Editing Malaria (section)

==Pathophysiology==
{{further|Plasmodium falciparum#Pathogenesis}}
[[File:Maternal malaria placenta - cropped - very high mag.jpg|thumb|right|[[Micrograph]] of a [[placenta]] from a [[stillbirth]] due to maternal malaria. [[H&E stain]]. Red blood cells are anuclear; blue/black staining in bright red structures (red blood cells) indicate foreign nuclei from the parasites.]]
[[File:Red blood cells infected with malaria.jpg|thumb|Electron micrograph of a ''Plasmodium falciparum''-infected red blood cell (center), illustrating adhesion protein "knobs"]]

Malaria infection develops via two phases: one that involves the [[liver]] (exoerythrocytic phase), and one that involves red blood cells, or [[erythrocyte]]s (erythrocytic phase). When an infected mosquito pierces a person's skin to take a blood meal, sporozoites in the mosquito's saliva enter the bloodstream and migrate to the liver where they infect hepatocytes, multiplying asexually and asymptomatically for a period of 8–30 days.<ref name="Bledsoe-2005" />

After a potential dormant period in the liver, these organisms [[cellular differentiation|differentiate]] to yield thousands of merozoites, which, following rupture of their host cells, escape into the blood and infect red blood cells to begin the erythrocytic stage of the life cycle.<ref name="Bledsoe-2005" /> The parasite escapes from the liver undetected by wrapping itself in the [[cell membrane]] of the infected host liver cell.<ref name="Vaughan-2008" />

The parasites multiply asexually within red blood cells, periodically breaking out to infect new ones. This repeated cycle results in synchronized waves of merozoites escaping and invading red blood cells, which cause the characteristic fever patterns.<ref name="Bledsoe-2005" />

Some ''P.&nbsp;vivax'' sporozoites do not immediately develop into exoerythrocytic-phase merozoites, but instead, produce hypnozoites that remain dormant for periods ranging from several months (7–10 months is typical) to several years.<ref name="White-2011" /> After a period of dormancy, they reactivate and produce merozoites. Hypnozoites are responsible for long incubation and late relapses in ''P.&nbsp;vivax'' infections,<ref name="White-2011" /> although their existence in ''P.&nbsp;ovale'' is uncertain.<ref name="Richter-2010" />

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 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.&nbsp;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="Tilley-2011" /> The blockage of the microvasculature causes symptoms such as those in placental malaria.<ref name="Mens-2010" /> Sequestered red blood cells can breach the [[blood–brain barrier]] and cause cerebral malaria.<ref name="Rénia-2012" />

===Genetic resistance===
{{Main|Human genetic resistance to malaria}}
Due to the high levels of [[death|mortality]] and [[morbidity]] caused by malaria—especially the ''P.&nbsp;falciparum'' species—it has placed the greatest [[Selection (biology)|selective pressure]] on the [[human genome]] in recent history. Several genetic factors provide some resistance to it including [[sickle cell trait]], [[thalassaemia]] traits, [[glucose-6-phosphate dehydrogenase deficiency]], and the absence of [[Duffy antigen]]s on red blood cells.<ref>{{cite journal | vauthors = Pierron D, Heiske M, Razafindrazaka H, Pereda-Loth V, Sanchez J, Alva O, Arachiche A, Boland A, Olaso R, Deleuze JF, Ricaut FX, Rakotoarisoa JA, Radimilahy C, Stoneking M, Letellier TD| title = Strong selection during the last millennium for African ancestry in the admixed population of Madagascar | journal = Nature Communications | volume = 9 | issue = 1 | pages = 932 | date = March 2018 | pmid = 29500350 | pmc = 5834599 | doi = 10.1038/s41467-018-03342-5 | bibcode = 2018NatCo...9..932P }}</ref><ref name="Kwiatkowski-2005" /><ref name="Hedrick-2011" />

The effect of sickle cell trait on malaria immunity illustrates some evolutionary trade-offs that have occurred because of endemic malaria. Sickle cell trait causes a change in the haemoglobin molecule in the blood. Normally, red blood cells have a very flexible, biconcave shape that allows them to move through narrow [[capillaries]]; however, when the modified [[hemoglobin S|haemoglobin&nbsp;S]] molecules are exposed to low amounts of oxygen, or crowd together due to dehydration, they can stick together forming strands that cause the cell to distort into a curved sickle shape. In these strands, the molecule is not as effective in taking or releasing oxygen, and the cell is not flexible enough to circulate freely. In the early stages of malaria, the parasite can cause infected red cells to sickle, and so they are removed from circulation sooner. This reduces the frequency with which malaria parasites complete their life cycle in the cell. Individuals who are [[homozygous]] (with two copies of the abnormal haemoglobin beta [[allele]]) have [[sickle-cell anaemia]], while those who are heterozygous (with one abnormal allele and one normal allele) experience resistance to malaria without severe anaemia. Although the shorter life expectancy for those with the homozygous condition would tend to disfavour the trait's survival, the trait is preserved in malaria-prone regions because of the [[heterozygote advantage|benefits]] provided by the heterozygous form.<ref name="Hedrick-2011" /><ref name="Weatherall-2008" />

===Liver dysfunction===
Liver dysfunction as a result of malaria is uncommon and usually only occurs in those with another liver condition such as [[viral hepatitis]] or [[chronic liver disease]]. The syndrome is sometimes called ''malarial hepatitis''.<ref name="Bhalla-2006" /> While it has been considered a rare occurrence, malarial hepatopathy has seen an increase, particularly in Southeast Asia and India. Liver compromise in people with malaria correlates with a greater likelihood of complications and death.<ref name="Bhalla-2006" />

=== Effects on vaccine response ===
Malaria infection affects the immune responses following [[vaccination]] for various diseases. For example, malaria suppresses immune responses to polysaccharide vaccines. A potential solution is to give curative treatment before vaccination in areas where malaria is present.<ref name="Cunnington-2010">{{cite journal | vauthors = Cunnington AJ, Riley EM | title = Suppression of vaccine responses by malaria: insignificant or overlooked? | journal = Expert Review of Vaccines | volume = 9 | issue = 4 | pages = 409–429 | date = April 2010 | pmid = 20370551 | doi = 10.1586/erv.10.16 }}</ref>