An endoparasitic protozoan that causes malaria, Plasmodium, requires two hosts to complete its life cycle in; usually a mosquito and a vertebrate. Female Anopheles mosquito is responsible in the transmission of malaria in human beings. Human malaria is caused by four identified species of Plasmodia, namely Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium ovale. Recently, in addition to these four species, the simian parasite Plasmodium knowlesi have been identified to infect humans in Malaysia (Cox-Singh, Singh, 2008). Malaria can be treated in just 48 hours; however the delay in diagnosis and treatment can cause fatal complications. Malaria caused by P. falciparum is also called malignant or falciparum malaria (Rich et al., 2009), which is observed to be the most dangerous form of malaria with the highest rates of complications and mortality. A dormant stage in the life cycle of P. vivax and P. ovale may results into relapses long afterwards. The malaria due to P. knowlesi can also cause life threatening symptoms(Cox-Singh et al., 2008). P. malariae is associated with milder clinical manifestations in comparison to other species.
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The systematic position of malaria parasite described by (Mhelhorn H. and Walldorf V., 1988) is as follows:
Sub Kingdom Protozoa
Sub Class Coccidia
Sub Order Aconoidina
1.2 History of Malaria
The term malaria is derived from Italian word mala "bad" and aria "air". Italians used this word to refer the cause of intermittent fevers associated with exposure to marsh air or miasma. In the first century A.D., Roman scholar Marcus Terentius Varro (116-27 BC) suggested that swamps breed "certain animalcula which is not visible with naked eyes and we breathe it through our mouth and nose into the body, where they cause grave maladies". Later, about 30 A.D., two types of tertian fevers were described by Celsus. He concurred with the views expressed by Varro.
In 1716, Italian physician Giovanni Maria Lancisi, first demonstrated a characteristic black pigmentation of the brain and spleen in the victims of malaria. In 1816, Giovanni Rasori (1766-1837) of Parma suggested microorganism as a cause for the disease. Later, in 1847, a German physician, Heinrich Meckel, identified round, spindle-shaped or ovoid structures containing black pigment granules in protoplasmic masses in the microscopic slides of blood from a patient with fever and observed similar entities in the spleen of an insane person during the autopsy. In 1848 Schutz observed these pigments in the internal organs of patient who had died of malaria. Soon afterwards, Virchow (1849) observed these pigmented bodies in the blood of a patient who had died from chronic malaria and specifically associated it with malaria. Finally, Charles Louis Alphonse Laveran in 1888 named a living organism as Oscillaria malariae and suggests it as the malaria parasite.
In 1885 Camillo Golgi, established that there were at least two forms of the disease, one with tertian periodicity (fever every other day) and one with quartan periodicity (fever every third day). He demonstrated that the rupture of shizoints and release of merozoites into the blood stream coincided with the fever and correlated the severity of symptoms with parasite load in the blood. In 1906, Nobel Prize was awarded in Medicine for his discoveries in neurophysiology. In 1897, the sexual cycle of malaria parasite was demonstrated by Dr. McCallum, William G and Opie of Johns Hopkins Hospital. In the same year, Ronald Ross demonstrated the presence of oocysts in the midgut of female anopheline mosquito and soon afterwards, he (1898) demonstrated the sporozoites infection in salivary glands of the mosquito and also carried out transmission of malaria in birds with an infected mosquito. He was awarded the Nobel Prize in 1902 for establishing the fact that infected mosquitoes are responsible for transmission of malaria. In 1907, Charles Louis Alphonse Laveran, was awarded the Nobel Prize for Medicine and Physiology for his discovery of the malarial parasite and other significant contribution to parasitology.
In 1975 William Trager cultured P. falciparum in a medium of red blood cells. In 1987, a Colombian biochemist named Dr. Manuel Elkin Patarroyo developed the first synthetic Spf66 vaccine for P. falciparum infection. In 2002, the genome of parasite Plasmodium falciparum and the vector Anopheles gambiae were successfully sequenced.
1.3 Public and Global Health Burden
Always on Time
Marked to Standard
Malaria is one of the oldest infectious diseases known to mankind. Malaria influenced outcomes of many wars and fates of many kings would have been different. It has competently forced many military defeats and responsible for decline of nations, often caused casualties more than the weapons could have. For centuries it has been responsible in preventing economic development in various regions of the earth.Â Malaria occurred in more than 100 countries and affects more than 2400 million people in the tropics, from South America to the Indian peninsula. Human malaria in tropical and subtropical areas accounts approximately 40% of the world at risk for the disease. The cause of this distribution in tropics is because of ideal breeding and living conditions for the anopheles mosquito. About 300 million to 500 million people suffer from malaria annually. Most lethal form of malaria infection is focused in the African continent, especially among children under five. In total, sub- Saharan Africa show most (90%) of the malarial cases and two thirds of the remaining 10% cases occur in six countries- India, Sri Lanka, Colombia, Vietnam, Brazil and Solomon Islands (Figure 1.1). WHO forecasts a 16% augmentation in malaria cases annually and about 1.5 million to 3 million deaths due to malaria every year (85% of these occur in Africa), accounting for about 4-5% of all moartality in the world. One child dies every 20 sec. due to malaria somewhere in Africa and there is one malarial death every 12 sec somewhere in the world. 50 million peoples have died of malaria. Among the major infectious diseases, malaria ranks third in cause of martality- after pneumococcal acute respiratory infections and tuberculosis (WHO., 2005). A brief account stated that ~ 30000 visitors who visited endemic countries developed malaria; where as 1% may succumb to the disease. Malaria can be accounted for 2.6 % of the world's overall burden of diseases, thus raising expectations that it can climb to number one of the highest killer infectious diseases by the end of the century. Total global estimates of the annual expenditure (in 1995) showed a whooping US$ 2 billion directed towards malaria. World Health Organization reported it as a re-emerging infectious disease, and specify as "infectious killer and number 1 priority tropical disease" (WHO., 2005). The recent WHO World Malaria Report registers a global impact of approximately 225 million new clinical malaria infections associated with 781,000 deaths (WHO., 2010). Particularly, in the tropical countries, malaria is a health problem that setbacks social and economical developments. Malaria is commonly associated with poverty, and represents a major burden to economic and social development, costing an estimated sum of greater than US$ 6 billion for the year 2010 (Sachs. J and Malaney. P, 2002; WHO., 2010). Early diagnosis and prompt treatment are two basic elements in easing the impact of malaria. While progress in these areas has been remarkable, the emerging insecticide resistant vectors, population movements, environmental disturbances, disintegrative health services and wide spread antimalarial drug resistance have constrained this mission. In early 60's, under the guidance of the
Figure 1.1 Global distribution of malaria. (Reprinted from Nat Rev Microbiol.) (Bell et al., 2006)
World Health Organization, malaria was nearly eradicated from most parts of the world owing to well planned anti malarial campaigns over the world. However, soon after, a resurgence of malaria took place in 1970's, which could be due to several reasons described below.
Man made complacency and laxity in anti malarial campaigns; conflicts and wars; migrations; deteriorating health systems; poverty
Drug resistance in parasite
Insecticide resistance in vector and ban on use of DDT
Environment global warming causing increased breeding and life span of the vector
Jet age shrinking world - spread of malaria from endemic areas to all other
parts of the world.
1.4 Life Cycle of Malaria PARASITE
The complex life cycle of malaria parasite involves two hosts; an insect vector (anopheles mosquito) and a vertebrate host (human). In search of a blood meal, a malaria-infected female Anopheles mosquito inoculates the infectious sporozoites into the human host. The malaria infection begins as these viable sporozoites invade liver cells and develop into mature schizonts, which in turn rupture and release invasive merozoites into blood stream. In P. vivax and P. ovale an arrested phase [hypnozoites] can remain dormant in the liver and re-invade the bloodstream after weeks, or even years later and cause infection, this delayed primary blood infection is termed as relapse. The initial asexual replication in liver is termed as exo-erythrocytic schizogony. In the normal developing exo-erythrocytic schizont, the cytoplasm of the parasite becomes subdivided and the ensuing invasive merozoites develop. These emergent merozoites are then released upon rupture of the mature schizont and invade the erythrocyte. The parasites undergo asexual multiplication in the erythrocyte, termed as erythrocytic schizogony. Redifferentiation of intra-erythrocytic merozoites into the feeding trophozoites occurs then. The ring stage
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Figure 1.2 Life cycle of malaria parasite (Plasmodium falciparum)
trophozoites mature into schizonts and when rupture releasing merozoites to begin another cycle of red blood cell infection. However, the majority of merozoites entering an erythrocyte will develop into asexual schizonts, a small fraction can develop into the first sexual stage of life cycle (gametocytes). The rupture of mature schizont also releases the metabolic debris, which is toxic to the host and play a role in stimulating the clinical manifestations of the disease.
The female anopheles mosquito must take blood meals on regular basis to support the
development of eggs in successive batches. When biting malaria infected vertebrate host,
she will take up infected erythrocyte and the gametocytes. Both female (macrogametocytes) and male (microgametocytes) are ingested by female anopheles mosquito during a blood meal. The asexual division of parasites in the mosquito is termed as sporogonic cycle. While in the mosquito's gut gametocytes are triggered by the fall in temperature and begin the formation of gametes. The microgamete penetrates the macrogamete generating zygote. Soon after the zygotes become motile and elongated structure termed as ookinetes, which invade the midgut wall of the mosquito where they develop into oocysts. The sporozoites emerge from ruptured oocysts make their way to reside in the mosquito salivary glands. Inoculation of these viable sporozoites into a new human host to maintain the malaria life cycle (Figure 1.2) (Bannister, Mitchell, 2003).
1.5 THE PLASMODIUM GENOME SEQUENCE
The genome sequences of six Plasmodium species have now been published. The complete sequences of the P.falciparum 3D7 strain and the rodent malaria P.y. yoelii 17XNL clone (Carlton et al., 2002; Gardner et al., 2002) appeared in 2002 and the genomic data of two more rodent malaria species, the P.berghei ANKA clone and P. chabaudi AS clone, were published in 2005 (Hall et al., 2005). Recently, the genome sequences of the human malaria P.vivax Salvador 1 strain and the human/simian malaria P.knowlesi H strain, along with a comparative analysis with P.falciparum, were released (Carlton et al., 2008; Pain et al., 2008). Thus, this genus has the highest number of sequenced species of any eukaryotic organism yet (Birkholtz et al., 2008).
Comparative analysis of the publicly of the available Plasmodium genomes revealed that they are all haploid with a standard size of 23-27 Mb, which is distributed among 14 linear chromosomes between 0.5-3.0 Mb in size. The base composition varies among the different species, with the rodent and P.falciparum genomes being extremely A+T rich (80.6% on average and close to 90% in introns and intergenic regions in P.falciparum) in contrast with the more G+C rich P.knowlesi and P.vivax genomes (37.5% and 42.3% respectively) Each Plasmodium genome has in the order of 5000-6000 predicted genes, most of which (51%) contain at least one intron and ~60% are orthologus among the different species (Hall, Carlton, 2005; Hall et al., 2005). The difference in gene number is the result of the differential gene expansion in distinct lineages and the presence of large variant gene families that are involved with antigenic variation (Hall, Carlton, 2005). The unique genes of the different species are often localised within the subtelomeric regions and code for immunodominant antigens (Hall, Carlton, 2005). The mean gene length of the three sequenced human malarias (including P. knowlesi) is~ 2.2 to 2.3 kb, compared to the average of 1.3 to 1.6 kb in other organisms (Gardner et al., 2002). The reason for these long gene lengths is not known and this is compounded by the fact that these long genes usually encode hypothetical proteins with unknown function (Gardner et al., 2002). Gene-mapping studies of conserved genes have shown that gene location, order and even exon-intron boundaries have been preserved over large regions across the three sequenced rodent Plasmodium species and P.falciparum(Hall, Carlton, 2005).
In addition to the nuclear genome , the parasites also have a liner mitochondrial genome of ~6 kb in the case of P.falciparum , which is smallest mitochondrial genome known (Painter et al., 2007) and a ~35 kb circular apicoplast genome (Gardner et al., 2002). The P.falciparum nuclear genome exhibits minimal redundancy in transfer RNA (tRNA) and encodes 43 tRNAs (Gardner et al., 2002) compared to the ~30 of Homo sapiens (Strachan T and Read A, 1998). The parasite tRNA bind all 64 possible codons except TGT and TGC that both specify cysteine (Cys). As no other codons specify Cys, it is possible that these tRNA genes are located within the currently unsequenced regions , since Cys is incorporated into P.falciparum proteins (Gardner et al., 2002). The small P.falciparum mitochondrial genome does not encode any tRNAs (Vaidya et al., 1989) compared to the 22 tRNA of the circular 16.6 kb human mitochondrial genome (Anderson et al., 1981). The P.falciparum mitochondrion therefore imports tRNAs from the cytoplasm , whereas the apicoplast genome encodes sufficient tRNAs for protein synthesis within the organelle (Wilson et al., 1996).
The P.falciparum genome does not contain tandemly repeated ribosomal RNA (rRNA) gene clusters as seen in many other eukaryotes, but it contains individual 18S-5.8S-28S rRNA units at loci on seven of the chromosomes(Gardner et al., 2002). The sequence of the particular rRNA genes is distinct in the different units and the expression of each unit is developmentally regulated, depending on the stages of the parasite life cycle It is anticipated that by transcribing different rRNAs at different life stages, the parasite could change its ribosomal properties and the translation rate of all or specific messenger RNA (mRNA), which could alter the cell growth rate or cell development pattern. Previously , the rRNA expressed in the mosquito was described as S(sexual)-type and that expressed in the human host as A (asexual) type(Gardner et al., 2002). Parasite rRNA is also species-specific and can be assessed for diagnostic purposes (Singh et al., 2004). More than 60% of the predicted 5268 open reading frames (ORFs) of P.falciparum have no sequence similarity to genes from other sequenced organisms (Gardner et al., 2002). The absence of sequence similarity complicates characterization of the unknown ORFs, but might hold the answer to finding selective drug targets (Bozdech et al., 2003). There is currently a dedicated initiative aimed at improving the annotation status of P.falciparum led by the Plasmodium database, PlasmoDB (www.plasmodb.org).
1.6 Malaria Incidence in Different States of India
The malariometric index evaluated as annual parasite incidence (API) indicates the number of malaria cases per thousand of population. As per the National Vector Borne Disease Control Programme (NVBDCP) incidence records, in most part of India, the API was < 2,whereas 2-5 API was scattered in various regions, and regions with > 5 API were scattered in the states of Gujarat, Goa, Rajasthan, Madhya Pradesh, Chhattisgarh, Jharkhand, Orissa, the northeastern states and Karnataka (Kumar A et al., 2007). The proportion of occurrence of P. falciparum and P. vivax differs in various parts of India. Most of the indo-gangatic plains, northwestern India, northern hilly states, and southern state like Tamil Nadu have > 90% P. vivax infections, and the rest are P. falciparum. This situation is reversed in forested areas inhabited by ethnic tribes, where the proportion of P. falciparum is 30-90%. In the remaining areas P. falciparum prevail between 10% and 30%. Although Orissa has a population of 36.7 million (3.5%), it contributed most (25%) of a total of 1.5-2 million reported annual malaria cases, 39.5% of total P. falciparum malaria, and 30% of deaths caused by malaria in India (Source NVBDCP, India). Similarly, in the other states, forest ecosystems inhabited by ethnic tribe's lives mainly in
Figure 1.3 Prevalance of Plasmodium falciparum in India
meso to hyperendemic conditions of malaria, where the preponderance of P. falciparum exist upto the extent of 90% or even more (Kumar et al., 2007) (Figure 1.3).
1.7 MALARIA Control and Prevention
A global strategy for malaria control was developed by W.H.O. in a ministerial conference at Amsterdam, held in October 1992. The strategy broadly suggests emphasis on diagnosis and treatment in place of earlier trend of emphasis on vector control as a strategy for malaria control. The salient aspects of this strategy were early diagnosis and treatment; prevention of malarial deaths; promotion of personal protection measures like use of ITMs; forecasting, early detection and control of malaria epidemics; monitoring, evaluation and integration of activity in primary health centres; and operational research in field sites. Malaria prevention was classified at the level of personal protection, the prophylaxis and the malaria vaccines. Protective measures adopted at individual level and at family level not only help in protection of the individual against mosquito bites but also prevents spread of malaria in locality. These measures indirectly helped in reducing the mosquito population by denying the blood meal which is an essential for nourishment of the mosquito eggs in the female anopheles.
Protection measures at personal level against mosquitoes includes: Prevention of mosquitoes from entering the house, protection from mosquito bites and prohibiting the mosquitoes from resting inside house. All these prevention activities need the following;
i. Protective Clothing
ii. Mosquito Repellents
iii. Insecticide vaporizers
iv. Mosquito nets
v. Air conditioning
The absence of vaccines necessitates the use of drugs against malaria. All visitors from non-endemic area to a malarious area should have presumptive antimalarial drugs which offer protection against clinical attacks of malaria in that particular malaria endemic area (www.who.int/malaria).
The practice of anti-malarial drugs to prevent the development of malaria is known as chemoprophylaxis. The choice of chemoprophylaxis differs depending on the species and drug resistance prevalence in a country. It must be remembered that no chemoprophylaxis regime provides 100% protection. Therefore it is essential to have personal protection from mosquito bites as well as to practice the chemoprophylaxis. Drugs used for chemoprophylaxis include: chloroquine, sulfadoxine, pyrimethamine, atovaquone plus proguanil, proguanil, halofantrine, doxycycline and mefloquin (www.ncbi.nlm.nih.gov/antimalarialdrug.html).
The effective way to control any infectious disease is indeed to have a safe and effective vaccine, but even after decades of malaria research, an effective malaria vaccine is still elusive. The major culprit in not having an effective malaria vaccine is complex life cycle of the parasite which involves vector mosquitoes and human. In turn, parasite's allelic diversity and antigenic variations make the development and implementation of effective malaria control intervention more problematic. In the present scenario of increasing resistance against antimalarials by parasite and the insecticide resistance shown by the anopheles mosquito, it is evident that an intervention at multiple stages of life cycle will be an appropriate way of combating malaria. Malaria vaccines for different stages of life cycle will therefore play a major role in future malaria interventions. Evaluation of new malaria vaccine candidates in malaria endemic countries is required. The present situation demands sufficient sites in malaria endemic countries for testing potential malaria vaccines in future.
1.8 Antimalarial drug resistance
One of the major control strategies against malaria is prompt treatment of malaria patients with effective antimalarial drugs; however one of the major challenges in the battle against malaria in recent years is the development of drug resistance in the malaria parasites. A continuous research and monitoring is crucial when trying to control and diminish this development. Antimalarial drug resistance in the malaria parasite, both in vitro and in vivo has been related to changes at molecular level in the malaria parasite (P. falciparum and P. vivax).