An endoparasitic protozoon that causes malaria, Plasmodium, requires two hosts to finish its life rhythm in ; normally a mosquito and a craniate. Female Anopheles mosquito is responsible in the transmittal of malaria in human existences. Human malaria is caused by four identified species of Plasmodia, viz. Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium ovale. Recently, in add-on to these four species, the simian parasite Plasmodium knowlesi have been identified to infect worlds in Malaysia ( Cox-Singh, Singh, 2008 ) . Malaria can be treated in merely 48 hours ; nevertheless the hold in diagnosing and intervention can do fatal complications. Malaria caused by P. falciparum is besides called malignant or falciparum malaria ( Rich et al. , 2009 ) , which is observed to be the most unsafe signifier of malaria with the highest rates of complications and mortality. A hibernating phase in the life rhythm of P. vivax and P. ovale may consequences into backslidings long afterwards. The malaria due to P. knowlesi can besides do life endangering symptoms ( Cox-Singh et al. , 2008 ) . P. malariae is associated with milder clinical manifestations in comparing to other species.
The systematic place 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 mention the cause of intermittent febrilities associated with exposure to marsh air or miasma. In the first century A.D. , Roman bookman Marcus Terentius Varro ( 116-27 BC ) suggested that swamps breed “ certain animalcule which is non seeable with bare eyes and we breathe it through our oral cavity and nose into the organic structure, where they cause sedate maladies ” . Later, approximately 30 A.D. , two types of tertian febrilities were described by Celsus. He concurred with the positions expressed by Varro.
In 1716, Italian doctor Giovanni Maria Lancisi, foremost demonstrated a characteristic black pigmentation of the encephalon and lien in the victims of malaria. In 1816, Giovanni Rasori ( 1766-1837 ) of Parma suggested micro-organism as a cause for the disease. Later, in 1847, a German doctor, Heinrich Meckel, identified unit of ammunition, fusiform or egg-shaped constructions incorporating black pigment granules in protoplasmic multitudes in the microscopic slides of blood from a patient with febrility and observed similar entities in the lien of an insane individual during the necropsy. In 1848 Schutz observed these pigments in the internal variety meats of patient who had died of malaria. Soon afterwards, Virchow ( 1849 ) observed these pigmented organic structures 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 life being as Oscillaria malariae and suggests it as the malaria parasite.
In 1885 Camillo Golgi, established that there were at least two signifiers of the disease, one with tertian cyclicity ( fever every other twenty-four hours ) and one with quartan cyclicity ( fever every 3rd twenty-four hours ) . He demonstrated that the rupture of shizoints and release of merozoites into the blood watercourse coincided with the febrility and correlated the badness of symptoms with parasite burden in the blood. In 1906, Nobel Prize was awarded in Medicine for his finds in neurophysiology. In 1897, the sexual rhythm of malaria parasite was demonstrated by Dr. McCallum, William G and Opie of Johns Hopkins Hospital. In the same twelvemonth, Ronald Ross demonstrated the presence of oocysts in the midgut of female anopheline mosquito and shortly afterwards, he ( 1898 ) demonstrated the sporozoites infection in salivary secretory organs of the mosquito and besides carried out transmittal of malaria in birds with an septic mosquito. He was awarded the Nobel Prize in 1902 for set uping the fact that infected mosquitoes are responsible for transmittal of malaria. In 1907, Charles Louis Alphonse Laveran, was awarded the Nobel Prize for Medicine and Physiology for his find of the malarial parasite and other important part to parasitology.
In 1975 William Trager cultured P. falciparum in a medium of ruddy blood cells. In 1987, a Colombian biochemist named Dr. Manuel Elkin Patarroyo developed the first man-made Spf66 vaccinum 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
Malaria is one of the oldest infective diseases known to mankind. Malaria influenced results of many wars and destinies of many male monarchs would hold been different. It has aptly forced many military lickings and responsible for diminution of states, frequently caused casualties more than the arms could hold. For centuries it has been responsible in forestalling economic development in assorted parts of the earth.A Malaria occurred in more than 100 states and affects more than 2400 million people in the Torrid Zones, from South America to the Indian peninsula. Human malaria in tropical and semitropical countries histories about 40 % of the universe at hazard for the disease. The cause of this distribution in Torrid Zones is because of ideal genteelness and life conditions for the Anopheless mosquito. About 300 million to 500 million people suffer from malaria yearly. Most deadly signifier of malaria infection is focused in the African continent, particularly among kids under five. In entire, sub- Saharan Africa show most ( 90 % ) of the malarial instances and two tierces of the staying 10 % instances occur in six countries- India, Sri Lanka, Colombia, Vietnam, Brazil and Solomon Islands ( Figure 1.1 ) . WHO forecasts a 16 % augmentation in malaria instances yearly and about 1.5 million to 3 million deceases due to malaria every twelvemonth ( 85 % of these occur in Africa ) , accounting for about 4-5 % of all moartality in the universe. One kid dies every 20 sec. due to malaria someplace in Africa and there is one malarial decease every 12 sec someplace in the universe. 50 million peoples have died of malaria. Among the major infective diseases, malaria ranks 3rd in cause of martality- after pneumococcal ague respiratory infections and TB ( WHO. , 2005 ) . A brief history stated that ~ 30000 visitants who visited endemic states developed malaria ; where as 1 % may yield to the disease. Malaria can be accounted for 2.6 % of the universe ‘s overall load of diseases, therefore raising outlooks that it can mount to figure one of the highest slayer infective diseases by the terminal of the century. Entire planetary estimations of the one-year outgo ( in 1995 ) showed a whooping US $ 2 billion directed towards malaria. World Health Organization reported it as a re-emerging infective disease, and stipulate as “ infective slayer and figure 1 precedence tropical disease ” ( WHO. , 2005 ) . The recent WHO World Malaria Report registers a planetary impact of about 225 million new clinical malaria infections associated with 781,000 deceases ( WHO. , 2010 ) . Particularly, in the tropical states, malaria is a wellness job that setbacks societal and economical developments. Malaria is normally associated with poorness, and represents a major load to economic and societal development, bing an estimated amount of greater than US $ 6 billion for the twelvemonth 2010 ( Sachs. J and Malaney. P, 2002 ; WHO. , 2010 ) . Early diagnosing and prompt intervention are two basic elements in easing the impact of malaria. While advancement in these countries has been singular, the emerging insect powder immune vectors, population motions, environmental perturbations, disintegrative wellness services and broad spread antimalarial drug opposition have constrained this mission. In early 60 ‘s, under the counsel of the
Figure 1.1 Global distribution of malaria. ( Reprinted from Nat Rev Microbiol. ) ( Bell et al. , 2006 )
World Health Organization, malaria was about eradicated from most parts of the universe owing to good planned anti malarial runs over the universe. However, shortly after, a revival of malaria took topographic point in 1970 ‘s, which could be due to several grounds described below.
Man made complacence and laxness in anti malarial runs ; struggles and wars ; migrations ; deteriorating wellness systems ; poorness
Drug opposition in parasite
Insecticide opposition in vector and prohibition on usage of DDT
Environment planetary warming doing increased genteelness and life span of the vector
Jet age shriveling universe – spread of malaria from endemic countries to all other
parts of the universe.
1.4 Life Cycle of Malaria PARASITE
The complex life rhythm of malaria parasite involves two hosts ; an insect vector ( Anopheless mosquito ) and a craniate host ( human ) . In hunt of a blood repast, a malaria-infected female Anopheles mosquito inoculates the infective sporozoites into the human host. The malaria infection begins as these feasible sporozoites invade liver cells and develop into mature schizonts, which in bend rupture and release invasive merozoites into blood watercourse. In P. vivax and P. ovale an arrested stage [ hypnozoites ] can stay hibernating in the liver and re-invade the blood stream after hebdomads, or even old ages subsequently and do infection, this delayed primary blood infection is termed as backsliding. The initial nonsexual reproduction in liver is termed as exo-erythrocytic schizogony. In the normal developing exo-erythrocytic schizont, the cytol of the parasite becomes subdivided and the resulting invasive merozoites develop. These emergent merozoites are so released upon rupture of the mature schizont and occupy the red blood cell. The parasites undergo nonsexual generation in the red blood cell, termed as erythrocytic schizogony. Redifferentiation of intra-erythrocytic merozoites into the eating trophozoites occurs so. The ring phase
Figure 1.2 Life rhythm of malaria parasite ( Plasmodium falciparum )
trophozoites mature into schizonts and when rupture let go ofing merozoites to get down another rhythm of ruddy blood cell infection. However, the bulk of merozoites come ining an red blood cell will develop into nonsexual schizonts, a little fraction can develop into the first sexual phase of life rhythm ( gametocytes ) . The rupture of mature schizont besides releases the metabolic dust, which is toxic to the host and play a function in exciting the clinical manifestations of the disease.
The female Anopheless mosquito must take blood repasts on regular footing to back up the
development of eggs in consecutive batches. When seize with teething malaria infected craniate host,
she will take up infected red blood cell and the gametocytes. Both female ( macrogametocytes ) and male ( microgametocytes ) are ingested by female Anopheless mosquito during a blood repast. The nonsexual division of parasites in the mosquito is termed as sporogonic rhythm. While in the mosquito ‘s intestine gametocytes are triggered by the autumn in temperature and get down the formation of gametes. The microgamete penetrates the macrogamete bring forthing fertilized ovum. Soon after the fertilized ovums become motile and extended construction termed as ookinetes, which invade the midgut wall of the mosquito where they develop into oocysts. The sporozoites emerge from ruptured oocysts make their manner to shack in the mosquito salivary secretory organs. Inoculation of these feasible sporozoites into a new human host to keep the malaria life rhythm ( 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 gnawer malaria P.y. yoelii 17XNL ringer ( Carlton et al. , 2002 ; Gardner et al. , 2002 ) appeared in 2002 and the genomic informations of two more gnawer malaria species, the P.berghei ANKA ringer and P. chabaudi AS ringer, 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 ) . Therefore, this genus has the highest figure of sequenced species of any eucaryotic being yet ( Birkholtz et al. , 2008 ) .
Comparative analysis of the publically of the available Plasmodium genomes revealed that they are all haploid with a standard size of 23-27 Mb, which is distributed among 14 additive chromosomes between 0.5-3.0 Mb in size. The base composing varies among the different species, with the gnawer and P.falciparum genomes being highly A+T rich ( 80.6 % on norm and close to 90 % in noncoding DNAs and intergenic parts in P.falciparum ) in contrast with the more G+C rich P.knowlesi and P.vivax genomes ( 37.5 % and 42.3 % severally ) Each Plasmodium genome has in the order of 5000-6000 predicted cistrons, most of which ( 51 % ) contain at least one noncoding DNA and ~60 % are orthologus among the different species ( Hall, Carlton, 2005 ; Hall et al. , 2005 ) . The difference in cistron figure is the consequence of the differential cistron enlargement in distinguishable line of descents and the presence of big variant cistron households that are involved with antigenic fluctuation ( Hall, Carlton, 2005 ) . The alone cistrons of the different species are frequently localised within the subtelomeric parts and codification for immunodominant antigens ( Hall, Carlton, 2005 ) . The average cistron length of the three sequenced human malarias ( including P. knowlesi ) is~ 2.2 to 2.3 kilobit, compared to the norm of 1.3 to 1.6 kilobits in other beings ( Gardner et al. , 2002 ) . The ground for these long cistron lengths is non known and this is compounded by the fact that these long cistrons normally encode conjectural proteins with unknown map ( Gardner et al. , 2002 ) . Gene-mapping surveies of conserved cistrons have shown that cistron location, order and even exon-intron boundaries have been preserved over big parts across the three sequenced gnawer Plasmodium species and P.falciparum ( Hall, Carlton, 2005 ) .
In add-on to the atomic genome, the parasites besides have a line drive mitochondrial genome of ~6 kilobit in the instance of P.falciparum, which is smallest mitochondrial genome known ( Painter et al. , 2007 ) and a ~35 kilobit round apicoplast genome ( Gardner et al. , 2002 ) . The P.falciparum atomic genome exhibits minimum redundancy in transportation RNA ( transfer RNA ) and encodes 43 transfer RNA ( Gardner et al. , 2002 ) compared to the ~30 of Homosexual sapiens ( Strachan T and Read A, 1998 ) . The parasite transfer RNA 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 transfer RNAs cistrons are located within the presently unsequenced parts, since Cys is incorporated into P.falciparum proteins ( Gardner et al. , 2002 ) . The little P.falciparum mitochondrial genome does non encode any transfer RNA ( Vaidya et al. , 1989 ) compared to the 22 transfer RNA of the round 16.6 kilobit human mitochondrial genome ( Anderson et al. , 1981 ) . The P.falciparum chondriosome therefore imports transfer RNA from the cytol, whereas the apicoplast genome encodes sufficient transfer RNA for protein synthesis within the cell organ ( Wilson et al. , 1996 ) .
The P.falciparum genome does non incorporate tandemly repeated ribosomal RNA ( rRNA ) cistron bunchs as seen in many other eucaryotes, but it contains single 18S-5.8S-28S rRNA units at venue on seven of the chromosomes ( Gardner et al. , 2002 ) . The sequence of the peculiar rRNA cistrons is distinguishable in the different units and the look of each unit is developmentally regulated, depending on the phases of the parasite life rhythm It is anticipated that by transcribing different rRNAs at different life phases, the parasite could alter its ribosomal belongingss and the interlingual rendition rate of all or specific courier RNA ( messenger RNA ) , which could change the cell growing rate or cell development form. Previously, the rRNA expressed in the mosquito was described as S ( sexual ) -type and that expressed in the human host as A ( nonsexual ) type ( Gardner et al. , 2002 ) . Parasite rRNA is besides species-specific and can be assessed for diagnostic intents ( Singh et al. , 2004 ) . More than 60 % of the predicted 5268 unfastened reading frames ( ORFs ) of P.falciparum have no sequence similarity to cistrons from other sequenced beings ( Gardner et al. , 2002 ) . The absence of sequence similarity complicates word picture of the unknown ORFs, but might keep the reply to happening selective drug marks ( Bozdech et al. , 2003 ) . There is presently a dedicated enterprise aimed at bettering the note position 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 one-year parasite incidence ( API ) indicates the figure of malaria instances per 1000 of population. As per the National Vector Borne Disease Control Programme ( NVBDCP ) incidence records, in most portion of India, the API was & lt ; 2, whereas 2-5 API was scattered in assorted parts, and parts with & gt ; 5 API were scattered in the provinces of Gujarat, Goa, Rajasthan, Madhya Pradesh, Chhattisgarh, Jharkhand, Orissa, the northeasterly provinces and Karnataka ( Kumar A et al. , 2007 ) . The proportion of happening of P. falciparum and P. vivax differs in assorted parts of India. Most of the indo-gangatic fields, northwesterly India, northern hilly provinces, and southern province like Tamil Nadu have & gt ; 90 % P. vivax infections, and the remainder are P. falciparum. This state of affairs is reversed in forested countries inhabited by cultural folks, where the proportion of P. falciparum is 30-90 % . In the staying countries P. falciparum prevail between 10 % and 30 % . Although Orissa has a population of 36.7 million ( 3.5 % ) , it contributed most ( 25 % ) of a sum of 1.5-2 million reported one-year malaria instances, 39.5 % of entire P. falciparum malaria, and 30 % of deceases caused by malaria in India ( Source NVBDCP, India ) . Similarly, in the other provinces, forest ecosystems inhabited by cultural folk ‘s lives chiefly 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 planetary scheme for malaria control was developed by W.H.O. in a ministerial conference at Amsterdam, held in October 1992. The scheme loosely suggests accent on diagnosing and intervention in topographic point of earlier tendency of accent on vector control as a scheme for malaria control. The outstanding facets of this scheme were early diagnosing and intervention ; bar of malarial deceases ; publicity of personal protection steps like usage of ITMs ; prediction, early sensing and control of malaria epidemics ; monitoring, rating and integrating of activity in primary wellness Centres ; and operational research in field sites. Malaria bar was classified at the degree of personal protection, the prophylaxis and the malaria vaccinums. Protective steps adopted at single degree and at household degree non merely assist in protection of the person against mosquito bites but besides prevents spread of malaria in vicinity. These steps indirectly helped in cut downing the mosquito population by denying the blood repast which is an indispensable for nutriment of the mosquito eggs in the female Anopheless.
Protection steps at personal degree against mosquitoes includes: Prevention of mosquitoes from come ining the house, protection from mosquito bites and forbiding the mosquitoes from resting inside house. All these bar activities need the followers ;
I. Protective Clothing
two. Mosquito Repellents
three. Insecticide vaporisers
four. Mosquito cyberspaces
v. Air conditioning
The absence of vaccinums necessitates the usage of drugs against malaria. All visitants from non-endemic country to a malarious country should hold presumptive antimalarial drugs which offer protection against clinical onslaughts of malaria in that peculiar malaria endemic country ( www.who.int/malaria ) .
The pattern of anti-malarial drugs to forestall the development of malaria is known as chemoprophylaxis. The pick of chemoprophylaxis differs depending on the species and drug opposition prevalence in a state. It must be remembered that no chemoprophylaxis government provides 100 % protection. Therefore it is indispensable to hold personal protection from mosquito bites every bit good as to pattern the chemoprophylaxis. Drugs used for chemoprophylaxis include: chloroquine, sulfadoxine, pyrimethamine, atovaquone plus proguanil, proguanil, halofantrine, Vibramycin and mefloquin ( www.ncbi.nlm.nih.gov/antimalarialdrug.html ) .
The effectual manner to command any infective disease is so to hold a safe and effectual vaccinum, but even after decennaries of malaria research, an effectual malaria vaccinum is still elusive. The major perpetrator in non holding an effectual malaria vaccinum is complex life rhythm of the parasite which involves vector mosquitoes and human. In bend, parasite ‘s allelomorphic diverseness and antigenic fluctuations make the development and execution of effectual malaria control intercession more debatable. In the present scenario of increasing opposition against antimalarials by parasite and the insecticide opposition shown by the Anopheless mosquito, it is apparent that an intercession at multiple phases of life rhythm will be an appropriate manner of battling malaria. Malaria vaccinums for different phases of life rhythm will therefore play a major function in future malaria intercessions. Evaluation of new malaria vaccine campaigners in malaria endemic states is required. The present state of affairs demands sufficient sites in malaria endemic states for proving possible malaria vaccinums in future.
1.8 Antimalarial drug opposition
One of the major control schemes against malaria is prompt intervention of malaria patients with effectual antimalarial drugs ; nevertheless one of the major challenges in the conflict against malaria in recent old ages is the development of drug opposition in the malaria parasites. A uninterrupted research and monitoring is important when seeking to command and decrease this development. Antimalarial drug opposition in the malaria parasite, both in vitro and in vivo has been related to alterations at molecular degree in the malaria parasite ( P. falciparum and P. vivax ) .