Pregnancy-associated malaria (PAM) or placental malaria is a presentation of the common illness that is particularly life-threatening to both mother and developing fetus. [1] PAM is caused primarily by infection with Plasmodium falciparum , [1] [2] the most dangerous of the four species of malaria-causing parasites that infect humans. [3] During pregnancy, a woman faces a much higher risk of contracting malaria and of associated complications. [4] Prevention and treatment of malaria are essential components of prenatal care in areas where the parasite is endemic – tropical and subtropical geographic areas. [5] [6] Placental malaria has also been demonstrated to occur in animal models, including in rodent and non-human primate models. [7]
While the average adult citizen of an endemic region possesses some immunity to the parasite, [8] pregnancy causes complications that leave the woman and fetus extremely vulnerable. [1] The parasite interferes with transmission of vital substances through the fetal placenta, [1] [9] often resulting in stillbirth, spontaneous abortion, or dangerously low birth weight. [1] The tragedy of malaria in developing countries, particularly sub-Saharan Africa, receives abundant attention from the international health community, but until recently PAM and its unique complications were not adequately addressed. [6]
Some initial symptoms of malaria include feeling unwell, experiencing headaches and fatigue, and having muscle aches and abdominal pain. This can eventually progress to a fever. Other common symptoms consist of nausea, vomiting, and orthostatic hypertension. Malaria can also lead to seizures which may precede going into a comatose state. [10]
In regions of high transmission, such as Africa, women experiencing PAM may exhibit normal symptoms of malaria, but may also be asymptomatic or present with more mild symptoms, including a lack of the characteristic fever. This is due to the fact that these women most likely have partial immunity, which may prevent a woman from seeking treatment despite the danger to herself and her unborn child. [11] [12] Conversely, in regions of low malaria transmission, PAM is associated with a higher likelihood of symptoms as these women most likely did not acquire immunity. [11]
Transmission of malaria occurs when humans get bitten by infected mosquitos carrying the parasite known as Plasmodium falciparum . The saliva from the mosquito transfers the P. falciparum into the blood as sporozoites which then travel to the liver where they are converted to the merozite form and further replicated. [13] After undergoing these changes in the liver, the parasite is then able to infect erythrocytes in the bloodstream. It can take 7 to 30 days after being bitten by a mosquito before symptoms start to arise. It is believed that pregnant women are more susceptible to malaria infection due to being immunocompromised and because infected erythrocytes tend to congregate around the placenta. [14] As a result, the WHO recommends that pregnant women avoid traveling to high endemic regions. [15]
The disease results from the aggregation of erythrocytes infected by Plasmodium falciparum which have been shown to adhere to chondroitin sulfate A (CSA) on placental proteoglycans causing them to accumulate in the intervillous spaces of the placenta, blocking the crucial flow of nutrients from mother to embryo. [1] Infected erythrocytes express the VAR2CSA variant of P. falciparum erythrocyte membrane protein 1 (PfEMP1) which allows them to bind to CSA on the placenta. [16] The accumulation of infected erythrocytes in the placenta inhibit the exchange of nutrients between the mother and fetus and also causes local inflammation. [17]
In areas of high malaria transmission such as Africa, women experiencing their first pregnancies have the highest risk of infection compared to in lower transmission areas where the number of pregnancies has less of an effect on infection rates. [11] This is because women who are pregnant for the first time generally lack antibodies to VAR2CSA on erythrocytes that have been infected by the parasite. Women are most susceptible to malaria infection early on in the first trimester but the risk of infection decreases in the second trimester due to the development of antibodies to the infectious agent over time following the initial exposure. The infection risk also decreases after successive pregnancies. [18]
Women that are infected with human immunodeficiency virus (HIV) are also at a high risk of having a higher parasite burden within the placenta during pregnancy. [19] This increased parasite burden can show up as increased reporting of symptoms associated with PAM and an increased likelihood of adverse maternal and fetal outcomes. There is also an increased risk of an HIV-positive woman developing pregnancy-associated malaria in subsequent pregnancies. [19] Although the exact biological mechanism around how HIV and malaria disease states affect each other, it is thought that each condition affects how the immune system reacts to the other condition. [20]
P. falciparum expresses proteins on the surface of parasite-infected erythrocytes (IE) helping them bind to an unusually low-sulfated form of chondroitin sulfate A (CSA) in the placental intervillous space. [21] [22] By this process, the parasite avoids being filtered through the spleen where it would be cleared from the bloodstream and killed. [23] [24] When selected in vitro for CSA-binding, the only upregulated gene expressed in the P. falciparum parasites was the var2csa gene. [25] Parasite clones where the var2csa gene was disrupted lost the ability to adhere to CSA by blocking the binding of IE. [22] [26] Its protein, VAR2CSA (Variant Surface antigen 2-CSA), belongs to the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family and contains six Duffy binding-like (DBL) domains. The regions that mediate binding to CSA have not been defined, but DBL2, DBL3, and DBL6 have shown the highest affinity for CSA binding when testing with recombinant single-domains. [22] [27]
A unique var gene (PFL0030c or var2csa) encodes this particular PfEMP1, which is differently regulated than other genes from the var family. [28] It is also only expressed as protein in pregnant women, even though the transcript is present in children, men and non-pregnant women. [29] It has a unique regulatory region, a uORF located upstream from the ORF that codes for the VAR2CSA protein. The expression of a protein named PTEF (after Plasmodium falciparum translation-enhancing factor) has been described to be necessary for the translation machinery to overcome the uORF and produce VAR2CSA protein, [30] but the mechanism behind it remains to be elucidated.
In general, women with PAM have a higher likelihood of premature birth and their infants having a low birthweight. [31] In examination of possible malarial immunity, some studies have shown that the presence of P. falciparum antibodies (specifically CSA adhesion inhibitory antibodies or IgG antibodies) may decrease the likelihood of low birthweight in the infants of women who have had pregnancy-associated malaria, but these findings do not specifically correlate to malarial immunity during pregnancy. [32] However, the relationship between many P. falciparum antibodies during pregnancy and maternal and birth outcomes remains variable.[ citation needed ]
Lower birthweight of infants born from mothers with PAM can be attributed to placental infection, as well as other complications such as anemia and malnutrition, since the malarial parasite can be passed vertically from mother to the infant via infected red blood cells. [33] Children who are born with a below-average birthweight are at risk for other health problems, including increased risk of mortality. [33]
Anemia is a great concern as an adverse effect of pregnancy-associated malaria, since it can be life-threatening to the mother. [33] Its cause is often compounded with other factors, such as nutrition and genetics. Some studies have suggested that iron supplementation can help with maternal anemia, but more research on malaria-endemic regions is required to make a better recommendation for mothers with PAM. [34]
One systematic review showed that children of women with PAM are also more likely to contract clinical malaria and P. falciparum parasitaemia, although the reasoning for this is uncertain. [35]
Maternal death is one of the biggest complications of malaria in some areas during epidemics. Furthermore, its cause is compounded with other malarial complications, such as anemia.
Prevention of pregnancy-associated malaria can be done with the use of various antimalarial drugs that are given before or during pregnancy to susceptible populations. [36] Some of the antimalarial drugs used include Chloroquine, Mefloquine, and Sulfadoxine/pyrimethamine since they are safe for use during pregnancy. [36] [37] For regions of moderate or high malaria risk, preventative measures include insecticide-treated nets (ITNs) and intermittent preventive treatment in pregnancy (IPTp). [38] [39] ITNs act as two layers of protection, one from the physical net and another from the chemical nature and effects of the insecticide. [40] Because IPTp plays a role in altering the immune response that the infant can display, the World Health Organization recommends starting IPTp as soon as possible during the 2nd trimester. [38] These treatments are with doses of Sulfadoxine/pyrimethamine and are given at each antenatal visit, as long as the visits are one month apart. [41] One concern with the use of Sulfadoxine/pyrimethamine along with other antimalarial drugs is P. falciparum developing resistance. In areas that have higher rates of resistance to the antimalarial Sulfadoxine/pyrimethamine, two doses of the drug is effective in reducing maternal parasitemia in women that do not have HIV while more doses are needed to reduce maternal parasitemia in HIV positive women. [42]
Non-pharmacological treatment of PAM consists of utilizing the Artemisia annua plant as an herbal remedy. The basis for this reasoning is because A. annua acts as the plant source for Artemisinin-based combination therapy (ACT), a commonly used pharmacological treatment of PAM. However, the WHO currently does not support the use of A. annua as there are no standardization guidelines for plant harvest and preparation. Additionally, its clinical safety and efficacy have not yet been proven. [43]
Treatment of PAM is highly dependent on the mother's current pregnancy stage (i.e. trimester) and the species responsible for the disease transmission.[ citation needed ]
For infection caused by P. falciparum, the WHO recommends during the first trimester a treatment consisting of both Quinine and Clindamycin for a duration of 7 days. During the second and third trimester, the WHO recommendations of ACT, are the same as ones for non-pregnant individuals. [44] [45]
For infection caused by the other species, which include Plasmodium malariae , Plasmodium vivax , and Plasmodium ovale , the WHO recommends Chloroquine or Quinine during the first trimester. Quinine is used as an alternative if chloroquine-resistance is detected. During the second and third trimester, the WHO recommends either ACT or Chloroquine. If chloroquine-resistance is detected, ACT is the treatment of choice. [44] [45] The Centers for Disease Control and Prevention (CDC) has similar recommendations to the WHO. [46]
Globally, an estimated 125 million or more pregnant women per year risk contracting PAM. [47] Pregnancy-related malaria causes around 100,000 infant deaths each year, due in large part to low birth weight. [11]
Due to the nature of disease transmission (i.e. via mosquitoes) and life cycle of the parasite, malaria is prevalent in warm, humid climates, such as tropical and subtropical regions. [48] Consistent with previous years, the incidence of malaria in general is greatest in African regions, specifically sub-Saharan Africa, as defined by the World Health Organization (WHO), although there was a decline in numbers from 2010 to 2018. [33] Particularly, in Central and West Africa, the number of pregnancies with malarial infection reached around 35% of all pregnancies in those regions in 2018. [33] The regions that follow Africa in terms of malaria cases are Southeast Asia and the Mediterranean, although it is important to note that Africa has the largest number of cases by far; these regions comprise over 90% of the global incidences[ spelling? ] of malaria. [33]
In the realm of pregnancy, individual immunity and level of transmission within the area play an important role in the malarial complications that manifest. [33] For example, areas with high level of transmission are also associated with higher incidence of immunity. Therefore, infection from P. falciparum is usually associated with no symptoms in pregnant women. [33] However, it is not to conclude that the presence of P. falciparum is completely benign, as it has been associated with maternal anaemia. [33] Specifically, in these settings, women in their first pregnancy are at greatest risk of complications that arise from P. falciparum. [49] Similarly to P. falciparum, Plasmodium vivax (P. vivax), another malarial pathogen found primarily in Asia and South America, has also been associated with maternal anaemia and low birthweight. [33] [50] On the contrary, women who live in areas with lower transmission are at a very high risk of adverse malarial outcomes despite their number of pregnancies. [49]
Each VAR2CSA domain has a potential affinity to CSA, but there are large areas not exposed to the immune system and appear to be buried in the quaternary structure. [24] [51] Data has indicated that these domains interact, forming a binding site that is specific for low-sulfated CSA found in the placenta. [24] [52] [53] The binding of antibodies to one of these domains would prevent adhesion of parasitic IE in the placenta.
Moreover, studies have shown that women acquire immunity to PAM through antibody recognition of the VAR2CSA domain, also known as VSAPAM, after exposure during their first pregnancy. By measuring circulating levels of IgG antibodies that presumably target VAR2SCA, the study demonstrated that subsequent pregnancies confer progressively greater protection to PAM. Thus, PfEMP1 proteins such as the VAR2CSA domain could prove attractive as potential candidates for vaccine targets. [16]
Additional genetic testing relating to pregnancy-associated malaria is currently being researched which involves looking at glucose-6-phosphate dehydrogenase (G6PD) which is an enzyme that is responsible for keeping red blood cells protected from being destroyed too soon by things such as foods and medications. [54] [55] The gene for this enzyme is found on the X chromosome which means that women in particular can have G6PD function that is normal, intermediate (which often shows up on lab tests as normal), and deficient. [54] This gene is important in determining if certain antimalarial drugs such as Primaquine and Tafenoquine can be used since these antimalarial drugs are more likely to cause red blood cell hemolysis in women with a G6PD deficiency and worsen any anemia that comes from the malaria infection. [55] Although these drugs would most likely be used after delivery for treatment of pregnancy-associated malaria, this genetic testing can help avoid inducing anemia in women more prone to red blood cell breakdown.
A vaccine to prevent a pregnancy-associated malaria called PAMVAC is currently undergoing clinical trials. PAMVAC is based on a recombinant form of the VAR2CSA domain and has been shown to be well-tolerated when injected in malaria-naive volunteers while also successfully inducing the production of antibodies against VAR2CSA. [56] Although the vaccine was injected in healthy participants who did not have malaria, the study provided insight into the vaccine's safety before administration into the target population – women with PAM. [56] [57]
A second vaccine candidate against pregnancy-associated malaria called PRIMVAC is also currently undergoing clinical trials in healthy adult women as a 3 dose course. This vaccine is based on the DBL1x-2x domain of VAR2CSA which is able to bind to CSA in the placenta. In preclinical studies, PRIMVAC injected in rats led to the production of antibodies against VAR2CSA on infected erythrocytes and also resulted in reduction of their binding to CSA. The vaccine was also shown to be well-tolerated in rats without any notable adverse reactions. [58]
Malaria is a mosquito-borne infectious disease that affects humans and other vertebrates. Human malaria causes symptoms that typically include fever, fatigue, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. Symptoms usually begin 10 to 15 days after being bitten by an infected Anopheles mosquito. If not properly treated, people may have recurrences of the disease months later. In those who have recently survived an infection, reinfection usually causes milder symptoms. This partial resistance disappears over months to years if the person has no continuing exposure to malaria.
Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target groups, young children and pregnant women. As of 2018, modern treatments, including for severe malaria, continued to depend on therapies deriving historically from quinine and artesunate, both parenteral (injectable) drugs, expanding from there into the many classes of available modern drugs. Incidence and distribution of the disease is expected to remain high, globally, for many years to come; moreover, known antimalarial drugs have repeatedly been observed to elicit resistance in the malaria parasite—including for combination therapies featuring artemisinin, a drug of last resort, where resistance has now been observed in Southeast Asia. As such, the needs for new antimalarial agents and new strategies of treatment remain important priorities in tropical medicine. As well, despite very positive outcomes from many modern treatments, serious side effects can impact some individuals taking standard doses.
Plasmodium is a genus of unicellular eukaryotes that are obligate parasites of vertebrates and insects. The life cycles of Plasmodium species involve development in a blood-feeding insect host which then injects parasites into a vertebrate host during a blood meal. Parasites grow within a vertebrate body tissue before entering the bloodstream to infect red blood cells. The ensuing destruction of host red blood cells can result in malaria. During this infection, some parasites are picked up by a blood-feeding insect, continuing the life cycle.
Plasmodium falciparum is a unicellular protozoan parasite of humans, and the deadliest species of Plasmodium that causes malaria in humans. The parasite is transmitted through the bite of a female Anopheles mosquito and causes the disease's most dangerous form, falciparum malaria. It is responsible for around 50% of all malaria cases. P. falciparum is therefore regarded as the deadliest parasite in humans. It is also associated with the development of blood cancer and is classified as a Group 2A (probable) carcinogen.
CD36, also known as platelet glycoprotein 4, fatty acid translocase (FAT), scavenger receptor class B member 3 (SCARB3), and glycoproteins 88 (GP88), IIIb (GPIIIB), or IV (GPIV) is a protein that in humans is encoded by the CD36 gene. The CD36 antigen is an integral membrane protein found on the surface of many cell types in vertebrate animals. It imports fatty acids inside cells and is a member of the class B scavenger receptor family of cell surface proteins. CD36 binds many ligands including collagen, thrombospondin, erythrocytes parasitized with Plasmodium falciparum, oxidized low density lipoprotein, native lipoproteins, oxidized phospholipids, and long-chain fatty acids.
Plasmodium malariae is a parasitic protozoan that causes malaria in humans. It is one of several species of Plasmodium parasites that infect other organisms as pathogens, also including Plasmodium falciparum and Plasmodium vivax, responsible for most malarial infection. Found worldwide, it causes a so-called "benign malaria", not nearly as dangerous as that produced by P. falciparum or P. vivax. The signs include fevers that recur at approximately three-day intervals – a quartan fever or quartan malaria – longer than the two-day (tertian) intervals of the other malarial parasite.
Merozoitesurface proteins are both integral and peripheral membrane proteins found on the surface of a merozoite, an early life cycle stage of a protozoan. Merozoite surface proteins, or MSPs, are important in understanding malaria, a disease caused by protozoans of the genus Plasmodium. During the asexual blood stage of its life cycle, the malaria parasite enters red blood cells to replicate itself, causing the classic symptoms of malaria. These surface protein complexes are involved in many interactions of the parasite with red blood cells and are therefore an important topic of study for scientists aiming to combat malaria.
Antigenic variation or antigenic alteration refers to the mechanism by which an infectious agent such as a protozoan, bacterium or virus alters the proteins or carbohydrates on its surface and thus avoids a host immune response, making it one of the mechanisms of antigenic escape. It is related to phase variation. Antigenic variation not only enables the pathogen to avoid the immune response in its current host, but also allows re-infection of previously infected hosts. Immunity to re-infection is based on recognition of the antigens carried by the pathogen, which are "remembered" by the acquired immune response. If the pathogen's dominant antigen can be altered, the pathogen can then evade the host's acquired immune system. Antigenic variation can occur by altering a variety of surface molecules including proteins and carbohydrates. Antigenic variation can result from gene conversion, site-specific DNA inversions, hypermutation, or recombination of sequence cassettes. The result is that even a clonal population of pathogens expresses a heterogeneous phenotype. Many of the proteins known to show antigenic or phase variation are related to virulence.
Malaria culture is a method for growing malaria parasites outside the body, i.e., in an ex vivo environment. Although attempts for propagation of the parasites outside of humans or animal models reach as far back as 1912, the success of the initial attempts was limited to one or just a few cycles. The first successful continuous culture was established in 1976. Initial hopes that the ex vivo culture would lead quickly to the discovery of a vaccine were premature. However, the development of new drugs was greatly facilitated.
Malaria prophylaxis is the preventive treatment of malaria. Several malaria vaccines are under development.
Malaria antigen detection tests are a group of commercially available rapid diagnostic tests of the rapid antigen test type that allow quick diagnosis of malaria by people who are not otherwise skilled in traditional laboratory techniques for diagnosing malaria or in situations where such equipment is not available. There are currently over 20 such tests commercially available. The first malaria antigen suitable as target for such a test was a soluble glycolytic enzyme Glutamate dehydrogenase. None of the rapid tests are currently as sensitive as a thick blood film, nor as cheap. A major drawback in the use of all current dipstick methods is that the result is essentially qualitative. In many endemic areas of tropical Africa, however, the quantitative assessment of parasitaemia is important, as a large percentage of the population will test positive in any qualitative assay.
Malaria vaccines are vaccines that prevent malaria, a mosquito-borne infectious disease which annually affects an estimated 247 million people worldwide and causes 619,000 deaths. The first approved vaccine for malaria is RTS,S, known by the brand name Mosquirix. As of April 2023, the vaccine has been given to 1.5 million children living in areas with moderate-to-high malaria transmission. It requires at least three doses in infants by age 2, and a fourth dose extends the protection for another 1–2 years. The vaccine reduces hospital admissions from severe malaria by around 30%.
Haemozoin is a disposal product formed from the digestion of blood by some blood-feeding parasites. These hematophagous organisms such as malaria parasites, Rhodnius and Schistosoma digest haemoglobin and release high quantities of free heme, which is the non-protein component of haemoglobin. Heme is a prosthetic group consisting of an iron atom contained in the center of a heterocyclic porphyrin ring. Free heme is toxic to cells, so the parasites convert it into an insoluble crystalline form called hemozoin. In malaria parasites, hemozoin is often called malaria pigment.
Human genetic resistance to malaria refers to inherited changes in the DNA of humans which increase resistance to malaria and result in increased survival of individuals with those genetic changes. The existence of these genotypes is likely due to evolutionary pressure exerted by parasites of the genus Plasmodium which cause malaria. Since malaria infects red blood cells, these genetic changes are most common alterations to molecules essential for red blood cell function, such as hemoglobin or other cellular proteins or enzymes of red blood cells. These alterations generally protect red blood cells from invasion by Plasmodium parasites or replication of parasites within the red blood cell.
Russell J. Howard is an Australian-born executive, entrepreneur and scientist. He was a pioneer in the fields of molecular parasitology, especially malaria, and in leading the commercialisation of one of the most important methods used widely today in molecular biology today called “DNA shuffling" or "Molecular breeding", a form of "Directed evolution".
KAHRP is a protein expressed by Plasmodium falciparum infecting erythrocytes. KAHRP is a major component of knobs, feature found on Plasmodium falciparum infected erythrocytes.
Sanaria is a biotechnology company developing vaccines protective against malaria and other infectious diseases as well as related products for use in malaria research. Sanaria's vaccines are based on the use of the sporozoite (SPZ) stage of the malaria parasite, Plasmodium, as an immunogen, and as a platform technology for liver-vectored gene delivery. SPZ are normally introduced into humans by mosquito bite where they migrate to the liver and further develop to liver stages, and eventually back into the blood stream where the parasite infects red blood cells (RBC) and causes malaria. Plasmodium falciparum is the species responsible for more than 95% deaths caused by malaria. The WHO estimates there were 249 million clinical cases and 608,000 deaths in 2022 alone.
Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a family of proteins present on the membrane surface of red blood cells that are infected by the malarial parasite Plasmodium falciparum. PfEMP1 is synthesized during the parasite's blood stage inside the RBC, during which the clinical symptoms of falciparum malaria are manifested. Acting as both an antigen and adhesion protein, it is thought to play a key role in the high level of virulence associated with P. falciparum. It was discovered in 1984 when it was reported that infected RBCs had unusually large-sized cell membrane proteins, and these proteins had antibody-binding (antigenic) properties. An elusive protein, its chemical structure and molecular properties were revealed only after a decade, in 1995. It is now established that there is not one but a large family of PfEMP1 proteins, genetically regulated (encoded) by a group of about 60 genes called var. Each P. falciparum is able to switch on and off specific var genes to produce a functionally different protein, thereby evading the host's immune system. RBCs carrying PfEMP1 on their surface stick to endothelial cells, which facilitates further binding with uninfected RBCs, ultimately helping the parasite to both spread to other RBCs as well as bringing about the fatal symptoms of P. falciparum malaria.
The Plasmodium helical interspersed subtelomeric proteins (PHIST) or ring-infected erythrocyte surface antigens (RESA) are a family of protein domains found in the malaria-causing Plasmodium species. It was initially identified as a short four-helical conserved region in the single-domain export proteins, but the identification of this part associated with a DnaJ domain in P. falciparum RESA has led to its reclassification as the RESA N-terminal domain. This domain has been classified into three subfamilies, PHISTa, PHISTb, and PHISTc.
Reticulocyte binding protein homologs (RHs) are a superfamily of proteins found in Plasmodium responsible for cell invasion. Together with the family of erythrocyte binding-like proteins (EBLs) they make up the two families of invasion proteins universal to Plasmodium. The two families function cooperatively.
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