Did you know…?

This is going to be my last post for now on the neglected tropical disease of malaria, I hope you have enjoyed my research journey as much as I have. For this one I am going to leave you with some of the most (in my opinion) interesting facts about malaria that I have discovered along the way. You might even be surprised by them; enjoy!

Sir Ronald Ross, a British Doctor, was the one who discovered the transmission of malaria by mosquitoes whilst he was researching malaria in India, on 20 August 1897; this is now known as World Mosquito Day. He was awarded the Nobel Prize for Medicine in 1902 for his work.

Some people can be more prone to being bitten than others, as mosquitos are attracted to certain specific stimuli. They have chemical sensors, which allow them to detect CO2 and lactic acid, both produced naturally by mammals when we breathe. They also use heat sensors and visual sensors to find living organisms; they are more likely to be attracted to warmer things that produce more movement, as these are strong indications of life.

Papaya happens to be a favourite fruit for the male mosquito. One recent (2010) attempt to control mosquito numbers was by poisoning papaya fruit with a chemical that caused them to become infertile. As mozzies only mate once, and the females have no way of knowing if the males are fertile or not, this was thought to be a possible solution to reduce mosquito populations in areas endemic for malaria.

Famous people who have been affected with malaria include: George Clooney, Cheryl Fernandez-Versini, Michael Caine, Lord Nelson, Didier Drogba, Mahatma Gandhi and a grand total of THREE US Presidents; George Washington, Theodore Roosevelt and John F. Kennedy.

The malaria virus has actually had its uses in the past: Before antibiotics it was used as a form of therapy for syphilis – the high temperatures induced by the infection destroyed the syphilis bacterium. Three or four bouts of fever were usually sufficient to get rid of the syphilis, and quinine was used to control the malaria. Although some patients died of the malaria, for the majority it was a risk worth taking to avoid certain death from syphilis.

mosquito-son-courtesy-of-devothoughts-com

Thank you for reading!

Fighting the good fight

Embedded into this blog post is a Podcast of my interview with Professor Peter Brophy; a professor of parasitology at Aberystwyth University. The interview covers the subject of vaccines, specifically with regards to parasites and malaria, to support my own research into malaria vaccines, have a listen! Any questions feel free to post.

At this current moment in time we have no official vaccines for malaria, our only real medicinal defence is treatment. However, the effectiveness of these drugs is frequently subject to resistance; a problem that is only going to get worse until new and novel malarial treatments are produced.

The Plasmodium parasite needs to be able to survive inside its host long enough to develop, reproduce and transfer back to its mosquito vector to ensure the life cycle continues, but to do this they need to avoid detection and destruction by the primary host’s immune system (that’s us and our white blood cells). Plasmodium parasites live intracellularly; inside our red blood cells and liver cells. RBCs have no nucleus and when infected they are not recognised by the host’s immune system.

Different stages of the life cycle express different surface antigens, making it difficult for the immune cells to target them. There are three stages in the life cycle of the parasite inside the host that are being studied as possible targets for a vaccine.

First is the infection or pre-erythrocytic stage. This is targeted by using antibodies to recognise and target CS (circumsporozoite) & TRAP proteins expressed on surface of sporozoites in the liver cells (hepatocytes). The current vaccine is called RTS,S and is at stage 3 trials with GlaxoSmithKline, but has only shown 46% efficacy at preventing disease so far; unlikely to be good enough to make it to wide scale production.

Secondly; the disease or asexual blood stage. Again an antibody response to the surface proteins is utilised, however the problem with this stage is that immune evasion can happen when blocking antibodies get in the way; they bind to sites close enough to the targeted surface protein that they effectively block the antibodies from reaching the active sites of the proteins. The vaccine being developed for this stage is currently at stage 2 trials.

The third stage being considered is the transmission or sexual stage, which involves targeting the surface proteins on the gametes and ookinetes with antibodies. This stage however has not shown as much promise for vaccination as the other stages, and at present has no ongoing clinical trials.

I’ll admit this is a more in depth look at vaccines than I’ve done in previous posts, but the references below should help!

  • Pleass & Holder (2005) Antibody-based therapies for malaria. Nature Review: Microbiology. 3:893-9.
  • Druilhe & Barnwell (2007) Pre-erythrocytic stage malaria vaccines: time for a change in path. Current Opinion in Microbiology. 10:371-8.
  • http://www.malariavaccine.org/rd-rtss.php
  • Pradel (2007) Proteins of the malaria parasite sexual stages: expression, function and potential for transmission blocking strategies. Parasitology, 134(Pt.14), pp.1911–29.

A Day in the Life of… Plasmodium?

Ok, so maybe not a day. The erythrocytic part of the life cycle (which is responsible for the cyclic paroxysms as previously mentioned) takes more like 36 hours, or 48 or 76 depending on which species it is.

Whichever one you look at, the process if not the timing is essentially the same; when an infected mosquito bites a human it injects saliva. This contains chemicals that act as vaso-dilatators, anti-coagulants and anti-haemostatics, which are all necessary for the mosquito to have a successful blood meal. However if the mosquito is infected with Plasmodium, it is likely to be carrying Plasmodium sporozoites in its salivary glands. These are injected along with the other chemicals in the saliva, and then travel to the liver, where they reproduce asexually and enter the bloodstream. The sporozoites enter red blood cells and again reproduce asexually, eventually causing the red blood cells to rupture releasing merozoites. This process is repeated exponentially, as every time a red blood cell bursts it infects others, destroying large numbers of red blood cells and resulting in the typical symptoms of malaria sufferers; anaemia and paroxysms (chills and fever). In some cases the merozoites will develop into male and female gametocytes inside the red blood cells, which in turn can be taken up in a blood meal by the female Anopheles when feeding on an infected human host. The mosquito is an essential part of the Plasmodium life cycle as the gut of the mosquito is where the gametocytes fuse, producing ookinetes which further develop into oocysts and then finally to sporozoites, which migrate to the salivary glands ready to start the process all over again when the mosquito finds its next victim to feast on.

Plasmodium lifecycle
Life cycle of the Plasmodium parasite

For more information on feasting mozzies:

CDC: http://www.cdc.gov/malaria/about/biology/mosquitoes/

Life of Anopheles

Female Anopheles mosquitoes lay their eggs in batches of 70-100 on still patches of water, usually at night. The eggs are laid on surface of the water and in nice tropical temperatures can take 2-3 days to hatch, or 2-3 weeks in chilly cold weather. In the subsequent ten days the larvae lie just below the surface and go through 4 larval stages (or moults) shedding their outer skin each time to allow for growth. All stages are voracious eaters; they will devour any bacteria, algae, fungal spores and general microscopic detritus in the water. They then take 2 days to morph from comma shaped pupa to adults, which break the surface of the water and rest to dry their wings before flying off.

Anopheles lifecycle

The Anopheles lifespan can be between 1 week and 1 month long. Females mate only once, and store the sperm to fertilise their eggs when laying. As I’ve mentioned previously, they must take a blood meal before laying to provide them with adequate protein and nutrients for their ovaries to develop sufficiently, whilst the males content themselves with fruit nectar.

nectar feeding

Should you wish to intrude some more on their lives:

http://malaria.wellcome.ac.uk/doc_WTD023872.html

Know your Enemy: The Facts

‘Keep your friends close, and your enemies closer’… Of course in the case of mosquitoes infected with malaria, I’d rather not. However it is good to know as much as possible about the parasites these nasty little beggars carry, especially if you intend to visit their native habitats.

The malaria parasite is a protozoan of the genus Plasmodium and has 4 different species capable of infecting humans:

Plasmodium falciparum – Estimated 50% of infections, common in tropics and sub-tropics

Plasmodium vivax – ~43% of infections, common in tropics and sub tropics but rare in Africa

Plasmodium malariae – Only 7% of infections, mainly found in sub-tropics

Plasmodium ovale – Quite rare, usually seen in West Africa

Now skilled analysts in a laboratory can frequently distinguish between each species using microscopy, but otherwise you could take a guess by looking more closely at the symptoms; each parasite species has slight variations in their life cycle which affect the timing of the cyclic paroxysms of fever, chills and uncontrollable shivering which are the most typical symptoms of malaria. This is due to the lysis (splitting) of red blood cells to release merozoites (immature stages of the parasite) which can cause anaemia if many red blood cells (RBCs) are affected. The erythrocytic part of the cycle is responsible for this and is shortest in P. falciparum at 36 hours. P. vivax and P. ovale take 48 hours and P. malariae is the longest at 76 hours.

In the very unlikely and peculiar event that you had the option of which species to be infected by, I would strongly recommend against choosing P. falciparum. This species has the propensity to cause the most severe cases of malaria due to the nature of infection; it does not distinguish between the ages of red blood cells and can infect all equally, unlike the other malaria strains. P. vivax and P. ovale infect young RBCs and P. malariae infects older RBCs. This means that the numbers of RBCs infected by the parasite are limited, so these strains rarely cause life-threatening infections. P. falciparum is also the only strain that causes RBCs to sequester (stick together) and adhere to the walls of capillaries causing clots, leading to cerebral malaria if these happen in the brain. Oh, and as it has the shortest erythrocyte cycle the bouts of fever are more frequent. No thank you.

'Twenty six mosquitos and one fish.'

A few links to investigate:

World Health Organisation: http://www.who.int/ith/diseases/malaria/en/

Miserable Mozzies

Mosquitoes. When summer comes we do all sorts just to stop these irritating insects biting us; we squash them, spray them and sometimes even spray ourselves with repellents/insecticides, and rightly so; who wants itchy bites to bother them? Though at least if we do get bitten we need only put some antiseptic cream on to sooth the area, and possibly an antihistamine should a severe allergy to the bug’s saliva become apparent. But what if there was more to worry about than just an itchy red swelling on our skin? When a female mosquito takes a blood meal, she uses a slender protective sheath called the proboscis, at the end of which are two pairs of stylets that cut through the skin of the victim, allowing the mosquito to probe for tiny blood vessels. Now if at first she doesn’t find a blood vessel the mosquito will try again through the same hole, but at a slightly different angle (good thing their saliva contains an anaesthetic so we don’t feel this part).

'I try to be considerate and always sterilize my stinger before biting into a new victim.'
If only they did…!

The proboscis contains two hollow tubes; one which injects saliva containing a lovely cocktail of anticoagulants (to increase blood flow) and anaesthetics into the tiny incision and one that draws blood. If infected with Plasmodium the parasites mature in the mosquito’s gut and then migrate to the salivary gland in order to be passed on to its next host when the mosquito bites. It is also possible that some blood from a mosquito’s last victim is injected along with the saliva or when drawing blood; this contributes not only to the spread of Malaria, but also Yellow Fever, AIDS and West Nile Virus, among others. The male mosquito is actually not directly to blame for spreading these diseases, as it is only the female that must take a blood meal before laying her eggs; blood is an excellent source of protein to fuel reproduction. Talk about a femme fatale!

c-01769
Meet Annie Awful – she was a cartoon designed to remind US soldiers to use their mosquito nets!

Some links to stick your proboscises into (and yes, that is the plural, honest!):

Journal of Experimental Biology: ‘Experimental analysis of the blood-sucking mechanism of female mosquitoes’ by Bo Heum Kim, Hae Koo Kim and Sang Joon Lee. http://jeb.biologists.org/content/214/7/1163.short

NHS: http://www.nhs.uk/Conditions/Bites-insect/Pages/Symptoms.aspx

Web MD: http://www.webmd.boots.com/a-to-z-guides/tc/bites-insect-introduction

The Madness that is Malaria

I should probably start by introducing the disease this blog is all about; Malaria. Very briefly (I will go into more detail in later posts) it is caused by a microscopic parasite and transmitted by mosquitoes. It can cause many unpleasant symptoms, including (but not limited to) cycles of fever, chills, anaemia, hepatosplenomegaly (enlargement of the liver and spleen), coma and often eventually death if not treated. It is most common in tropical, hot, humid climates such as Africa, Asia, Central and South America and parts of the Middle East, where conditions are optimal for the mosquitoes transmitting the parasite to breed. Malaria was responsible for over 1.24million deaths in 2014, over 90% of which occurred in Africa, the majority young children; the majority of relevant statistics suggest that every 30-60 seconds a child dies from malaria.

This is the short of it; a pandemic disease causing pain, suffering and death in many African countries and those with similar climates… But why should we care? It’s not affecting us, it’s not here in the United Kingdom. When we travel to visit these places under the guise of a holiday/humanitarian outreach/research trip we take anti-malarial tablets. Should we fall ill on returning we have one of the best health systems in the world to turn to for free treatment. We may see an advert on TV playing emotional music and appealing for aid, or read a Facebook post of a passionate acquaintance bemoaning the suffering of these far-away countries and we may feel sorrow, compassion and sympathy. But these are all too often fleeting emotions; we have no personal incentive to worry overtly, to campaign or protest, to invest in extensive research…. Or do we?

The worrying thing is, we may want to think about Malaria as more than just a tropical disease with little direct impact on us. The climate is warming (this IS a fact, not just scientific conjecture) and our country will experience climatic changes in one direction or another. Now, this warming could actually cause the jet stream and/or the gulf stream to change position, in which case the UK could experience cooling, possibly even something akin to an ice-age. Then I’m sure we would have other issues to address. However should the gulf stream and jet stream remain as they are currently, our country’s climate will become milder. This is likely to open up our doors to the many tropical diseases we so conveniently ignore at present, as more of the insects that carry them (known as hosts or vectors) would be able to survive through the winters and possibly even thrive in our warmer temperatures. Some possible host species already live in the UK, however there is not a reservoir of disease here as of yet. Food for thought, no?

malariadistribution

If you fancy doing your own research, here are some links I found useful:

J. Sachs, P. Malaney (2002). The economic and social burden of malaria. Nature415, 680-685 (February 2002), doi:10.1038/415680a (http://www.nature.com/nature/journal/v415/n6872/full/415680a.html)

An inconvenient truth, by Al Gore (the whole book isn’t available online, but is well worth getting)

Centre for Disease Control http://www.cdc.gov/malaria/about/index.html