plasmodium

Pathogens of human malaria

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Plasmodium is the pathogen of human malaria. There are four kinds of malaria parasites parasitic on human body, namely Plasmodium vivax （P.vivax Grassi and Feletti，1890）、 Plasmodium malariae （P.malariae Laveran，1881）、 Plasmodium falciparum (P.falciparum Welch, 1897) and Plasmodium ovale （P.ovale Graig，1900）^{[4 ]} , of Chromophyta -Apical gate - Anvertebral class- Haemosporidium Item- Plasmodiaceae 。^[1]

These malaria parasites include mosquitoes and people host , including those in mosquitoes sexual propagation And asexual proliferation in human body. Anopheles mosquitoes carrying malaria parasites spread by biting people, causing malaria Alternating cold and heat Seizure, commonly known as "swinging". Other kinds of malaria parasites will infect other animals, including others Primates Animals Rodentia Animals Sauropsida animal^[2] 。

Chinese name: Plasmodium
Foreign name: plasmodium
Latin name: Plasmodium
Total domain: New wall total area
field: Eukaryotic domain
Evolutionary branch: Double flagellate organism

Evolution branch 2: Multiform organism
circles: Chromophyta
door: Top compound door
Outline: Anavertebral class
order: Haemosporida
section: Plasmodiaceae
genus: Plasmodium

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There are many kinds of malaria parasites. There are four kinds of malaria parasites parasitic on human beings, namely Plasmodium falciparum [Plasmodium falciparum(Welch，1897) Schaudinn，1902]、 Plasmodium vivax [Plasmodium vivax(Grassi and Felletti，1890) Labbe，1899]、 Plasmodium malariae [Plasmodium malaria E (Laveran, 1881) Grassi and Felletti, 1890] and Ovale malaria Protozoa [Plasmodium ovale Stephens, 1922], respectively Falciparum malaria 、 Vivax malaria 、 Three-day malaria And ovale malaria. The main infections in China are malignant and sporadic malaria Occasionally, there are three days of afferent malaria and ovoid malaria.

Plasmodium Basic structure Including nuclear Cytoplasm and Cell membrane , the ring will be digested and decomposed in later stages hemoglobin The final product after - Malarial pigment 。 Blood slice by Ji's or Reiss dye After staining, the nucleus is purple red, the cytoplasm is sky blue to dark blue, and the malaria pigment is brown yellow, brown or black brown. The basic structure of the four human malaria parasites is the same, but the morphology of each development stage is different, which can be used for identification. Except for the malaria parasite itself morphological character Parasitic red blood cell Morphological changes can also occur. Whether there are changes in the morphology of the parasitized red blood cells and the characteristics of the changes are very helpful to identify the species of malaria parasites.

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Developmental stage

Plasmodium grows, develops and reproduces in red blood cells, and its morphology changes greatly. It is generally divided into three main parts Developmental stage 。

（1） Trophozoite （ trophozoite ）: It is the stage of feeding, growth and development of plasmodium in red blood cells. According to the development sequence, trophozoites can be divided into early and late stages. The early trophozoites have small nuclei, few cytoplasm, and vacuoles in the middle. Most of the trophozoites are annular, so they are also called ring forms. Later, when the worm grows up, the nucleus also increases, the cytoplasm increases, and sometimes protrudes Pseudopodia Malaria pigment began to appear in the cytoplasm. Plasmodium vivax The red blood cells parasitic with Plasmodium ovale can become larger, deformed, and lighter in color, often with obvious red Schuffner's dots; cover Plasmodium falciparum The parasitic red blood cells have large purple brown Maurer's dots; The red blood cells parasitized by Plasmodium malariae can have Ziemann's dots. This time is called late trophozoite, also called big trophozoite.

(2) Schizont（ schizont ）The late trophozoite develops and matures, and the nucleus begins to divide Schizont 。 After repeated division of the nucleus, the cytoplasm finally splits, and each nucleus is wrapped by some cytoplasm, becoming Merozoite ( merozoite ）The early schizonts are called immature schizonts, and the later schizonts that contain a certain amount of merozoites and have concentrated malaria pigments are called mature schizonts.

（3） Gametophyte （ gametocyte ）: Plasmodium has passed several times Fission proliferation After that, some merozoites invade red blood cells and grow up, the nucleus increases without division, the cytoplasm increases without pseudopodia, and finally develop into round, oval or crescent shaped individuals, called gametophytes; Gametophytes can be divided into female and male (or size) gametophytes: female (large) gametophytes are large, with dense cytoplasm, many and thick malarial pigments, and dense nuclei that lean to one side or center of the body; The male (small) gametophyte is small, its cytoplasm is thin, and its malaria pigment is small and small, Nucleoplasm Loose, large and located in the center of the insect body.

ultrastructural

Plasmodium under microscope

(1) Merozoite: the merozoite in the inner phase of red blood cell is oval, with Surface membrane composite membrane (pellicular complex) wrapping. The size varies slightly with the species, with an average length of 1.5 µ m and an average diameter of 1 µ m.

Surface membrane (pellicle) consists of plasma membrane It is composed of two layers of intima. The plasma membrane is about 7.5 nm thick, and the inner membrane is about 15 nm thick Membrane pore 。 Just below the intima is a row starting from the top Polar ring (polar ring) and released to the rear microtubule （subpellicular microtubule）。 Endometrium and Subependymal microtubule Possible Cytoskeleton It can make merozoite hard. Free merozoitic adventitia A surface coat with a thickness of about 20 µ m is covered. This watch is made of electronic dense and solid filaments, which seem to be protein , which may be used for immune reaction In response. There is one on the lateral surface membrane of merozoite Stoma ( cytostome ）, each stage of erythrocytic phase protozoan Ingestion through the stoma host cell Slurry.

The top of the merozoite is a truncated conical process called Parietal process There are three polar rings. Two electron dense Rod-shaped body (rhoptry) and several micronemes. The rod-shaped body and the microtome may play a role when the merozoite invades the host cell. A mitochondrion can be seen at the back of merozoite. Endoplasmic reticulum Few, but Cytoplasm Rich ribosome 。 Gorky's complex Not obvious. The nucleus of merozoite is large and round, located in the back half of the worm body nuclear membrane so Nuclear pore , no nucleolus 。

(2) Sporozoite: Sporozoite It is slender, about 11 µ m long and 1.0 µ m in diameter. It is often bent in C or S shape. The front end is slightly thin, the top is flat, the back end is blunt and round, and the body surface is smooth. Intrasporozoitic Organelle Basically similar to merozoites. The surface membrane consists of an outer membrane, a double-layer inner membrane and a layer under the surface membrane microtubule form. Submembrane microtubules extend backward from the polar ring to the nucleus or terminate slightly across the nucleus. The weak movement of the worm may be caused by the contraction of microtubules under the membrane. At the top of the front end of the sporozoite, there is an inward concave upper cup, that is, apical process, around which there are 3-4 polar rings. nucleus One, long. There is a pair of electron dense rods, which may open in the top ring. In front of or behind the nucleus, there are a large number of microtubules, which are round, oval or long.

life history

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Life history of plasmodium

Four Plasmodium Species Parasitic to Human Body life history Basically the same, requiring people and anopheles Two hosts. Successively parasitized in human body Hepatocyte and red blood cell Inside, proceed Fission proliferation ( schizogony )。 In red blood cells, in addition to fission proliferation, some Merozoite formation Gametophyte , Start Sexual reproduction The early development of. In mosquito body, complete Gametogenesis ( gametogony ）, followed by spore proliferation（ sporogony )。

Development in human body

Extraerythrocytic stage (development in hepatocytes) and intraerythrocytic stage (development and proliferation in erythrocytes and formation of male and female gametophytes):

(1) Exo erythrocytic cycle (infrared phase for short): when Salivary gland Medium with maturity Sporozoite （ sporozoite ）When the female Anopheles mosquito (Anopheles sinensis) aspirates human blood, the sporozoites enter the human body with saliva. After about 30 minutes, the sporozoites invade the liver cells with the blood flow, absorb the nutrients in the liver cells, develop and split the body to proliferate, forming an extraerythrocytic phase Schizogenesis Body. Mature extracellular phase Schizont It contains tens of thousands of merozoites. Some merozoites are released after they burst the liver cells macrophage Phagocytosis, and the rest invades red blood cells, starting the development of the inner phase of red blood cells. Plasmodium vivax It takes about 8 days to complete the extracellular phase, Plasmodium falciparum About 6 days, Plasmodium malariae 11~12 days, Plasmodium ovale 9 days.

It is generally believed that the sporozoites of Plasmodium vivax and Plasmodium ovale have two genetically different types, namely, rapid sporozoites (TS) and delayed sporozoites (BS). When the sporozoite enters the liver cell, the rapid type sporozoite continues to develop and complete the split proliferation of the extraerythrocytic phase, while the late type sporozoite needs to go through a period of long or short (several months to more than years) Dormancy period After that, the exoerythrocytic fission proliferation was completed. The resting sporozoites are called Dormant (hypnozoite)。 Plasmodium falciparum and Plasmodium malariae have no resting particles.

plasmodium

(2) Erythrocytic cycle: merozoites in the extracellular phase of red blood cells are released from liver cells and soon invade red blood cells after entering the blood stream. The process of merozoites invading red blood cells includes the following steps: ① merozoites recognize and attach to red blood cells through specific sites Erythrocyte membrane Surface receptor ；② red blood cell Universality Deformation, red blood cell membrane is formed by concavity around merozoite parasitophorous vacuole ；③ After the merozoite invasion, the vacuoles of the nanoworms were sealed. In the process of invasion, the cell surface of merozoites was shed in red blood cells.

The invading merozoites first form rings to absorb nutrients, Growth and development , Jingda Trophozoite Immature schizoites form mature schizoites containing a certain number of merozoites. After the red blood cells break, merozoites are released, some of which are engulfed by macrophages, and the rest invade others Normal red blood cell And repeat the split proliferation process of its erythrocytes (Fig. 11-3). It takes about 48 hours for Plasmodium vivax, 36~48 hours for Plasmodium falciparum, 72 hours for Plasmodium three-day and 48 hours for Plasmodium ovale to complete the first generation of erythrocytic fission. The early trophozoite of Plasmodium falciparum develops in the peripheral blood for more than ten hours, and then gradually hides in the capillary 、 Blood sinus Or other places with slow blood flow, continue to develop into late trophozoites and schizoites, these two periods are generally not easy to see in the peripheral blood.

plasmodium

After several generations of intraphase fission proliferation of erythrocytes, some merozoites invade erythrocytes and no longer undergo fission proliferation, but develop into female Male gametophyte 。 The gametophyte of Plasmodium falciparum mainly develops in the sinuses or microvessels of liver, spleen, bone marrow and other organs, and appears in the peripheral blood after maturity. It appears in the peripheral blood about 7-10 days after the emergence of the asexual body. The further development of gametophyte needs to be carried out in the mosquito stomach, otherwise it will be cleared after aging and degeneration in the human body for 30~60 days.

Four species of plasmodium are parasitic on red blood cells at different stages of development. Plasmodium vivax and Plasmodium ovale are mainly parasitic on Reticulocyte , Plasmodium malariae Polypharasitic In the older red blood cells, Plasmodium falciparum can parasitism in the red blood cells of various development stages.

Development in mosquitoes

When female Anopheles mosquitoes sting patients or Carrier The stages of development in red blood cells protozoan It enters mosquito stomach with blood, only female and male gamete The body can continue to develop in the mosquito stomach, and the protozoa in other stages are digested. In the mosquito stomach, Male gamete Somatic nucleus Split into 4-8 pieces, Cytoplasm 4-8 filaments also protrude outward; Soon, each small piece of nucleus enters a filament, which breaks away from the mother body and forms male gamete in the mosquito stomach. The male gamete swims in the mosquito stomach, and then Female gamete （ female Gamete) in vivo, formed by fertilization Zygote （ zygote ）。 The zygote grows, becomes active, and becomes Kinetochore (ookinete)。 Moving zygote crossing Gastric wall epithelial cells Or its gap, in the mosquito stomach basement membrane To form a spherical oocyst（ oocyst )。 When the oocysts grow up, the nucleus and cytoplasm in the oocysts divide repeatedly for spore proliferation, and spawn sporozoites from the surface of sporoblasts, forming tens of thousands of sporozoites. The sporozoite is released along with the rupture of the oocyst or by Cyst wall After drilling, the haemolymph is concentrated in the anopheles salivary gland It develops into mature sporozoites. When Infected When mosquitoes suck blood again, the sporozoites can enter the human body with saliva and begin to develop in the human body again. Under the optimal conditions, the time required for the development and maturation of malaria parasites in Anopheles mosquitoes is about 9-10 days for Plasmodium vivax, 10-12 days for Plasmodium falciparum, 25-28 days for Plasmodium three-day and 16 days for Plasmodium ovale.

The development of malaria parasites in mosquitoes is affected by many factors, such as gametophytic Infectivity (Maturity) and activity, density and number ratio of male and female gametophytes, biochemical conditions in mosquito body and mosquito body's Immunoreactivity , and the influence of external temperature and humidity changes on the mosquito stage development of Plasmodium.

Nutrient metabolism

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Plasmodium can penetrate through the surface membrane or pass through the mouth to Swallow a drink The way to take nutrition. stay Hepatocyte Internal parasitism The plasmodium in the extracellular phase of the red blood cell is nourished by the cytoplasm of the liver cell.

glucose metabolism

Erythrocytic plasmodium Glycogen Little storage, glucose It is the main energy source of plasmodium in the erythrocytic phase. Plasmodium parasitism changes the erythrocyte membrane and enhances the Active transshipment Or remove some factors that inhibit transport, so that malaria parasites can continuously obtain glucose from the host plasma for metabolism. 6-phosphate glucose dehydrogenase（ G6PD ）Yes Pentose phosphate pathway The lack of G6PD in the red blood cells of the malaria parasite affects the decomposition of glucose by the malaria parasite, leading to the development obstacle of the parasite. Whether the selective resistance of patients lacking G6PD to Plasmodium falciparum is related to this remains to be further studied.

protein metabolism

Free obtained by plasmodium amino acid Mainly from hemoglobin in red blood cells Hydrolysate And also from the plasma and red blood cells of the host Amino acid bank And organic carbon. Hemoglobin is swallowed from the mouth of the malaria parasite and exits from the mouth base Food bubble , stomatal integument Membrane sealing 。 Acidity of hemoglobin in food bubbles Peptide chain Endonuclease and Aminopeptidase Of Synergy Digestion and decomposition into Globin and hemoglobin 。 Under the action of enzyme, globin is decomposed into several amino acids to synthesize the protein of the worm itself. Heme finally forms a complex, namely malaria pigment. The malaria pigment is not dissolved and absorbed but remains on the wall of the food bubble. In the process of erythrocytic fission proliferation, the malarial pigment gradually fuses into clusters, and is discharged into the blood stream after the fission proliferation is completed.

Nucleic acid metabolism

Plasmodium No Ab initio synthesis The purine pathway only depends on one Remedial approach Utilize off the shelf purine Base and nucleoside 。 The enzymes involved in the purine recovery pathway are Adenylate dehydrogenase Purine - Nucleoside phosphorylase Etc.

In the variety of malaria parasites Biosynthetic pathway Medium, P-aminobenzoic acid ( PABA )、 Tetrahydrofolate ( THF ）Waiting is very important Cofactor 。 If PABA is lacking in the host's food, the production of THF will be affected, and the growth and reproduction of malaria parasites in the host will be hindered, thus the infection will be suppressed.

Lipid metabolism

Plasmodium None lipid Storage, nor can Synthetic fatty acids And cholesterol , completely dependent on the host, such as from host plasma free fatty acids Cholesterol plays an important role in maintaining the integrity of the membrane of malaria parasites and infected cells. Lipids needed by malaria parasites in red blood cells can be absorbed by glucose metabolism The product composition of phospholipid The increase of phospholipids is related to the synthesis of plasmodium membrane.

Pathogenic stage

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The main pathogenic stage of plasmodium is the fission proliferation stage in the erythrocytic stage. Pathogenicity The strength is related to the species and quantity of the invading insects and the immune state of the human body.

incubation period

incubation period ( incubation period ）It refers to the time interval between the invasion of plasmodium and the appearance of clinical symptoms, including the time for the development of extraerythrocytic protozoa and the time required for the proliferation of intraerythrocytic protozoa to a certain number through several generations of fission bodies. The length of incubation period is closely related to the species of protozoa entering the human body, the number of sporozoites and the immunity of the body. The incubation period of falciparum malaria is 7~27 days; Three-day malaria The incubation period of; The incubation period of ovale malaria is 11-16 days; The short incubation period of vivax malaria is 11-25 days, and the long incubation period of vivax malaria is 6-12 months or longer.

Volunteers from Henan, Yunnan, Guizhou, Guangxi and Hunan provinces were repeatedly infected with Plasmodium vivax sporozoites experimental observation The results showed that there were two types of vivax malaria with long and short incubation periods in all regions, and the proportion of the two types increased from north to south. from Transfusion infection Induced malaria The incubation period is generally short.

Malaria attack

Paroxysm, a typical attack of malaria shiver 、 High fever And sweating to reduce fever. The attack is caused by the fission proliferation in the inner phase of red blood cells. After several generations of fission proliferation in the inner phase of red blood cells, the density of protozoa in the blood reaches fever Threshold: for example, 10~500/μ l blood for Plasmodium vivax and 500~1300/μ l blood for Plasmodium falciparum. After the mature schizont in the inner stage of red blood cell distends the red blood cell, a large number of merozoites and protozoa Metabolites And red blood cell fragments into the blood stream, some of which are Neutrophils Phagocytosis stimulates these cells to produce endogenous pyroplasm, which acts on the host together with the metabolites of plasmodium hypothalamus Of Thermoregulatory center , causing fever.

Encyclopedia x confusion: diagram of malaria

With the blood a stimulus After being swallowed and degraded, the body gradually returns to normal temperature through a lot of sweating, and the body enters the intermittent stage of attack. Since the proliferation of erythrocytic lysosomes is the basis of the attack, the attack is cyclical, and this cycle is consistent with the proliferation cycle of erythrocytic lysosomes. Typical vivax malaria and ovale malaria attack once every other day; Three-day malaria Once every two days; Plasmodium falciparum attacks once every 36-48 hours. If the proliferation of parasitic malaria parasites is not synchronized, the interval between attacks is irregular, such as in patients with initial onset. When different kinds of malaria parasites are co infected or different batches of the same malaria parasite are repeatedly infected, the attack is also more atypical. The number of malaria attacks mainly depends on whether the patient is properly treated and the speed of immune enhancement. As the body's immunity to malaria parasites gradually increases, a large number of parasites are eliminated, and the attack can stop automatically.

Reburning and recurrence

Relapse and recurrence of malaria（ recrudescence ）After the initial onset of malaria stops, if the patient has no reinfection, the malaria attack is caused only by the reproduction of a small number of residual erythrocytic plasmodium under certain conditions, which is called malaria resurgence. Reburning and host resistance Specific immunity The decline of force and plasmodium Antigenic variation of Recurrence of malaria (Relapse) refers to that the plasmodium in the erythrocytic stage of the initial malaria patient has been eliminated, and has not been infected by mosquito vectors Zhou Zhi More than years later, another outbreak of malaria occurred, which was called relapse. The mechanism of recurrence is still unclear, and the theory of sporozoite dormancy believes that Hepatocyte The dormant cell in the cell revives, and the merozoites released during development enter the red blood cell to reproduce, causing the onset of malaria. Plasmodium falciparum and Plasmodium malariae have no late type sporozoites, so there is only rekindling without recurrence. Plasmodium vivax and Plasmodium ovale have both relapses and relapses.

anemia

anemia (anemia). After several malaria attacks, anemia may occur, especially falciparum malaria. Pregnant women and children are the most common, and the prevalence rate is high in epidemic areas mortality It is related to severe anemia.

In addition to the direct destruction of red blood cells by malaria parasites, the causes of anemia are also related to the following factors: ① Hypersplenism , engulf a large number of normal red blood cells. ② Immunopathology Damage. When malaria parasites parasitize on red blood cells, they expose the hidden antigens of red blood cells and stimulate the body to produce autoantibody , leading to the destruction of red blood cells. In addition, after the host produces specific antibodies, it is easy to form Antigen antibody complex , attached to red blood cells Immune complex Accessible Complement fixation , so that the erythrocyte membrane changes significantly and has its own Immunogenicity And cause red blood cells to dissolve or be engulfed by macrophages. The degree of anemia in malaria patients often exceeds the degree of direct destruction of red blood cells by malaria parasites. ③ bone marrow Hematopoietic function Inhibited.

Splenomegaly

Most patients with initial onset begin to swell the spleen after 3 to 4 days of attack, and do not heal for a long time or Repeated infection Person, Splenomegaly Obviously, it can reach below the umbilicus. The main reasons are splenic congestion and mononuclear macrophage proliferation. After active antimalarial treatment in the early stage, the spleen can return to normal size. In chronic patients, due to the thickening of the spleen capsule, the tissue is highly fibrotic, and the texture becomes hard. Although it has been eradicated by anti malaria, it cannot return to normal. In Africa or Asia In some tropical malaria endemic areas, "tropical megasplenic syndrome" may be caused by malaria immune reaction Caused by. Most patients are accompanied by Hepatomegaly 、 Portal hypertension Hypersplenism, megasplenia, anemia and other symptoms; The level of IgM in blood increased.

Dangerous malaria

Dangerous malaria Most are caused by Plasmodium falciparum, but most are caused by Plasmodium vivax Cerebral malaria It has been reported in China. Most scholars believe that the pathogenesis of dangerous malaria is concentrated in Cerebrovascular Red blood cells and blood vessels parasitized by plasmodium endothelial cells It is caused by adhesion, microvascular obstruction and local hypoxia. This type of malaria mostly occurs in children, non immune tourists and floating population in endemic areas.

The clinical manifestations are complex, and the common ones are brain type and superelevation Thermotype , mostly manifested as persistent high fever, systemic failure Consciousness obstacle Respiratory distress, multiple convulsions , coma pulmonary edema , abnormal bleeding jaundice 、 Renal failure 、 Hemoglobinuria and Pernicious anemia Etc. Fierce malaria is very fierce. If it cannot be treated in time, the mortality rate will be very high.

Cerebral malaria (cerebra malaria, CM) mostly occurs in falciparum malaria patients, but it has been reported that it is caused by vivax malaria in China, which is the main cause of children and non immune adults Cause of death , clinically Central nervous system symptoms Obvious, such as severe headache, coma Delirium , convulsions, convulsions, body temperature up to 40~41oC, but there are some people who do not have fever. They often die of coma complicated with infection. CM's Pathogenesis It is reported that it is an immunopathological disease involving multiple factors. Some of the patients cell factor , adhesion factors and carbon monoxide It is an important factor that causes the pathogenesis of CM, such as excessive activation of cytokines such as TNF - α and IFN - γ endothelial cells Expression of adhesion receptors and enhancement of endothelial cell Adhesion , so that the dyed red blood cells can adhere to the microvessels of the brain, leading to vascular obstruction, resulting in local hypoxia and nutrient depletion of the brain complication 。

In different malaria endemic areas High risk population And clinical manifestations are very different. At a stable height malaria In the epidemic area, babies born for several months and children under 5 years old are the high incidence population of dangerous malaria. The main clinical manifestations are Pernicious anemia 。 In areas with moderate malaria prevalence, cerebral malaria and Metabolic acidosis It is a common and dangerous malaria in children. In low malaria endemic areas, acute renal failure Jaundice and pulmonary edema are common clinical manifestations in adults, anemia Hypoglycemia And convulsion are more common in children, while cerebral malaria and metabolic acidosis are more common in all age group Both are available.

Malarial nephropathy

by Plasmodium antigen The immune complex formed with antibody is deposited on Glomerular capillary On the basement membrane. The occurrence of ke in long-term chronic patients Nephrotic syndrome , represented by proteinuria , Systemic edema ascites and hypertension It is mainly seen in those who have not recovered from three-day malaria for a long time.

Congenital malaria

It refers to the infection of the fetus from the mother. If the infected mother has placental lesions, malaria parasites can enter the fetus and produce rare congenital malaria, usually resulting in stillbirth or Newborn weight Deficiency, anemia, splenomegaly, and malaria parasites can be found in the blood. Clinically, the common congenital malaria is caused by the mixing of infected maternal blood and fetal blood during production or the contamination of fetal wounds. Newborns get sick more than 4 to 12 weeks ago, and some of them become sick within one week. If they are not treated in time, they are likely to die.

Transfusion malaria

Malaria caused by blood transfusion.

Immune type

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Innate resistance

congenital Resistance (natural resistance), which has nothing to do with the host's malaria infection history, but is related to the host's type and Genetic characteristics of E.g. more than 90% West Africa Black people are Duffy antigen negative blood group, while the receptor of plasmodium vivax merozoite on the erythrocyte membrane is Duffy Blood group antigen Duffy is needed for merozoites to invade red blood cells Blood group substance As a receptor, Duffy blood group negative persons have no such receptor on the erythrocyte membrane, so Plasmodium vivax cannot invade the erythrocyte. Caused by genetic factors Sickle cell anemia People are not susceptible to Plasmodium falciparum. stay Africa Falciparum malaria in children with sickle cell anemia infection rate Lower than normal children, and the former is severe malaria And the proportion of deaths due to malaria is far less than the latter. This is because potassium in red blood cells under hypoxia Ion concentration Decline, which may cause death of malaria parasites; Because sickle cell hemoglobin is difficult to dissolve in water, the phagocytosis and Pinocytosis Occurrence of obstacles; stay Oxygen partial pressure At a low level, hemoglobin can form microcrystals and penetrate the surface membrane of plasmodium, thus affecting its survival. glucose —6— phosphoric acid dehydrogenase ( G6PD ）The deficient also have innate resistance to malaria parasites, clinical research It is confirmed that children with G6PD deficiency can avoid severe disease pernicious malaria 。 The red blood cells of the deficient are particularly sensitive to oxidants, and the development of the malaria parasite requires the use of the reduced coenzyme II in the host cell, so the infected red blood cells have a tendency to dissolve naturally before the malaria parasite matures. The study of genetic factors of innate resistance will contribute to the development of antimalarial vaccines and antimalarial drugs. contrary, Thalassemia Due to its red blood cell ATP The low level is conducive to the development of malaria parasites, so such patients have poor resistance to malaria parasites and suffer from malaria Hour Case fatality rate Higher.

Acquired immunity

Human body is induced to produce effective immunity after malaria infection. This immunity is Species specificity , basically has no protective effect against the attack of heterologous plasmodium, in addition, there are strains and stages of Specificity The human body's resistance to one developmental stage of the malaria parasite may not be resistant to other developmental stages.

（1） Plasmodium antigen : Plasmodium antigen comes from the surface or inside of the parasite, including plasmodium residual cytoplasm, pigmented membrane binding particles, dead or deformed merozoites, and plasmodium vacuoles during the formation of merozoites Contents And its membrane, merozoite secretion, and the surface coating materials that are modified or shed when malaria parasites invade red blood cells. Intraspecific and interspecific malaria parasites may have Common antigen Other antigens are species and phase specific. These species and phase specific antigens may play an important role in the production of protective antibodies.

From host cells antigen Not only those damaged by plasmodium Hepatocyte And red blood cells, including Local ischemia Or activation of auxiliary immune mechanism (such as Complement system ）Many others destroyed Histiocyte 。

（2） humoral immunity Humoral immunity plays an important role in malaria protective immunity. When protozoaemia occurs IgG 、 IgM The levels of IgA and IgA increased significantly, especially in the previous two. But these Igs are specific for malaria parasites antibody Only a small part. adopt monoclonal antibody and Immune serum Inhibition of the growth of plasmodium in vitro and its application in the body Passive transfer Immune experiments can prove the important role of humoral immunity on malaria parasites.

Antibodies can prevent merozoites from invading red blood cells in the following ways: complement Mediated damage to merozoites; Spatially interfere with the recognition of red blood cell ligands to affect the invasion process; prevent Surface protein Maturity; When schizoites break, they are prevented from releasing by agglutinating merozoites.

（3） Cell mediated immunity Cell mediated immunity plays an important role in malaria infection. Cell mediated immunity mainly includes Mononuclear phagocyte , T cells and Natural killer cells , and by these Cell secretion Of cell factor , such as IFN-γ 、 TNF Etc.

In conclusion, the immune mechanism of anti malaria is very complex, and non-specific Specific immunity Mutual conditions and complementation, body fluid and cellular immunity Mutual regulation and balance, malaria antigen and host MHC The relationship between them may have an impact on the immune process and its consequences, and many problems need to be further studied.

（4） Carrier immunity and Immune escape : The immunity generated by human infection with malaria parasite can resist the same kind of malaria parasite Reinfection At the same time, there is a low level of protozoaemia in its blood, which is called preimmunization. Passively inject the infected person's serum or sensitized lymphocyte Giving susceptible hosts can make them resistant to the infection of malaria parasites, which indicates that the body has a specific ability to inhibit the development of malaria parasites in red blood cells Immune effect 。

Although the host produces various humoral immunity and Cellular immune response The ability to inhibit the development and proliferation of malaria parasites, but malaria parasites also have a strong adaptability To fight against the host's immune killing effect. The mechanism of malaria parasite escaping host immune attack is very complex, and the main factors related to it include the following aspects:

① Parasitic site: Plasmodium, whether in extraerythrocytic or intraerythrocytic stage, mainly grows and develops in host cells to escape host immune attack.

② Antigenic variation (antigenic variation) and Antigenic polymorphism (polymorphism): that is, a variant with slightly changed antigenicity of its predecessor. Plasmodium knowlesi stay Chronic infection There are antigenic variations in every reignition in 30% monkeys. A lot of evidence shows that there are many malaria parasites in the same species antigenicity Different plants.

effective immune reaction Frequently exposed height Polymorphism Antigen restriction. Several Plasmodium Proteins Sequence polymorphism It is very common, especially for proteins with extensive repeat regions, such as cyclosporine protein (CSP), which can down regulate antibody maturation and high affinity antibody production; Plasmodium falciparum merozoite surface protein-1 (MSP-1) can induce the "blocking antibody" of MSP-1, which can block the connection of any antibody with inhibitory ability.

③ Change the immune response of host: when suffering from acute malaria, the immune response and Lymphocyte subsets In peripheral blood, spleen and lymph gland The distribution in has changed significantly. Generally, T Cells Of absolute value Decrease, B cell Relative value Increase, at the same time Immunosuppression Polyclonal lymphocyte activation, lymphocytotoxic antibody and soluble circulating antigen.

（5） Malaria vaccine The research on malaria vaccine has still achieved remarkable results in the last 30 years. A series of candidate vaccines for each stage of the life cycle of malaria parasites have been developed. Malaria vaccine can be divided into sporozoite vaccine (anti infection vaccine), liver phase vaccine (anti erythrocyte phase vaccine), asexual blood phase vaccine (anti erythrocyte phase vaccine and anti schizoite vaccine) and sexual phase vaccine (transmission blocking vaccine).

Because there are many antigenic stages and complex antigenic components of malaria parasite, the vaccine with single antigenic component Immune effect Poor. Multi stage multi antigen composite vaccine is the focus of research, some of which have achieved encouraging results, such as using the CS segment of plasmodium Repeating sequence Of B cell epitope And non repeating area T helper cells Epitope MASP Immune animals It can produce high protective immunity, but it is still a long way from practical application.

2、 Immunity of Anopheles vector to Plasmodium Anopheles It is the vector of malaria, not only for the gamete reproduction and Sporogenesis Provides the necessary internal environment And related factors, and immune system It also plays a role in the development and reproduction of malaria parasites inhibition 。 When mosquitoes suck blood, a large number of gametophytes usually enter the mosquito stomach with the blood meal, but only about 1/10 to 1/20 of the malaria parasites in the mosquito stomach can develop into zygotes when they are attacked by the immune response of the Anopheles mosquito. When the zygotes pass through the epithelial cells of the mosquito stomach, only a few oocysts mature, and spore reproduction produces a large number of sporozoites that are released to the mosquito Haemolymph Medium, but can salivary glands Only a few of them develop into infectious sporozoites. This shows that the immune system of Anopheles can inhibit the development of malaria parasites. The killing effect of Anopheles on malaria parasites is mainly through Blackening coating reaction In addition, the NO and Antibacterial peptide It also has a certain inhibitory effect on the development of malaria parasites in mosquitoes.

Blackening coating reaction is a kind of humoral melanization reaction. And others insect Similarly, the melanization reaction of Anopheles mosquitoes is Phenol oxidase Cascade reaction (prophenoloxidase cascade). By activating the pre phenoloxidase activating enzyme, the pre phenoloxidase is converted into active phenoloxidase (PO), and then PO is hydroxylated Monophenol oxidase And oxidize bisphenol oxidase to produce a large number of quinones Intermediate product Polymerization formation melanin 。 These melanins synergistically have Cytotoxicity The quinone intermediates of pathogen Around, it can isolate and kill pathogens, that is, blacken the coating reaction.

Experimental diagnosis

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Etiological diagnosis

Thick, thin Blood membrane Staining microscopy Is the most commonly used method. From examinee Peripheral blood The detection of plasmodium in the fluid is the most reliable basis for diagnosis. It is best to take blood for examination before taking medicine. Take the peripheral blood to make thick and thin blood membranes Reiss dye Staining and microscopic examination to find malaria parasites. The plasmodium in the thin blood membrane has complete and typical morphology, which is easy to identify and identify the species, but it is easy to miss detection when the density of the plasmodium is low. Due to the concentration of protozoa, the thick blood membrane is easy to detect, but the red blood cells are dissolved during the dyeing process, and the protozoa morphology has changed, so it is difficult to identify the species. Therefore, the best one slide The thick and thin blood membranes are made at the same time. If the protozoa are found in the thick blood membrane and it is difficult to identify, the thin blood membrane can be checked again. Falciparum malaria At the beginning of the attack, Vivax malaria Blood collection can be improved from a few hours to more than 10 hours after the attack Detection rate 。

immunological diagnosis

(1) Cycle Antibody test : The common methods are indirect Fluorescent antibody Test Indirect hemagglutination test and ELISA Etc. Since the antibody can still last for a period of time after the patient is cured individual difference Therefore, the detection of antibodies is mainly used for malaria Of epidemiological investigation Evaluation of prevention and treatment effect and screening of blood transfusion objects, which are only used for auxiliary diagnosis in clinic.

(2) Circulating antigen detection: using serology Methods The detection of circulating antigen of plasmodium can better explain whether the tested object has active infection. Common methods are Radioimmunity Test, inhibition ELISA Sandwich method Enzyme linked immunosorbent assay and rapid immunochromatographic test card (ICT), etc.

Molecular Biology Technology

PCR and Nucleic acid probe It has been used for malaria diagnosis, molecular biology Detection technology The most outstanding advantage of Hematemia The detection rate is high. Detection of Plasmodium falciparum by nucleic acid probe susceptibility The density of protozoa in infected red blood cells can reach 0.0001%. Domestic scholars adopt nested mode PCR technology The 120 bp specific fragment of the SSU rRNA gene of Plasmodium vivax was amplified, and its sensitivity reached 0.1 protozoa/μ l blood.

epidemiology

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Prevalence

Malaria is one of the diseases seriously endangering human health world health organization According to the statistics of WHO, there are still more than 90 countries in the world where malaria is endemic, and the number of patients in the world every year reaches 300 million to 500 million death toll It reaches 1 million to 2 million, of which more than 80% cases occur in Africa 。

Before the founding of the People's Republic of China, malaria was seriously prevalent in China. The epidemic areas can be divided into four categories:

(1) High malaria area: south of 25 ° north latitude, namely Nanling Mountains The area to the south is the area with the most serious malaria epidemic in China. In addition to vivax malaria, falciparum malaria and Three-day malaria In addition, ovale malaria is occasionally reported. Falciparum malaria and mixed infection The proportion is high.

(1) Stable moderate and low malaria areas: between 25~33 ° N, namely, Nanling Mountains and Qinling Mountains 、 Huaihe River Between regions. Mainly vivax malaria, with falciparum malaria, often Epidemic outbreak 。

(2) Unstable low malaria area: To the north of 33 ° N, namely the area north of Qinling Mountains and Huaihe River, malaria prevalence is relatively mild. Plasmodium vivax is the only parasite species, but there are also epidemics caused by the import of falciparum malaria.

(4) Natural malaria free areas: including Qinghai Tibet Plateau , Northwest China, Inner Mongolia desert and Northeast forest area 。 Xinjiang Yili River Basin and Southern Xinjiang A few areas have only a few cases of vivax malaria.

According to incomplete statistics, there were at least 30 million malaria patients every year in China in the 1940s, Case fatality rate About 1%. In the early 1950s, there were 1829 counties (cities) with malaria epidemic in China, accounting for 70% - 80% of the total number of counties (cities) at that time.

With the progress of anti malaria work, the epidemic scope of falciparum malaria gradually narrowed, and after 1995 Hainan In addition to the prevalence of falciparum malaria in Yunnan, other provinces, autonomous regions and municipalities directly under the Central Government have no falciparum malaria transmission. The death rate of malaria has dropped from 0.49% in 1950 to 0.08% in 1998. From 1996 to 1998, the incidence of malaria in China dropped to more than 30000 cases, but in 2000, the incidence rose to 266000, especially in China Central region Some outbreaks have occurred in Jiangsu, Henan, Anhui, Hubei and other provinces.

The population carrying rate is an important indicator of malaria prevalence. In the 1950s, the carrying rate of residents in the provinces and autonomous regions in the south and southwest was generally 10% - 20%, up to more than 50%, and the carrying rate of people in the central region was generally 5% - 10%. After years of large-scale malaria control, the population carrying rate has decreased year by year. 1991~1998 Monitoring points Residents, students floating population A total of 4.848 million person times of blood tests were carried out among key populations. Except Hainan and Yunnan provinces, the carrying rate of the population was still 1%~3%, and other provinces, autonomous regions, and municipalities directly under the Central Government were all below 1%.

Prevention and control methods

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1946 DDT The success of the test of killing adult mosquitoes made it possible to eliminate malaria World health Assembly The former malaria control strategy was changed to the malaria eradication strategy. As time went by, people found that using insecticides to eliminate the vector Anopheles faced more and more problems, such as Drug resistance The emergence of mosquito species, environmental pollution caused by pesticides and ecological equilibrium The global malaria eradication program has suffered serious setbacks. In 1978, the 31st World Health Assembly decided to abandon the plan of global malaria eradication by a deadline malaria The prevention and control strategy of the "" is changed back to the control strategy. The two strategic changes experienced in the past 20 years not only reflect the complexity of the malaria problem, but also reflect the increasing awareness of people's struggle against malaria.

China's malaria control strategy is to implement the policy of "adjusting measures to local conditions, classifying guidance, highlighting key points", take corresponding comprehensive control measures, and persist in long-term combat and repeated struggle. In the Anopheles sinensis For the vast area with the only medium Infectious agent Focus on mosquito control and reduce the number of people inside and outside the village mosquito Comprehensive measures for breeding grounds. stay Anopheles minimus 、 Anopheles anthropophagus In areas where mosquitoes are the main vector, measures should be taken to eliminate mosquitoes and prevent and control the source of infection. stay Anopheles dirus Take measures to change ecological environment , prevention and control Media Comprehensive measures focusing on the prevention and treatment of infectious sources. In areas where malaria has been basically eradicated, where the incidence has dropped below 1/10000, measures focusing on malaria monitoring should be taken.

plasmodium

1. Prevention includes individual prevention and Mass prevention 。 preventive measure Mosquito vector control and preventive medication are available. Mosquito vector control includes killing mosquitoes and using mosquito nets and repellents. Preventive medicine is protection Susceptible population Is one of the important measures. Common preventive measures Antimalarial drug yes chloroquine (chloroquine), anti chloroquine falciparum malaria, available Piperaquine Piperaquine Pyrimethamine (pyrimethamine) or pyrimethamine plus Primaquine Primaquine. No matter individuals or groups take preventive drugs Pharmacotherapy It should not exceed half a year.

2. Treatment: malaria treatment should include the treatment of patients with current disease (killing of plasmodium in erythrocytes) and Malaria attack Treatment of resting period (killing the dormant son in the extracellular phase of red blood cells). Treatment during the rest period refers to malaria In the rest period of transmission, treatment should be given to those who have malaria history and carriers within 1-2 years to control the recurrence of vivax malaria and reduce the source of infection.

According to the effect of antimalarial drugs on different stages of plasmodium, they can be divided into killing exoerythrocytic fission Progeny And dormant anti relapse drugs, such as primaquinone; Kill erythrocytic endophyte Proliferative phase Anti clinical seizure drugs such as chloroquine Pyronaridine （pyronaridine）、 artemisinin (artmisinin) and drugs that kill sporozoites and inhibit the proliferation of spores in mosquitoes, such as pyrimethamine.

plasmodium

For current patients, chloroquine plus primaquine can be used to treat suspected malaria patients or vivax malaria; Primary aminoquinoline plus pyrimethamine Artesunate The effect of adding primaquinone is better; For falciparum malaria, chloroquine can be taken alone, while for falciparum malaria resistant to chloroquine, chloroquine is recommended Combined medication , such as piperaquine plus Sulfadoxine (sulfadoxine), pyronaridine plus sulfadoxine and primaquinine Compound Artemether Tablets Etc., artesunate alone Artemether 、 Dihydroartemisinin It also has certain curative effect; Severe malaria (such as Cerebral malaria ）Artemisinin drugs are preferred, such as artemether oil for intramuscular injection, artesunate sodium for intravenous injection, or dihydroartemisinin plus two for intravenous injection Quinoline hydrochloride ； In addition, artemisinin drugs suppository It is applicable to patients who cannot take oral medicine. The above antimalarial drugs must be sufficient and taken throughout the whole process to achieve a radical cure malaria The purpose of.

development history

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July 30, 2021, by Military Academy of Sciences Military Medical Research Institute Scientific researchers Developed Artificial intelligence system for malaria diagnosis It was officially launched in Beijing. This marks a major breakthrough in the construction of the malaria control system worldwide.^[3]

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