Which filarial parasites cause lymphatic filariasis?
Wuchereria bancrofti
Brugia malayi
Brugia timori
What causes onchocerciasis?
Onchocerca volvulus
What causes tropical eye worm?
Loa loa
What are the vectors for each filarial parasites?
- Wuchereria bancrofti, brugia malayi and brugia timori : mosquitos
- Onchocerca volvulus : black flies
- Loa loa : Tabanid flies
Why is distirbution of Wuchereria bancrofti wider than of Brugia?
More mosquito species can transmit Wuschereria
When does a Loa loa infection become dangerous?
During a coinfection with Onchocerca
Outline the life cycle of the lymphatic filarial worms
L3 (infectious larvae) burst out mouth of mosquito (too large for proboscis) and enter skin through mosquito bite site. Travel to the lymphatics and moult to form L4 and then adult, over around 3 months. Adults produce 100’s of microfilariae (L1 larvae), 100-200µm in length, per day. Microfilariae travel to blood where can they be picked up by mosquito during blood meal. L1 larvae travel to flight muscles and undergo moult to L2. L2 moults to L3 and travels to mouth. L1 to L3 in mosquito takes 14 days; exact time between feeding of female mosquito.
What is meant by microfilarial periodicity?
They make themselves available in the peripheral blood during the time of day that the vector feeds. 3 types; nocturnal periodic, diurnal periodic and nocturnal sub-periodic Also helpful in avoiding the spleen.
Outline the life cycle of Onchocerca volvulus
Black fly takes a blood meal and transmit L3 into blood wound. Initially enter lymphatics but travel to subcutaneous tissues, in particular bony protrusion, and develop into adults. Females form nodules, in which they are surrounded by fibrotic tissue, which males travels between to fertilise. Microfilariae are released and travel to skin, lymphatics, blood, urine and sputum. Black fly takes blood meal and infected by microfilariae in skin. Microfilariae penetrate midgut and travel to thoraic muscles to develop into L3 and then to mouth for next infection.
What makes up the nodules?
Balls of females but also host inflammatory cells, collagen and ECM
Outline the life cycle of Loa loa
Tabanid flies take blood meal and transmit L3 into blood wound. Initially enter lymphatics but travel to subcutaneous tissues and develop into adults. Males and females are migratory and move. Sheathed microfilariae are released and travel to spinal flouid, urine, sputum, peripheral blood and lungs. Tabanid flies takes blood meal and infected by microfilariae. Microfilariae shed sheath and penetrate midgut. Travel to thoraic muscles to develop into L3 and then to mouth for next infection.
What diseases are caused by lymphatic filariasis?
How?
- Filarial lymphoedemas; elaphantiasis and hydrocoele
Due to adults dying in the lymphatics causing irreparable damage to the lymphatics and loss of ability to remove fluid
What diseases are caused by onchocerciasis?
How?
- River blindness
- Dermiitis
Due to microfilariae dying
What effect can treatment for onchocerciasis have when patients have Loa loa coinfection?
Death of Loa loa microfilariae in nervous system can cause coma and death
Which endobacterium is seen in the species, except Loa loa, studied in this module?
Wolbachia
Where do you find Wolbachia in the worms?
How is it transmitted
In the hypodermis
Transmitted by the females into the microfilariae; bacteria found in the embryonic stem cells of their ovaries
What happens to the Wolbachia in embryogenesis?
Asymmetric mitotic segregation of Wolbachia into only the hypodermal cells
What happens to the numbers of Wolbachia in the host?
Stays low in insect vector then increases during development in human host (temperature)
What processes does Wolbachia affect?
- Larval development
- Embryogenesis
- Longevity of adults
Which genes does Wolbachia have?
Undergoing reductive evolution (on way to organelle)
Remaining genes for heme biosynthetic pathway, vitamin co-factors and excess nucelotide provision
Why are the Wolbachia genes needed?
Provide components needed by the worms, especially during rapid growth
Which Wolbachia function has been shown to be essential?
Heme biosynthesis; worms can’t make themselves and die without it
What genetic interactions have occurred between Wolbachia and the nematodes?
Lateral gene transfer; Wolbachia genes found in species that are now Wolbachia negative
How has Wolbachia been shown to be the major driver of innate inflammation?
- Nematodes without Wolbachia symbiote, Loa loa, have no innate inflammation seen in the Wolbachia positive nematodes in vitro
- Removal of Wolbachia, by tetracycline treatment, from nematodes causes loss of inflammatory response in vitro
- In vivo treatmnet with doxycycline shows nodules with fewer nuetrophils
How does Wolbachia interact with the innate immune system?
Toll-like receptors (TLR) 2 and 6, with adaptor protein MyD88, recognise peptidoglycan associated lipoprotein (PAL) and Type IV secretory pathway VirB6 components (VirB6) on Wolbachia
How does Wolbachia lead to river blindness during a Onchocerca volvulus infection?
Death of microfilariae releases wolbachia into eye, recognised by TLR2/6 and neutrophils are recruited, release their granules and cause visual impairment
Why does treatment with anti-filarial’s of Wolbachia positive nematodes sometimes have adverse effects?
Death of the nematodes causes release of the Wolbachia
Why do 3/5 patients not develop filarial lymphoedema?
These patients display suppressed T cell responses to helminth antigens. Up regulation of regulatory T cells and immunosuppressive cytokines
What is the target for the drugs currently used?
The microfilariae; so stop transmission
What treatment strategy is being used for filariasis?
Mass drug administration
- DEC and Albendazole (out of Africe)
- Ivermectin and Albendazole (In Africa)
Both treatments are given once a year for 4-6 years; until the adults are dead. Requires mass use across entire range of parasite
What treatment strategy is being used for onchocerciasis?
Give Ivermectin once a year (or more) to suppress microfilariae in skin and stop transmission. Will need >20 years and >80% coverage to fully break the cycle
What environment treatment has been used in west Africa to stop onchocerciasis?
Insecticides in water sources to kill the black flies
What are the challenges to African Programme for Onchococerciases control?
- No vector control
- Civil strife
- Insufficient health resources
- Political commitment and funding
- Loiasis (Loa loa coinfection) severe adverse events to ivermectin
What is the only curative treatment?
Doxycycline to kill the Wolbachia
- Kills the adults
- Reduces severity of limb lymphoedema
- Kills macrofilariae
What are the Doxycycline issues?
1) Long term course of treatment
2) Contraindication in children
What is the future?
Curative treatments that work faster then doxycycline; Macrolides real candidates