Malaria pathophysiology: Difference between revisions

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{{Malaria}}
{{Malaria}}
{{CMG}}
{{CMG}}; '''Associate Editor(s)-In-Chief:''' [[User:YazanDaaboul|Yazan Daaboul]], [[User:Sergekorjian|Serge Korjian]], {{AJL}} , {{Marjan}}


==Overview==
==Overview==
Malaria in humans develops via two phases: an exoerythrocytic (hepatic) and an erythrocytic phase. When an infected mosquito pierces a person's skin to take a blood meal, [[sporozoite]]s in the mosquito's saliva enter the bloodstream and migrate to the [[liver]].
Malaria in humans develops in two phases: an exo-erythrocytic ([[hepatic]]) and an erythrocytic phase. When an infected mosquito pierces an individual's skin for blood, [[sporozoite]]s in the mosquito's saliva enter the bloodstream and subsequently migrate to the [[liver]].


==Pathophysiology==
==Pathophysiology==
 
*Malaria is caused by [[protozoa]]n parasites of the genus ''[[Plasmodium]]'' (phylum [[Apicomplexa]]).  
Malaria is caused by [[protozoa]]n parasites of the genus ''[[Plasmodium]]'' (phylum[[Apicomplexa]]). In humans malaria is caused by ''[[Plasmodium falciparum|P. falciparum]]'', ''[[Plasmodium malariae|P. malariae]]'', ''[[Plasmodium ovale|P. ovale]]'', and ''[[Plasmodium vivax|P. vivax]]''. '' P. vivax'' is the most common cause of infection, responsible for about 80 % of all malaria cases. However, ''P. falciparum''is the most important cause of disease, and responsible for about 15% of infections and 90% of deaths.<ref>{{cite journal | author = Mendis K, Sina B, Marchesini P, Carter R |title = The neglected burden of Plasmodium vivax malaria. |url=http://www.ajtmh.org/cgi/reprint/64/1_suppl/97.pdf | journal = Am J Trop Med Hyg |volume = 64 | issue = 1-2 Suppl | pages = 97-106 | year = 2001 | pmid = 11425182}}</ref>
*In humans, malaria is caused by ''[[Plasmodium falciparum|P. falciparum]]'', ''[[Plasmodium malariae|P. malariae]]'', ''[[Plasmodium ovale|P. ovale]]'', ''[[Plasmodium vivax|P. vivax]]'' and Plasmodium knowlesi.  
*'' P. vivax'' is the most common cause of infection, responsible for about 80% of all malaria cases. ''P. falciparum'', the most significant cause of disease, is responsible for about 15% of infections and 90% of deaths.<ref>{{cite journal | author = Mendis K, Sina B, Marchesini P, Carter R |title = The neglected burden of Plasmodium vivax malaria. |url=http://www.ajtmh.org/cgi/reprint/64/1_suppl/97.pdf | journal = Am J Trop Med Hyg |volume = 64 | issue = 1-2 Suppl | pages = 97-106 | year = 2001 | pmid = 11425182}}</ref><ref name="pmid28389518">{{cite journal| author=Long CA, Zavala F| title=Immune Responses in Malaria. | journal=Cold Spring Harb Perspect Med | year= 2017 | volume=  | issue=  | pages=  | pmid=28389518 | doi=10.1101/cshperspect.a025577 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28389518  }} </ref>


===Life Cycle===
===Life Cycle===
The life cycle of ''Plasmodium'' parasite starts when the sporozoite, a haploid form of the parasite, is injected into the human bloodstream by the female Anopheles mosquito.{{cite web |url=http://www.niaid.nih.gov/topics/malaria/pages/lifecycle.aspx |title= Malaria |date= Apr. 3 2012 |website= National Institute of Allergy and Infectious Diseases|publisher=NIH|accessdate=Jul 24 2014}} The sporozoites then travel in the bloodstream into the liver and invade human hepatocytes. Over 1-2 weeks later, the sporozoites grow and produce thousands of merozoites in each hepatocyte in the exoerythrocytic phase. The merozoite is also a halpoid form of the parasite. While some hepatocytes rupture and release the merozoites within, other parasites remain dormant within the liver. The release of these merozoites from the hepatocytes into the bloodsteam causes the symptoms of malaria. Most importantly, this latency of cell rupture between various hepatocytes and the consequent merozoite release into the bloodstream is responsible for the characteristic periodic fever associated with malaria infections.
*The life cycle of ''[[Plasmodium]]'' parasites begin when the [[sporozoite]], a haploid form of the parasite, is injected into the human bloodstream by the female Anopheles mosquito.<ref name=NIH>{{cite web |url=http://www.niaid.nih.gov/topics/malaria/pages/lifecycle.aspx |title= Malaria |date= Apr. 3 2012 |website= National Institute of Allergy and Infectious Diseases|publisher=NIH|accessdate=Jul 24 2014}}</ref>
 
*The [[sporozoite]]s travel in the bloodstream to the [[liver]] and invade human [[hepatocyte]]s. Over 1-2 weeks later, in the exo-erythrocytic phase, the [[sporozoite]]s grow into [[schizont]]s and produce thousands of merozoites in each [[hepatocyte]].  
As merozoites are released into the bloodstream, they infect erythrocytes (red blood cells). Some merozoites continue the cycle of asexual replication, while others develop into sexual forms, the gametocytes, which involve male and female parasites.
*The merozoite is a [[haploid]] form of the parasite.<ref name=NIH>{{cite web |url=http://www.niaid.nih.gov/topics/malaria/pages/lifecycle.aspx |title= Malaria |date= Apr. 3 2012 |website= National Institute of Allergy and Infectious Diseases|publisher=NIH|accessdate=Jul 24 2014}}</ref> While some hepatocytes rupture and release the merozoites, other parasites remain dormant within the liver.<ref name=NIH>{{cite web |url=http://www.niaid.nih.gov/topics/malaria/pages/lifecycle.aspx |title= Malaria |date= Apr. 3 2012 |website= National Institute of Allergy and Infectious Diseases|publisher=NIH|accessdate=Jul 24 2014}}</ref> The release of merozoites, by the [[hepatocytes]], into the bloodsteam results in the manifestation of the malarial symptoms.  
 
*The latency of cell rupture between various hepatocytes and the consequent merozoite release into the bloodstream, is responsible for the characteristic periodic fever associated with malarial infections.<ref name=NIH>{{cite web |url=http://www.niaid.nih.gov/topics/malaria/pages/lifecycle.aspx |title= Malaria |date= Apr. 3 2012 |website= National Institute of Allergy and Infectious Diseases|publisher=NIH|accessdate=Jul 24 2014}}</ref>
The bite of Anopheles mosquito allows it to ingest the gametocytes within the red blood cells. In the mosquito's gut, the cells burst and the gametocytes are then released allowing their development into mature gametes. The fusion of male and female gametes forms diploid zygotes and later form oocysts within the mosquito midgut wall. As oocysts continue to grow, they divide and form active haploid forms, the sporozoites. Thousands of sporozoites are produced in each oocyst. The latter bursts after 1-2 weeks and sporozoites travel to the mosquito salivary glands to re-infect humans when the mosquito bites humans and inject the sporozoite into the bloodstream, allowing the cycle of restart.
*As merozoites are released into the bloodstream, they infect [[erythrocyte]]s and undergo asexual multiplication ([[mitosis]]). Some merozoites continue the cycle of asexual replication into mature [[trophozoite]]s and [[schizont]]s, which rupture to re-release merozoites. Others develop into sexual forms, the gametocytes, which involve male (microgametocyte) and female (macrogametocyte) parasites.<ref name=NIH>{{cite web |url=http://www.niaid.nih.gov/topics/malaria/pages/lifecycle.aspx |title= Malaria |date= Apr. 3 2012 |website= National Institute of Allergy and Infectious Diseases|publisher=NIH|accessdate=Jul 24 2014}}</ref>
 
*Though biting, Anopheles mosquitos ingest the gametocytes within the red blood cells, initiating the sporogonic cycle inside the mosquito. In the mosquito's gut, the cells burst and the gametocytes are then released, allowing their development into mature gametes.
While parasites generally shift from a sporozoite into a morozoite as they invade red blood cells, some species, such as P. vivax and P. ovale are characterized by their ability to produce hypnozoites, an intermediate stage where the parasite remains dormant for a few months/years before reactivation into merozoites. The hypnozoite stage gives these species the capacity to demonstrate late relapses and long incubation periods.<ref>{{cite journal | author = Cogswell F | title = The hypnozoite and relapse in primate malaria. | url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=358221&blobtype=pdf| journal = Clin Microbiol Rev | volume = 5 | issue = 1 | pages = 26-35 | year = 1992 |id = PMID 1735093}}</ref>
*The fusion of male and female [[gamete]]s forms diploid zygotes, which become ookinetes, motile and elongated forms of the parasites. Within the mosquito midgut wall, they develop into [[oocyst]]s.<ref name=NIH>{{cite web |url=http://www.niaid.nih.gov/topics/malaria/pages/lifecycle.aspx |title= Malaria |date= Apr. 3 2012 |website= National Institute of Allergy and Infectious Diseases|publisher=NIH|accessdate=Jul 24 2014}}</ref>  
 
*As [[oocyst]]s continue to grow, they divide into active haploid forms, the [[sporozoite]]s. Thousands of [[sporozoite]]s are produced in each [[oocyst]]. When [[oocyst]]s burst following 1-2 weeks, [[sporozoite]]s travel to the mosquito's salivary glands, so that when the mosquito bites other humans they inject the [[sporozoite]]s into their bloodstream, leading the cycle to restart.<ref name=NIH>{{cite web |url=http://www.niaid.nih.gov/topics/malaria/pages/lifecycle.aspx |title= Malaria |date= Apr. 3 2012 |website= National Institute of Allergy and Infectious Diseases|publisher=NIH|accessdate=Jul 24 2014}}</ref>  
*Some species, such as ''[[P. vivax]]'' and ''[[P. ovale]]'' are characterized by their ability to produce hypnozoites, an intermediate stage where the parasite remains dormant for a few months/years before reactivation into merozoites. The hypnozoite stage allows teh species to demonstrate late relapses and long incubation periods.<ref>{{cite journal | author = Cogswell F | title = The hypnozoite and relapse in primate malaria. | url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=358221&blobtype=pdf| journal = Clin Microbiol Rev | volume = 5 | issue = 1 | pages = 26-35 | year = 1992 |id = PMID 1735093}}</ref>
[[Image:Malaria.jpg|thumb|left|250px|A ''Plasmodium'' sporozoite traverses the cytoplasm of a mosquito midgut epithelial cell in this false-color [[electron micrograph]].]]
 
[[Image:MalariacycleBig.jpg|thumb|left|400px|The life cycle of malaria parasites in the human body. The various stages in this process are discussed in the text.]]
 
===Escaping the Immune System===
 
The parasite is relatively protected from attack by the body's [[immune system]] because for most of its human life cycle it resides within the liver and red blood cells and is relatively invisible to immune surveillance.  However, circulating infected blood cells are destroyed in the [[spleen]]. To avoid this fate, the ''P. falciparum'' parasite displays adhesive [[protein]]s on the surface of the infected blood cells, causing the blood cells to stick to the walls of small blood vessels, thereby sequestering the parasite from passage through the general circulation and the spleen.<ref name=Chen>{{cite journal | author = Chen Q, Schlichtherle M, Wahlgren M | title = Molecular aspects of severe malaria. | url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=10885986 | journal = Clin Microbiol Rev | volume = 13 | issue = 3 |pages = 439-50 | year = 2000 | id = PMID 10885986}}</ref> This "stickiness"  is the main factor giving rise to [[hemorrhage|hemorrhagic]] complications of malaria. [[High endothelial venules]] (the smallest branches of the circulatory system) can be blocked by the attachment of masses of these infected red blood cells. The blockage of these vessels causes symptoms such as in placental and cerebral malaria. In cerebral malaria the sequestrated red blood cells can breach the [[blood-brain barrier|blood brain barrier]]possibly leading to coma.<ref>{{cite journal | author = Adams S, Brown H, Turner G |title = Breaking down the blood-brain barrier: signaling a path to cerebral malaria? |journal = Trends Parasitol | volume = 18 | issue = 8 | pages = 360-6 | year = 2002 | id =PMID 12377286}}</ref>
 
Although the red blood cell surface adhesive proteins (called PfEMP1, for ''Plasmodium falciparum'' erythrocyte membrane protein 1) are exposed to the immune system they do not serve as good immune targets because of their extreme diversity; there are at least 60 variations of the protein within a single parasite and perhaps limitless versions within parasite populations.<ref name=Chen/>  Like a thief changing disguises or a spy with multiple passports, the parasite switches between a broad repertoire of PfEMP1 surface proteins, thus staying one step ahead of the pursuing immune system.  
 
Some merozoites turn into male and female [[gametocyte]]s. If a mosquito pierces the skin of an infected person, it potentially picks up gametocytes within the blood. Fertilization and sexual recombination of the parasite occurs in the mosquito's gut, thereby defining the mosquito as the [[definitive host]] of the disease. New sporozoites develop and travel to the mosquito's salivary gland, completing the cycle. Pregnant women are especially attractive to the mosquitoes,<ref>{{cite journal | author = Lindsay S, Ansell J, Selman C, Cox V, Hamilton K, Walraven G | title = Effect of pregnancy on exposure to malaria mosquitoes. | journal = Lancet | volume = 355 | issue = 9219 | pages = 1972 | year = 2000 | id = PMID 10859048}}</ref> and malaria in pregnant women is an important cause of [[stillbirth]]s, infant mortality and low birth weight.<ref>{{cite journal | author = van Geertruyden J, Thomas F, Erhart A, D'Alessandro U | title = The contribution of malaria in pregnancy to perinatal mortality. |url=http://www.ajtmh.org/cgi/content/full/71/2_suppl/35 | journal = Am J Trop Med Hyg |volume = 71 | issue = 2 Suppl | pages = 35-40 | year = 2004 | id = PMID 15331817}}</ref>
 
===Evolution of Malarial Parasite===
{{further|[[Natural selection]]}}
Malaria is thought to have been the greatest [[selection|selective pressure]] on the[[human genome]] in recent history.<ref name=Kwiatkowski_2005>{{cite journal |author=Kwiatkowski, DP | title=How Malaria Has Affected the Human Genome and What Human Genetics Can Teach Us about Malaria| journal=Am J Hum Genet | year=2005 | volume=77 |pages=171-92 |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16001361 |id=PMID 16001361}}</ref> This is due to the high levels of[[death|mortality]] and [[morbidity]] caused by malaria, especially the ''[[Plasmodium falciparum|P. falciparum]]'' species.
 
===Sickle-cell Disease and Malaria===
[[Image:Sickle cell distribution.jpg|thumb|left|Distribution of the sickle cell trait.]]
[[Image:Malaria distribution.jpg|thumb|left|Distribution of Malaria.]]
The best-studied influence of the malaria parasite upon the human genome is the blood disease, [[sickle-cell disease]]. In sickle-cell disease, there is a mutation in the''HBB'' gene, which encodes the beta globin subunit of [[haemoglobin]]. The normal allele encodes a [[glutamate]] at position six of the beta globin protein, while the sickle-cell allele encodes a [[valine]].<ref name="pmid15942909">{{cite journal| author=Williams TN, Mwangi TW, Wambua S, Alexander ND, Kortok M, Snow RW et al.| title=Sickle cell trait and the risk of Plasmodium falciparum malaria and other childhood diseases. | journal=J Infect Dis | year= 2005 | volume= 192 | issue= 1 | pages= 178-86 | pmid=15942909 |doi=10.1086/430744 | pmc=PMC3545189 |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15942909  }} </ref> This change from a hydrophilic to a hydrophobic amino acid encourages binding between haemoglobin molecules, with polymerization of haemoglobin deforming red blood cells into a "sickle" shape.<ref name="pmid15942909">{{cite journal| author=Williams TN, Mwangi TW, Wambua S, Alexander ND, Kortok M, Snow RW et al.| title=Sickle cell trait and the risk of Plasmodium falciparum malaria and other childhood diseases. | journal=J Infect Dis |year= 2005 | volume= 192 | issue= 1 | pages= 178-86 | pmid=15942909 | doi=10.1086/430744| pmc=PMC3545189 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15942909  }} </ref> Such deformed cells are cleared rapidly from the blood, mainly in the spleen, for destruction and recycling.
 
In the merozoite stage of its life cycle, the malaria parasite lives inside red blood cells, and its metabolism changes the internal chemistry of the red blood cell. Infected cells normally survive until the parasite reproduces, but if the red cell contains a mixture of sickle and normal haemoglobin, it is likely to become deformed and be destroyed before the daughter parasites emerge.  Thus, individuals [[heterozygous]] for the mutated allele, known as sickle-cell trait, may have a low and usually unimportant level of [[anaemia]], but also have a greatly reduced chance of serious malaria infection. This is a classic example of [[heterozygote advantage]].<ref name="pmid15942909">{{cite journal| author=Williams TN, Mwangi TW, Wambua S, Alexander ND, Kortok M, Snow RW et al.| title=Sickle cell trait and the risk of Plasmodium falciparum malaria and other childhood diseases. | journal=J Infect Dis | year= 2005 |volume= 192 | issue= 1 | pages= 178-86 | pmid=15942909 | doi=10.1086/430744 |pmc=PMC3545189 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15942909  }} </ref>
 
Individuals [[homozygous]] for the mutation have full sickle-cell disease and in underdeveloped societies rarely live beyond adolescence. However, in populations where malaria is [[Endemic (epidemiology)|endemic]], the [[gene frequencies|frequency]] of sickle-cell genes is around 10%. The existence of four [[haplotype]]s of sickle-type hemoglobin suggests that this mutation emerged independently at least four times in malaria-endemic areas, further demonstrating its evolutionary advantage in such affected regions.<ref name="pmid14363831">{{cite journal| author=BEUTLER E, DERN RJ, FLANAGAN CL|title=Effect of sickle-cell trait on resistance to malaria. | journal=Br Med J | year= 1955 | volume= 1 | issue= 4923 | pages= 1189-91 | pmid=14363831 | doi= | pmc=PMC2062141 |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14363831  }} </ref>There are also other mutations of the HBB gene that produce haemoglobin molecules capable of conferring similar resistance to malaria infection. These mutations produce haemoglobin types HbE and HbC, which are common in Southeast Asia and Western Africa, respectively.<ref name="pmid15916466">{{cite journal| author=Williams TN, Mwangi TW, Roberts DJ, Alexander ND, Weatherall DJ, Wambua S et al.| title=An immune basis for malaria protection by the sickle cell trait. | journal=PLoS Med | year= 2005 | volume= 2| issue= 5 | pages= e128 | pmid=15916466 | doi=10.1371/journal.pmed.0020128 |pmc=PMC1140945 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15916466  }} </ref>
 
===Thalassaemias===
Another well-documented set of mutations found in the human genome associated with malaria are those involved in causing blood disorders known as [[thalassaemias]]. Studies in Sardinia and Papua New Guinea have found that the [[gene frequency]] of[[Thalassemia#Beta (β) thalassemias|β-thalassaemias]] is related to the level of malarial endemicity in a given population. A study on more than 500 children in Liberia found that those with β-thalassaemia had a 50% decreased chance of getting clinical malaria. Similar studies have found links between gene frequency and malaria endemicity in the α+ form of α-thalassaemia. Presumably these genes have also been [[natural selection|selected]] in the course of human evolution.


===Duffy Antigens===
[[Image:MalariacycleBig.jpg|thumb|center|600px|The life cycle of malaria parasites in the human body. The various stages in this process are discussed in the text.]]
The [[Duffy antigen]]s are [[antigens]] expressed on red blood cells and other cells in the body acting as a [[chemokine]] receptor. The expression of Duffy antigens on blood cells is encoded by Fy genes (Fya, Fyb, Fyc etc.). ''[[Plasmodium vivax]]'' malaria uses the Duffy antigen to enter blood cells. However, it is possible to express no Duffy antigen on red blood cells (Fy-/Fy-). This [[genotype]] confers complete resistance to''P. vivax'' infection. The genotype is very rare in European, Asian and American populations, but is found in almost all of the indigenous population of West and Central Africa.<ref>{{cite journal |author=Carter R, Mendis KN |title=Evolutionary and historical aspects of the burden of malaria |url=http://cmr.asm.org/cgi/content/full/15/4/564?view=long&pmid=12364370#RBC%20Duffy%20Negativity |journal=Clin. Microbiol. Rev.|volume=15 |issue=4 |pages=564-94 |year=2002 |pmid=12364370}}</ref> This is thought to be due to very high exposure to ''P. vivax'' in Africa in the last few thousand years.


===G6PD===
===Human Factors===
[[Glucose-6-phosphate dehydrogenase]] (G6PD) is an [[enzyme]] which normally protects from the effects of [[oxidative stress]] in red blood cells. However, a genetic deficiency in this enzyme results in increased protection against severe malaria.
*Some human factors may provide a protective advantage against malarial infection. Individuals with [[sickle cell trait]], defined as the heterozygous for the abnormal globin gene, ''HbS'', are protected against ''[[P. falciparum]]''.
*In individuals with [[sickle cell trait]], [[red blood cells]] invaded by ''[[P. falciparum]]'' tend to sickle more readily than other [[red blood cells]], leading them to be eliminated from the bloodstream by macrophages.<ref name="pmid23170194">{{cite journal| author=Luzzatto L| title=Sickle cell anaemia and malaria. | journal=Mediterr J Hematol Infect Dis | year= 2012 | volume= 4 | issue= 1 | pages= e2012065 | pmid=23170194 | doi=10.4084/MJHID.2012.065 | pmc=PMC3499995 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23170194  }} </ref>
*The preventative advantage demonstrated in heterozygous [[sickle cell]] patients is not observed in patients who have sickle cell anemia and carry a homozygous sickle gene. Contrarily, these patients are more susceptible to lethal complications of severe [[anemia]].<ref name="pmid23170194">{{cite journal| author=Luzzatto L| title=Sickle cell anaemia and malaria. | journal=Mediterr J Hematol Infect Dis | year= 2012 | volume= 4 | issue= 1 | pages= e2012065 | pmid=23170194 | doi=10.4084/MJHID.2012.065 | pmc=PMC3499995 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23170194  }} </ref>
*Other similar hematological diseases that provide a protective effect against malaria are [[thalassemia]], [[hemoglobin C]], and [[G6PD deficiency]].
*Individuals who have a negative [[Duffy blood group]] are resistant to infection by ''[[P. vivax]]''. These individuals are still susceptible to other species of malaria, especially ''[[P. ovale]]'', which frequently infects individuals with negative [[Duffy blood group]].<ref>{{cite web |url=http://www.cdc.gov/malaria/about/biology/human_factors.html |title= Malaria |date= Nov 9 2012 |website= Centers for Disease Control and Prevention|publisher=CDC|accessdate=Jul 24 2014}}</ref>
*P. falciparum infection have higher mean parasitaemia index, P. vivax infection generally exhibit low parasitaemia index due to its preference to invade reticulocytes rather than erythrocytes.<ref name="pmid19695492">{{cite journal |vauthors=Mueller I, Galinski MR, Baird JK, Carlton JM, Kochar DK, Alonso PL, del Portillo HA |title=Key gaps in the knowledge of Plasmodium vivax, a neglected human malaria parasite |journal=Lancet Infect Dis |volume=9 |issue=9 |pages=555–66 |date=September 2009 |pmid=19695492 |doi=10.1016/S1473-3099(09)70177-X |url=}}</ref>


===HLA and Interleukin-4===
==Associated Conditions==
[[Human leukocyte antigen|HLA-B53]] is associated with low risk of severe malaria. This[[Major histocompatibility complex|MHC class I]] molecule presents [[liver]] stage and[[sporozoite]] [[antigens]] to [[T-Cells]]. Interleukin-4, encoded by IL4, is produced by activated T cells and promotes proliferation and differentiation of antibody-producing B cells. A study of the Fulani of Burkina Faso, who have both fewer malaria attacks and higher levels of antimalarial antibodies than do neighboring ethnic groups, found that the IL4-524 T allele was associated with elevated antibody levels against malaria antigens, which raises the possibility that this might
be a factor in increased resistance to malaria.<ref>{{cite journal |author=Verra F, Luoni G, Calissano C, Troye-Blomberg M, Perlmann P, Perlmann H, Arcà B, Sirima B, Konaté A, Coluzzi M, Kwiatkowski D, Modiano D |title=IL4-589C/T polymorphism and IgE levels in severe malaria |journal=Acta Trop. |volume=90 |issue=2 |pages=205-9 |year=2004|pmid=15177147}}</ref>


===Chronic Malaria===
===Severe malarial anaemia===
Chronic malaria is seen in both ''P. vivax'' and ''P. ovale'', but not in ''P. falciparum''. Here, the disease can relapse months or years after exposure, due to the presence of latent parasites in the liver. Describing a case of malaria as cured by observing the disappearance of parasites from the bloodstream can therefore be deceptive. The longest incubation period reported for a ''P. vivax'' infection is 30 years. Approximately one in five of ''P. vivax'' malaria cases in temperate areas involve overwintering by hypnozoites (i.e., relapses begin the year after the mosquito bite).<ref>{{cite journal | author = Adak T, Sharma V, Orlov V | title = Studies on the Plasmodium vivax relapse pattern in Delhi, India. | journal = Am J Trop Med Hyg | volume = 59 | issue = 1 | pages = 175-9 | year = 1998 | id = PMID 9684649}}</ref>
*Severe malarial anaemia is defined as a haemoglobin concentration of <5 g/dL and the presence of high parasitaemia >10,000 parasites/μl.<ref name="pmid17341664">{{cite journal |vauthors=Lamikanra AA, Brown D, Potocnik A, Casals-Pascual C, Langhorne J, Roberts DJ |title=Malarial anemia: of mice and men |journal=Blood |volume=110 |issue=1 |pages=18–28 |date=July 2007 |pmid=17341664 |doi=10.1182/blood-2006-09-018069 |url=}}</ref>
*The proposed mechanisms involved in severe malaria anaemia is a cumulative of loss of RBCs due to infection, lysis of uninfected RBCs in the circulation, and impaired RBC production.<ref name="pmid19349210">{{cite journal |vauthors=Anstey NM, Russell B, Yeo TW, Price RN |title=The pathophysiology of vivax malaria |journal=Trends Parasitol. |volume=25 |issue=5 |pages=220–7 |date=May 2009 |pmid=19349210 |doi=10.1016/j.pt.2009.02.003 |url=}}</ref>
*In P. vivax infections, ~34 uninfected RBCs are removed for every infected RBCs in the circulation whereas in P.falciparum infections, about 8 uninfected RBCs are lysed for every infected RBC.<ref name="pmid11716124">{{cite journal |vauthors=Price RN, Simpson JA, Nosten F, Luxemburger C, Hkirjaroen L, ter Kuile F, Chongsuphajaisiddhi T, White NJ |title=Factors contributing to anemia after uncomplicated falciparum malaria |journal=Am. J. Trop. Med. Hyg. |volume=65 |issue=5 |pages=614–22 |date=November 2001 |pmid=11716124 |pmc=4337986 |doi= |url=}}</ref>
===Acute respiratory distress syndrome (ARDS)===
*This condition is associated with deep breathing, respiratory distress, pulmonary oedema, airway obstruction, impaired function of the alveoli and decreased gas exchange.<ref name="pmid22540175">{{cite journal |vauthors=Douglas NM, Anstey NM, Buffet PA, Poespoprodjo JR, Yeo TW, White NJ, Price RN |title=The anaemia of Plasmodium vivax malaria |journal=Malar. J. |volume=11 |issue= |pages=135 |date=April 2012 |pmid=22540175 |pmc=3438072 |doi=10.1186/1475-2875-11-135 |url=}}</ref>
*Autopsy studies in ARDS cases from P. vivax prior to antimalarial treatment has showed heavy infiltrates of intravascular mononuclear cells, endothelial and alveolar damages, and absence of parasite sequestration in the pulmonary vasculature.<ref name="pmid19861606">{{cite journal |vauthors=Valecha N, Pinto RG, Turner GD, Kumar A, Rodrigues S, Dubhashi NG, Rodrigues E, Banaulikar SS, Singh R, Dash AP, Baird JK |title=Histopathology of fatal respiratory distress caused by Plasmodium vivax malaria |journal=Am. J. Trop. Med. Hyg. |volume=81 |issue=5 |pages=758–62 |date=November 2009 |pmid=19861606 |doi=10.4269/ajtmh.2009.09-0348 |url=}}</ref>
*Study from Brazil has reported an infiltration of neutrophils in alveolar capillaries even after parasites were cleared from peripheral blood by antimalarial drug treatment.<ref name="pmid22772803">{{cite journal |vauthors=Lacerda MV, Fragoso SC, Alecrim MG, Alexandre MA, Magalhães BM, Siqueira AM, Ferreira LC, Araújo JR, Mourão MP, Ferrer M, Castillo P, Martin-Jaular L, Fernandez-Becerra C, del Portillo H, Ordi J, Alonso PL, Bassat Q |title=Postmortem characterization of patients with clinical diagnosis of Plasmodium vivax malaria: to what extent does this parasite kill? |journal=Clin. Infect. Dis. |volume=55 |issue=8 |pages=e67–74 |date=October 2012 |pmid=22772803 |doi=10.1093/cid/cis615 |url=}}</ref>
===Pregnancy-associated malaria===
*Pregnants are more susceptible to malaria infections because of their somewhat compromised immune status, especially during the first and second trimesters of pregnancy.<ref name="pmid18165470">{{cite journal |vauthors=Rogerson SJ, Mwapasa V, Meshnick SR |title=Malaria in pregnancy: linking immunity and pathogenesis to prevention |journal=Am. J. Trop. Med. Hyg. |volume=77 |issue=6 Suppl |pages=14–22 |date=December 2007 |pmid=18165470 |doi= |url=}}</ref>
*P. falciparum parasite has the ability to massively sequester in the placenta.<ref name="pmid16265906">{{cite journal |vauthors=Beeson JG, Duffy PE |title=The immunology and pathogenesis of malaria during pregnancy |journal=Curr. Top. Microbiol. Immunol. |volume=297 |issue= |pages=187–227 |date=2005 |pmid=16265906 |doi= |url=}}</ref>
*The sequestration of parasite-infected RBCs in the intervillous space of placenta and the adherence of infected RBCs to the syncytiotrophoblast cell layer are the contributors to pregnancy associated malaria pathogenesis.<ref name="pmid17251081">{{cite journal |vauthors=Rogerson SJ, Hviid L, Duffy PE, Leke RF, Taylor DW |title=Malaria in pregnancy: pathogenesis and immunity |journal=Lancet Infect Dis |volume=7 |issue=2 |pages=105–17 |date=February 2007 |pmid=17251081 |doi=10.1016/S1473-3099(07)70022-1 |url=}}</ref>
*The wide spread clinical conditions resulting from pregnancy associated malaria are severe anemia, intrauterine growth retardation, low birth weight, preterm delivery, miscarriage, perinatal mortality, and death in the mother.<ref name="pmid23459254">{{cite journal |vauthors=Souza RM, Ataíde R, Dombrowski JG, Ippólito V, Aitken EH, Valle SN, Álvarez JM, Epiphanio S, Epiphânio S, Marinho CR |title=Placental histopathological changes associated with Plasmodium vivax infection during pregnancy |journal=PLoS Negl Trop Dis |volume=7 |issue=2 |pages=e2071 |date=2013 |pmid=23459254 |pmc=3573078 |doi=10.1371/journal.pntd.0002071 |url=}}</ref>


==References==
==References==
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Yazan Daaboul, Serge Korjian, Alison Leibowitz [2] , Marjan Khan M.B.B.S.[3]

Overview

Malaria in humans develops in two phases: an exo-erythrocytic (hepatic) and an erythrocytic phase. When an infected mosquito pierces an individual's skin for blood, sporozoites in the mosquito's saliva enter the bloodstream and subsequently migrate to the liver.

Pathophysiology

  • Malaria is caused by protozoan parasites of the genus Plasmodium (phylum Apicomplexa).
  • In humans, malaria is caused by P. falciparum, P. malariae, P. ovale, P. vivax and Plasmodium knowlesi.
  • P. vivax is the most common cause of infection, responsible for about 80% of all malaria cases. P. falciparum, the most significant cause of disease, is responsible for about 15% of infections and 90% of deaths.[1][2]

Life Cycle

  • The life cycle of Plasmodium parasites begin when the sporozoite, a haploid form of the parasite, is injected into the human bloodstream by the female Anopheles mosquito.[3]
  • The sporozoites travel in the bloodstream to the liver and invade human hepatocytes. Over 1-2 weeks later, in the exo-erythrocytic phase, the sporozoites grow into schizonts and produce thousands of merozoites in each hepatocyte.
  • The merozoite is a haploid form of the parasite.[3] While some hepatocytes rupture and release the merozoites, other parasites remain dormant within the liver.[3] The release of merozoites, by the hepatocytes, into the bloodsteam results in the manifestation of the malarial symptoms.
  • The latency of cell rupture between various hepatocytes and the consequent merozoite release into the bloodstream, is responsible for the characteristic periodic fever associated with malarial infections.[3]
  • As merozoites are released into the bloodstream, they infect erythrocytes and undergo asexual multiplication (mitosis). Some merozoites continue the cycle of asexual replication into mature trophozoites and schizonts, which rupture to re-release merozoites. Others develop into sexual forms, the gametocytes, which involve male (microgametocyte) and female (macrogametocyte) parasites.[3]
  • Though biting, Anopheles mosquitos ingest the gametocytes within the red blood cells, initiating the sporogonic cycle inside the mosquito. In the mosquito's gut, the cells burst and the gametocytes are then released, allowing their development into mature gametes.
  • The fusion of male and female gametes forms diploid zygotes, which become ookinetes, motile and elongated forms of the parasites. Within the mosquito midgut wall, they develop into oocysts.[3]
  • As oocysts continue to grow, they divide into active haploid forms, the sporozoites. Thousands of sporozoites are produced in each oocyst. When oocysts burst following 1-2 weeks, sporozoites travel to the mosquito's salivary glands, so that when the mosquito bites other humans they inject the sporozoites into their bloodstream, leading the cycle to restart.[3]
  • Some species, such as P. vivax and P. ovale are characterized by their ability to produce hypnozoites, an intermediate stage where the parasite remains dormant for a few months/years before reactivation into merozoites. The hypnozoite stage allows teh species to demonstrate late relapses and long incubation periods.[4]
The life cycle of malaria parasites in the human body. The various stages in this process are discussed in the text.

Human Factors

  • Some human factors may provide a protective advantage against malarial infection. Individuals with sickle cell trait, defined as the heterozygous for the abnormal globin gene, HbS, are protected against P. falciparum.
  • In individuals with sickle cell trait, red blood cells invaded by P. falciparum tend to sickle more readily than other red blood cells, leading them to be eliminated from the bloodstream by macrophages.[5]
  • The preventative advantage demonstrated in heterozygous sickle cell patients is not observed in patients who have sickle cell anemia and carry a homozygous sickle gene. Contrarily, these patients are more susceptible to lethal complications of severe anemia.[5]
  • Other similar hematological diseases that provide a protective effect against malaria are thalassemia, hemoglobin C, and G6PD deficiency.
  • Individuals who have a negative Duffy blood group are resistant to infection by P. vivax. These individuals are still susceptible to other species of malaria, especially P. ovale, which frequently infects individuals with negative Duffy blood group.[6]
  • P. falciparum infection have higher mean parasitaemia index, P. vivax infection generally exhibit low parasitaemia index due to its preference to invade reticulocytes rather than erythrocytes.[7]

Associated Conditions

Severe malarial anaemia

  • Severe malarial anaemia is defined as a haemoglobin concentration of <5 g/dL and the presence of high parasitaemia >10,000 parasites/μl.[8]
  • The proposed mechanisms involved in severe malaria anaemia is a cumulative of loss of RBCs due to infection, lysis of uninfected RBCs in the circulation, and impaired RBC production.[9]
  • In P. vivax infections, ~34 uninfected RBCs are removed for every infected RBCs in the circulation whereas in P.falciparum infections, about 8 uninfected RBCs are lysed for every infected RBC.[10]

Acute respiratory distress syndrome (ARDS)

  • This condition is associated with deep breathing, respiratory distress, pulmonary oedema, airway obstruction, impaired function of the alveoli and decreased gas exchange.[11]
  • Autopsy studies in ARDS cases from P. vivax prior to antimalarial treatment has showed heavy infiltrates of intravascular mononuclear cells, endothelial and alveolar damages, and absence of parasite sequestration in the pulmonary vasculature.[12]
  • Study from Brazil has reported an infiltration of neutrophils in alveolar capillaries even after parasites were cleared from peripheral blood by antimalarial drug treatment.[13]

Pregnancy-associated malaria

  • Pregnants are more susceptible to malaria infections because of their somewhat compromised immune status, especially during the first and second trimesters of pregnancy.[14]
  • P. falciparum parasite has the ability to massively sequester in the placenta.[15]
  • The sequestration of parasite-infected RBCs in the intervillous space of placenta and the adherence of infected RBCs to the syncytiotrophoblast cell layer are the contributors to pregnancy associated malaria pathogenesis.[16]
  • The wide spread clinical conditions resulting from pregnancy associated malaria are severe anemia, intrauterine growth retardation, low birth weight, preterm delivery, miscarriage, perinatal mortality, and death in the mother.[17]

References

  1. ↑ Mendis K, Sina B, Marchesini P, Carter R (2001). "The neglected burden of Plasmodium vivax malaria" (PDF). Am J Trop Med Hyg. 64 (1-2 Suppl): 97–106. PMID 11425182.
  2. ↑ Long CA, Zavala F (2017). "Immune Responses in Malaria". Cold Spring Harb Perspect Med. doi:10.1101/cshperspect.a025577. PMID 28389518.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 "Malaria". National Institute of Allergy and Infectious Diseases. NIH. Apr. 3 2012. Retrieved Jul 24 2014. Check date values in: |accessdate=, |date= (help)
  4. ↑ Cogswell F (1992). "The hypnozoite and relapse in primate malaria". Clin Microbiol Rev. 5 (1): 26–35. PMID 1735093.
  5. ↑ 5.0 5.1 Luzzatto L (2012). "Sickle cell anaemia and malaria". Mediterr J Hematol Infect Dis. 4 (1): e2012065. doi:10.4084/MJHID.2012.065. PMC 3499995. PMID 23170194.
  6. ↑ "Malaria". Centers for Disease Control and Prevention. CDC. Nov 9 2012. Retrieved Jul 24 2014. Check date values in: |accessdate=, |date= (help)
  7. ↑ Mueller I, Galinski MR, Baird JK, Carlton JM, Kochar DK, Alonso PL, del Portillo HA (September 2009). "Key gaps in the knowledge of Plasmodium vivax, a neglected human malaria parasite". Lancet Infect Dis. 9 (9): 555–66. doi:10.1016/S1473-3099(09)70177-X. PMID 19695492.
  8. ↑ Lamikanra AA, Brown D, Potocnik A, Casals-Pascual C, Langhorne J, Roberts DJ (July 2007). "Malarial anemia: of mice and men". Blood. 110 (1): 18–28. doi:10.1182/blood-2006-09-018069. PMID 17341664.
  9. ↑ Anstey NM, Russell B, Yeo TW, Price RN (May 2009). "The pathophysiology of vivax malaria". Trends Parasitol. 25 (5): 220–7. doi:10.1016/j.pt.2009.02.003. PMID 19349210.
  10. ↑ Price RN, Simpson JA, Nosten F, Luxemburger C, Hkirjaroen L, ter Kuile F, Chongsuphajaisiddhi T, White NJ (November 2001). "Factors contributing to anemia after uncomplicated falciparum malaria". Am. J. Trop. Med. Hyg. 65 (5): 614–22. PMC 4337986. PMID 11716124.
  11. ↑ Douglas NM, Anstey NM, Buffet PA, Poespoprodjo JR, Yeo TW, White NJ, Price RN (April 2012). "The anaemia of Plasmodium vivax malaria". Malar. J. 11: 135. doi:10.1186/1475-2875-11-135. PMC 3438072. PMID 22540175.
  12. ↑ Valecha N, Pinto RG, Turner GD, Kumar A, Rodrigues S, Dubhashi NG, Rodrigues E, Banaulikar SS, Singh R, Dash AP, Baird JK (November 2009). "Histopathology of fatal respiratory distress caused by Plasmodium vivax malaria". Am. J. Trop. Med. Hyg. 81 (5): 758–62. doi:10.4269/ajtmh.2009.09-0348. PMID 19861606.
  13. ↑ Lacerda MV, Fragoso SC, Alecrim MG, Alexandre MA, Magalhães BM, Siqueira AM, Ferreira LC, Araújo JR, Mourão MP, Ferrer M, Castillo P, Martin-Jaular L, Fernandez-Becerra C, del Portillo H, Ordi J, Alonso PL, Bassat Q (October 2012). "Postmortem characterization of patients with clinical diagnosis of Plasmodium vivax malaria: to what extent does this parasite kill?". Clin. Infect. Dis. 55 (8): e67–74. doi:10.1093/cid/cis615. PMID 22772803.
  14. ↑ Rogerson SJ, Mwapasa V, Meshnick SR (December 2007). "Malaria in pregnancy: linking immunity and pathogenesis to prevention". Am. J. Trop. Med. Hyg. 77 (6 Suppl): 14–22. PMID 18165470.
  15. ↑ Beeson JG, Duffy PE (2005). "The immunology and pathogenesis of malaria during pregnancy". Curr. Top. Microbiol. Immunol. 297: 187–227. PMID 16265906.
  16. ↑ Rogerson SJ, Hviid L, Duffy PE, Leke RF, Taylor DW (February 2007). "Malaria in pregnancy: pathogenesis and immunity". Lancet Infect Dis. 7 (2): 105–17. doi:10.1016/S1473-3099(07)70022-1. PMID 17251081.
  17. ↑ Souza RM, Ataíde R, Dombrowski JG, Ippólito V, Aitken EH, Valle SN, Álvarez JM, Epiphanio S, Epiphânio S, Marinho CR (2013). "Placental histopathological changes associated with Plasmodium vivax infection during pregnancy". PLoS Negl Trop Dis. 7 (2): e2071. doi:10.1371/journal.pntd.0002071. PMC 3573078. PMID 23459254.


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