Onchocerca volvulus

Morphology

Onchocerca volvulus obtain nutrients from the human host by ingesting blood or by diffusion through their cuticle. They may be able to trigger blood vessel formation because dense vascular networks are often found surrounding the worms. They are distinguished from other human infecting filarial nematodes by the presence of deep transverse striations.

It is a dioecious species, containing distinct males and females, which form nodules under the skin in humans. Mature female worms permanently reside in these fibrous nodules, while male worms are free to move around the subcutaneous tissue. The males are smaller than females, with male worms measuring 23mm in length compared to 230-700mm in females.

The release of oocytes (eggs) in female worms is not dependant on the presence of a male worm, although they may attract male worms using unidentified pheromones. The first larval stage, microfilariae, are 300μm in length and unsheathed, meaning when they mature into microfilariae they exit from the envelope of the egg.

Life Cycle

The average adult worm lifespan is fifteen years and mature females can produce between 500 and 1,500 microfilariae per day. The normal microfilariae lifespan is 1 to 1.5 years; however, their presence in the bloodstream causes little to no immune response until death or degradation of the microfilariae or adult worms.

Blackfly Stages

1. The microfilariae of Onchocerca volvulus are found in the dermis layer of skin in the host.
2. When a female Simulium blackfly takes a blood meal from an infected host the microfilariae are also ingested.
3. From here the microfilariae penetrate the gut and migrate to the thoracic flight muscles where they enter the first juvenile phase, J₁.
4. After maturing into J₂, the second juvenile phase, they migrate to the proboscis where they are found in the saliva.
5. J₂ stage juveniles then mature into infectious stage three juveniles, J₃, in the saliva. The life cycle in the blackfly takes between one and three weeks.

Human Stages

1. When the female blackfly takes a blood meal, J₃ juveniles pass into the human bloodstream.
2. From here the juveniles migrate to the subcutaneous tissue where they form nodules and mature into adult worms over a period of six to twelve months.
3. After maturation, the smaller adult males migrate from nodules to subcutaneous tissue where they mate with the larger adult females.
4. The eggs mature internally to form stage one microfilariae, which are released from the female's body one at a time and remain in the subcutaneous tissue.
5. The microfilariae are taken up by a female blackfly when she takes a blood meal, thus completing the lifecycle of Onchocerca volvulus.

Disease

Onchocerca volvulus causes onchocerciasis, which causes severe itching. Long-term infection can cause keratitis, an inflammation of the cornea in the eye, and ultimately leads to blindness. Symptoms are caused by the microfilariae and the immune response to infection, rather than the adults themselves. The most effective treatment involves using ivermectin, although there are reports of resistance developing to this drug. Ivermectin prevents female worms from releasing microfilariae for several months, thus relieving symptoms. However, this does not kill adult worms so it must be taken once annually as long as adult worms are present.

Onchocerca volvulus has been proposed as the causative agent of nodding syndrome, a condition that affects children aged 5 to 15 and is currently only observed in South Sudan, Tanzania and northern Uganda. Although the cause of the disease is unknown, Onchocerca volvulus is being increasingly studied as a possible cause due to its ubiquity in areas where the disease is found.

Epidemiology

An estimated 187 million people are at risk of Onchocerca volvulus infection, with 17-25 million people infected and 0.8 million showing some impairment of vision. Onchocerca volvulus has not directly caused a single death, but has cost 1.1 million disability adjusted life years (DALYS). DALYs measure the number of years of healthy life lost due to a specific disease and show the burden of a disease.

Simulium blackfly adults require moving water to breed and eggs remain in water until they exit from the pupa and enter the adult stage of their lifecycle. Due to this restriction Onchocerca volvulus is only found around streams or rivers. Artificial water systems, such as hydroelectric power plants, built in Africa provide ideal conditions all year for blackfly development and make it difficult to control its spread.

99% of cases of onchocerciasis are found in 31 countries in Sub-Saharan Africa, although there are areas of limited transmission in Brazil, Venezuela and Yemen. The disease was thought to have been imported into Latin America through the slave trade. Onchocerciasis was eliminated from Colombia in 2013, Ecuador in 2014, Mexico in 2015 and Guatemala in 2016 due to control programs that used mass drug administration with ivermectin.

Genome

The total genome size of Onchocerca volvulus is 1.5x10⁸ bp and contains around 4,000 genes, with genes for collagen and cuticular proteins being highly expressed in the mature adults. Onchocerca volvulus has four chromosome pairs, which includes a single pair of sex chromosomes. A large X sex chromosome and a smaller Y sex chromosome determine male worms, while two X chromosomes determine female worms.

It is thought that one of the three non-sex chromosomes was formed by a fusion event between two smaller chromosomes.

Evolution

(Simplified phylogenetic tree of the Onchocerca genus.)

Onchocerca volvulus has low genetic variation between individuals. This suggests a population bottleneck occurred in the past that caused a rapid decrease in the population size. They also show high haplotype diversity, which is a measure of how unique a group of linked genes are. This pattern of low genetic variation and high haplotype diversity suggests fast population expansion after a bottleneck and has lead to the theory that a host shift event from cattle allowed Onchocerca volvulus to infect humans. This is also supported by genetic data that places Onchocerca ochengi (a cattle infecting strain) as the sister group to Onchocerca volvulus.

Immune Response

Adult worms are found in nodules and are hidden from most components of the human immune system. Microfilariae are more vulnerable to attack by immune cells because they exit nodules to complete their lifecycle. Onchocerca volvulus can be detected by the immune system through the release of soluble antigens and antigens found on the surface of microfilariae and infective J₃ juveniles. These antigens allow the immune system to detect the presence of a foreign organism in the body and trigger an immune response to clear infection.

The immune response involves raising antibodies (IgG, IgM and IgE type) that can react with soluble antigens released by Onchocerca volvulus. Opsonising antibodies that tag cells for destruction are also found against the infective J₃ stage and microfilariae, but there is not enough evidence at the moment to say whether this is protective.

The antigens of Onchocerca volvulus are highly complex and show cross-reactivity with several other filarial worms. There is little evidence that antibodies made are specific to Onchocerca volvulus. However, after the age of forty the number of parasites carried (the intensity of infection) decreases, suggesting that over time some sort of protective immune response develops.

Modulation by Onchocerca volvulus

Onchocerca volvulus microfilariae can also modulate the immune system to avoid destruction. The complement system is used to enhance the effect of antibodies and phagocytic cells, which engulf and destroy other cells. Microfilariae block this pathway by cleaving C3b - an important protein in this process – to form iC3b. iC3b cannot go on to activate the next step in the pathway and allows microfilariae to remain in the body with little to no attack by the immune system.

Endosymbiotic Relationship with Wolbachia

Onchocerca volvulus, along with most filarial nematodes, share an endosymbiotic relationship with the bacterium Wolbachia. In the absence of Wolbachia, larval development of the Onchocerca volvulus is disrupted or ceased. These bacteria have been proposed to enhance the symptoms and severity of onchocerciasis by triggering inflammatory responses in the host.