sub-Sahara Africa (plus Yemen) and six are in the Americas. Important foci exist also in Mexico, Guatemala, Venezuela and Ecuador. A total of 18 million people are infected with the disease and have dermal microfilariae, of whom 99% are in Africa. (WHO's Fact Sheets #95)

River blindness is the second leading infectious cause of blindness in the world. It is spread to humans by the bite of black flies infected with O. volvulus.

Life Cycle:

Human onchocerciasis is caused by the filarial parasite Onchocerca volvulus whose life cycle occurs in two different hosts: black flies, and human. The infective larvae (a: stage L3) are normally transmitted by the bite of Simulium flies (see picture below). Once in the human body, the larvae undergo molting to stage L4 (e), to then reach the adult stage in about one year (f). Adult females produce millions of microfilariae (h) that they shed in the blood of their human host. When female blackflies take a bloodmeal they ingest microfilariae. The microfilariae in the fly host transition to L2 life stage (j). L2 larvae then molt to L3 (a), the infective stage for humans.
		Simulium flies breed in fast flowing rivers i.e well oxygenated water, because their larvae have an obligatory aquatic stage during which they require high oxygen tension (see picture below). Hence, Onchocerciasis is associated with fast flowing rivers including rapids. That's why the blindness Onchocerciasis can lead to is often referred to as 'river blindness'.

The infective larvae of Onchocerca (stage L3) enter the body through the wound made by the bite of its host fly. The larvae then move to the subcutaneous tissues where they become encapsulated within nodules and mature into adults in approximately one year (cross section of worms in a subcutaneous nodule right).
		After mating the female sheds microfilariae 300 mm in length and 0.8 mm in diameter. The microfilariae are sheathless with sharply pointed, curved tails. The microfilariae can be found free in the fluid within the nodules and in the dermal layers of the skin spreading away from the nodules containing the adults. Microfilariae also can be found in the blood and eye during heavy infections. They infect their fly vectors while the flies are feeding on the human host and mature into third stage infective larvae in the flies' flight muscles (about 10 days total).

Pathology

One early sign of infection with Onchocerca is the raised nodules that can be seen under the skin. These are most often seen in areas over bony prominence. It is suggested that this phenomenon occurs because the larvae are immobilized in these locations (while the host is sleeping) long enough for them to be trapped by the body's cellular defense mechanisms.
	Reactions to dead microfilariae around these nodules can lead to several unpleasant conditions. In the skin there is destruction of the elastic tissues and the formation of redundant folds. There is also often a loss of pigmentation and the histological appearance of advanced cases often resembles the skin of very old normal subjects.
The microfilariae can also enter the eye by passing along the sheaths of the ciliary vessels and nerves from under the bulbar conjunctiva directly into the cornea, via the nutrient vessels into the optic nerve, and via the posterior perforating ciliary vessels into the choroid. Dead microfilariae in the eye lead to an inflammatory immune response and the eventual formation of secondary cataracts and ocular lesions. Because of this, heavy infections often lead to progressive blindness.	Recent research (Hoerauf and Volkmann, 2002) shows that Wolbachia bacteria associated with the nematode provoke a severe inflammatory response, leading to blindness and serious skin disorders.
	The microfilariae can also cause inflammation of regional lymph glands which remove foreign material from the distal skin. This inflammation along with the loss of tissue elasticity can lead to protruding lymph glands enfolded in pockets of skin. This condition is especially prominent in the areas around the scrotum (often called the 'hanging groin' effect) and in severe cases is classified as minor elephantiasis.

Life Cycle:

The female nematode lays eggs in the host blood stream and these enter fly when it bites the human, Changes into larval stage (the microfilariae) within 24 hours after fly has first blood meal. Spreads throughout hosts muscles (vector is the Simulium commonly known as "the black fly" - vector bites human and microfilariae enter through wound; gradually grow into adult stages; young can not grow until they enter vector first live mainly in skin tissues of humans (as adult forms) in hard coverings (nodules), but has also been found in urine, blood, eye tissue, and more rarely in hydrocele fluid and lymph nodes. Young inhabit vector known as "the black fly" (Simulium), live in stomach blood, and muscle tissues has developed long life span and can live up to 15 years, survives this long even though presence in human does cause an immune response to presence in host

Management:

Pinpointing bacteria as the direct factor behind the virulence suggests new therapies for combating river blindness, especially since recent studies in infected humans have shown that the bacteria can be killed by the common antibiotic doxycycline.

Antibiotic treatment of Wolbachia may help reduce the severity of the symptoms of river blindness in already-infected individuals.

Targeting Wolbachia could prevent the spread of Onchocerca. Recent studies have shown that doxycycline treatments in infected humans kills Wolbachia and also sterilize the nematodes, breaking the life cycle. In contrast, ivermectin treatments only reduce numbers of microfilariae for a few months and repeated treatments are necessary.