Tag Archives: Malaria

Nodding Syndrome: Autoimmune Reaction to the Parasitic Worms That Cause River Blindness?

We have described the above enigmatic disorder of young children in East Africa before; a degenerative brain disease characterised by repetitive nodding movement, an inability to swallow, and eventually global brain failure.[1] Authors of a recent study hypothesised that the disease may be caused by an autoimmune response to the river blindness parasite.[2] They detected auto-antibodies to the parasite more often in cases than age-matched controls from the same village. The antibody attacks various cell markers in the mouse brain among neural networks that are affected in nodding syndrome. But only about half the patients with nodding syndrome exhibited the antibodies. The authors speculate that a number of yet to be identified antibodies may also be involved. I wonder why the disease does not map onto the geography of river blindness, which appears to be much broader than that of nodding syndrome.

So, here is my hypothesis. Remember, a few News Blogs ago,[3] I articulated a ‘three hits hypothesis’ as the cause of many diseases. One example was cytomegalovirus infection, which in the presence of the malaria parasite, and along with genetic predisposition, leads to Burkitt’s lymphoma. So I suspect that exposure to river blindness may be a sensitising event, and propose a search for a further exposure that is more specific to the ‘nodding syndrome belt’ extending from South Sudan, through Uganda to North Tanzania (see Figure).

Map of African countries showing where River Blindness is endemic and where outbreaks of Nodding Disease have occurred.

Data on River Blindness taken from the World Health Organization.

— Richard Lilford, CLAHRC WM Director

References:

  1. Chilton PJ. A Mysterious Disease with Unknown Cause. NIHR CLAHRC West Midlands News Blog. 27 June 2014.
  2. Johnson TP, Tyagi R, Lee PR, et al. Nodding syndrome may be an autoimmune reaction to the parasitic worm Onchocerca volvulus. Sci Transl Med. 2017; 9.
  3. Lilford RJ. Three Hits Hypothesis. NIHR CLAHRC West Midlands News Blog. 7 April 2017.
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Three Hits Hypothesis

Quite a lot of diseases are brought about by the conflation of two factors. Mice infected with certain herpes viruses suffer no ill-effect unless a helminth infestation supervenes. Oral allergy syndrome arises when a certain pollen interacts with certain foods (usually raw fruits, vegetables and nuts). The hygiene hypothesis says that lack of exposure to certain gut bacteria sensitises the body to allergic reactions to a range of environmental allergens. The pathway for disease involves three hits:

Genetically predisposed person –> Exposure 1 –> Exposure 2 –> Disease.

An intriguing example of a three-hit condition is the severe disease of children – Burkitt’s lymphoma. This cancer arises in germinal centres of lymph nodes in the neck. It is known that Epstein-Barr (EB) virus infection is necessary for endemic Burkitt’s lymphoma to develop because it prevents apoptosis (cell death) when certain mutations occur in the cell. But endemic Burkitt’s lymphoma only occurs in the malaria belt, and why this is so has been a mystery until the last few years. Now we know that the malaria parasite Plasmodium falciparum ‘upregulates’ an enzyme that causes mutations in DNA in lymph cells. These mutations are a normal part of antibody production since rearrangements of chromosome segments is necessary for antibody specificity. But in people with falciparum malaria, the effect ‘spills over’ to cause mutations of cancer genes. The double hit of EB plus malaria sets the scene for carcinogenesis.[1] Why in the neck – perhaps because lymph cells in the necks of children work particularly hard eradicating throat and ear infections, in which case there is a ‘four hits’ hypothesis!

— Richard Lilford, CLAHRC WM Director

References:

  1. Thorley-Lawson D, Deitsch KW, Duca KA, Torgbor C. The Link between Plasmodium falciparum Malaria and Endemic Burkitt’s Lymphoma—New Insight into a 50-Year-Old Enigma. PLoS Pathog. 2016; 12(1): e1005331.

Tackling Malaria

CLAHRC Africa is planning a study with Anja Terlouw and Linda Mipando of the Malawi, Liverpool Wellcome Trust Centre, to reduce the prevalence of malaria in villages in Africa. Artemisinin therapy for clinical cases is the single most cost-effective measure for malaria control, while treatment of pregnant women can also bring an important health gain.[1] Major works to drain swamps and remove standing water are beyond scope. So we are considering community-based interventions.

There are many different community-based approaches to the scourge of malaria.[2] Improving the uptake of bed nets is a very widely used approach (for a beautiful map of how the use of bed nets has improved since 2000, see this Tweet by Bill Gates). Bed nets are impregnated with insecticides that are harmless to humans, and can reduce the load of infected vectors in a locality, as well as protect individuals. But uptake is not universal, in part because they are hard to use in the absence of a bed and many people, especially children, sleep on mats. We plan to investigate methods to mitigate the problems, perhaps including an erectable protective dome, like a small tent, for children:

Child underneath small tent

One problem with bed nets is that anopheline mosquitos are developing resistance to the insecticide.

Other approaches include regular indoor residual spraying so that surfaces are coated in a substance lethal to mosquitoes, but this requires fastidious application of the insecticide and is expensive. Yet another approach is mass treatment of whole populations, as discussed in a recent edition of Science.[3] However, this risks promoting resistant strains on a large scale, so a modification of the mass treatment approach, based on screening and treatment, has been advocated. However, that may be ruinously expensive.

Of course, there are approaches aimed at reducing breeding grounds for the vector, which are certainly effective if they can be implemented.[4] Diagnosing and treating pregnant women is an important strategy.[5] Malaria vaccines are starting to look promising,[6] while we wait for widespread application and evaluation of existential approaches, such as introducing sterile males into the unsuspecting anopheline population.

In the meantime, our plan is to select the most propitious community-based method and roll it out in collaboration with authorities, as part of a cluster RCT, perhaps using a step-wedge design.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Morel CM, Lauer JA, Evans DB. Cost effectiveness analysis of strategies to combat malaria in developing countries. BMJ. 2005; 331: 1299.
  2. Salam RA, Das JK, Lassi ZS, Bhutta ZA. Impact of community-based interventions for the prevention and control of malaria on intervention coverage and health outcomes for the prevention and control of malaria. Infect Dis Poverty. 2014; 3: 25
  3. Roberts L. Rubber workers on the front lines. Science. 2016; 352(6284): 404-5.
  4. Keiser J, Singer BH, Utzinger J. Reducing the burden of malaria in different eco-epidemiological settings with environmental management: a systematic review. Lancet Infect Dis. 2005; 5: 695-708.
  5. Hill J, Hoyt J, van Eijk AM, et al. Factors affecting the delivery, access, and use of interventions to prevent malaria in pregnancy in sub-Saharan Africa: a systematic review and meta-analysis. PLoS Med. 2013; 10(7): e1001488.
  6. Garner P, Gelband H, Graves P, et al. Systematic Reviews in Malaria: Global Policies Need Global Reviews. Infect Dis Clin N Am. 2009; 23: 387-404.