Wednesday, April 24, 2013

Controlling malaria- Perspectives


      The last 2 weeks have been the show of H7N9. The eyes of the whole world is concentrated on China. An extra ordinary effort is put into studying whatever is possible. Various teams have visited and in the process of scientific search. In that event let me ask you a question. What would be the most difficult and challenging infections globally? Someone would argue, most infectious diseases are important and challenging. But considering the best of the best, what bothers the most? I would say Tuberculosis, Influenza, HIV and Malaria. Decades of research is available in all these areas, yet we have failed to beat these, most of the times at least.

Photo 1: Female Anopheles.
    Malaria is a very interesting disease. Seen mainly in the tropics, caused by Plasmodium species and a vector borne problem. I often had wondered, if you should consider humans as the incubators for malaria so that we could infect the mosquito. We are the intermediate hosts and Mosquito is the definitive host. I can trash the argument by saying that humans suffer strong clinical symptoms from infection and fatal in many cases, but not so with mosquito. A second basic question is why only female anopheles? The answer is both males and females suck on plant and fruit saps for nutrition, but for the purpose of ovulation, materials are derived from mammalian blood. And since only females ovulate, only females need blood.

     Speaking about the Plasmodium, 4 different species are seen to infect humans- P vivax, P. falciparum, P. ovale, P. malariae. More recently a 5th species referred as P. knowlesi (Known to cause primate malaria), is seen to cause infections in humans, especially in South East Asian regions.

Table 1: Important features of Plasmodium
     Malaria control was once attempted by using DDT (1,1,1-trichloro-2,2-di (4-chlorophenyl) ethane). Though there was a heavy reduction, the whole problem bounced back, anopheles developed resistance to DDT. Since, we have tried variety of approaches. The best of all that has worked to date without problem is the use of bed nets. However, you cannot get a person inside a bed net all over the time and hence we need more methods.

       I have some good news. In the past few years the global malaria eradication problems have been successful, at least to a reasonable extent. The number of cases reported annually in most of the endemic countries has reduced by almost 80%. Armenia, Morocco, Turkmenistan, and the United Arab Emirates, which was known for a good number of malaria cases has been now convincingly certified as malaria free. I feel optimistic here, as it shows that we can achieve it. A review article in lancet by Cotter etal, discuss in detail how and what we have achieved in malaria control.

Fig 1: Malaria Control Strategies.
       There are different possible methods to control malaria. I have summarized the most well known methods in Fig 1 (Shown to the right). The physical methods are very promising if used right. They are often inexpensive. Use of mosquito repellants and Insect nets are the most common methods under this. More recently scientist at colombia university has developed a laser shield that can repel the mosquito. But the technique hasn't become famous enough yet. My most obvious argument is that if the person can afford laser based machines. they better invest in a simple net. But, it has an advantage that it can be installed in windows in such a way that the window is open for everything except mosquito. Read here

      The second method is vaccination. A very great deal of expectation was put forward on the RTS,S/AS01 vaccine targeting the CSP (circumsporozoite protein). RTS is a hybrid polypeptide consisting of a portion of the circumsporozoite protein (CS), a sporozoite surface antigen of the malaria parasite P. falciparum strain NF54, fused to the amino-terminal end of the hepatitis B virus S protein.  AS01 Adjuvant System consists of a liquid suspension of liposomes with two immuno-stimulant components- 3’-O-desacyl-4’-monophosphoryl lipid A (MPL) and Quillaja saponaria 21 (QS21). The recent publication in NEJM, cast some doubts on the efficacy of the vaccine (has been calculated to be modest only). However the final conclusive results are yet to be published.

Photo 2: Wolbachia in egg. Source
     The third method, that is gaining popularity is the Vector Control Programs. Vector control programs against malaria has some additional set of advantages. Once successful, they are calculated to be self sustaining (At least theoretically) and can also confer protection against other vector borne infections (caused by the same vector) over the long run. Impressive.

      The Biological Vector control Program against female anopheles, that has gained a very strong popularity is the use of Wolbachia. Wolbachia (alpha-proteobacteria member) are gram negative, intracellular, endosymbiontic bacteria, known to infect arthropods, insects and some nematodes. They are referred sometimes as gonad tampering bacteria. They have the ability to changing the sex of host and kill their offspring. This can be achieved either by distorting the host sex ratio and (or) by inducing cytoplasmic incompatibility. Moreover they are known to maternally transmit through the egg cytoplasm. W pipentis, is the potential candidate. The bacteria accumulates at the end of the egg that is destined to develop into the reproductive organs (See Photo 2). This induce the eggs of this wasp to develop into female offspring without fertilization. Source. The idea of using such a biological system to control the mosquito was proposed as early as 1967 and a few trials were conducted in India in 1970s with some field testing. However it had not received much interest and now there is a revived interest owing to its possible potential.

    Though many different mosquito varieties including Culex pipiens, C. quinquefasciatus, Aedes fluviatilis and A. albopictus are naturally infected, the most important vector A. aegypti and Anopheles species are not. To create a stable infection, embryonic microinjection of Wolbachia near the pole cells in pre-blastoderm embryosis is used, to incorporate Wolbachia into the developing germline and favor the transmission of Wolbachia. In addition to cytoplasmic incompatibility, Wolbachia is also shown to directly interfere with variety of virus such as Dengue and West Nile. The bacteria also confers a reduced life span for the insect and thus reduces transmission (Remember, it takes at least 2 blood meals ;2 weeks apart for the mosquito to successfully transmit plasmodium).

       The Second bacterium that has gained popularity is a bio-engineered strain of Pantoea agglomerans (previously known as Enterobacter agglomerans). In a recent blog post (Link), I had talked about how one bacteria can be engineered to sense another bacteria and secrete toxic molecules to destroy the pathogen. The approach has been used in many scenario, and the same tactic is employed here. A variety of secretable compounds such as dodecapeptide SM1, anti-Pbs21 single-chain variable-fragment (scFv) antibody and phospholipase A2 had been engineered into the bacteria. This can be secreted through a pelB or hlyA protein secretion pathways from P. agglomerans (Paratransgenic P. agglomerans strain). The studies show that when the plasmodium enters the mosquito gut, the bacteria secrete engineered compounds inhibiting the plasmodium life cycle

     The main hurdles in introducing such Biological control programs is to stabilize. The bacteria needs to have a fitness in transmission (Refer to Bartonian wave; Link)and not effect evolution. Our main aim in these new strategies is to inhibit the plasmodium life cycle (Or virus) and not destroy the mosquito. This gets around the problem of evolution and resistance emergence. A field trial (Started in 2011) is currently evaluated against Dengue in Australia, with awaited scientific results. A field trial is also scheduled in Brazil in May 2014. The trial will answer many questions. Link
Iturbe-Ormaetxe, I., Walker, T., & O' Neill, S. (2011). Wolbachia and the biological control of mosquito-borne disease EMBO reports, 12 (6), 508-518 DOI: 10.1038/embor.2011.84

Walker, T., & Moreira, L. (2011). Can Wolbachia be used to control malaria? Memórias do Instituto Oswaldo Cruz, 106, 212-217 DOI: 10.1590/S0074-02762011000900026

Bisi DC, & Lampe DJ (2011). Secretion of anti-Plasmodium effector proteins from a natural Pantoea agglomerans isolate by using PelB and HlyA secretion signals. Applied and environmental microbiology, 77 (13), 4669-75 PMID: 21602368

Wang, S., Ghosh, A., Bongio, N., Stebbings, K., Lampe, D., & Jacobs-Lorena, M. (2012). Fighting malaria with engineered symbiotic bacteria from vector mosquitoes Proceedings of the National Academy of Sciences, 109 (31), 12734-12739 DOI: 10.1073/pnas.1204158109

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