TEMPORAL VIEW OF MALARIA LIFECYCLE

PLASMODIUM FALCIPARUM

PLASMODIUM VIVAX
Key Facts
 Malaria is a life-threatening disease caused by parasites that are transmitted to people through the bites of infected
female Anopheles mosquitoes.

 Globally, in 2020 there were 241 million cases of malaria. And in that same year, there were an estimation of 627,000
malaria-related deaths.

 Malaria disease can be diagnosed, prevented and it is curable.

 Severe cases of malaria can cause organ failure and even death.

 children under five years of age, pregnant women and their unborn children are at severe risk the poorest and most
marginalized Malaria in pregnancy contributes significantly to deaths of mothers and young children.

Overview
Malaria is one of the most common lethal documented infectious diseases and the leading cause of death known from
the ancient times. It is a life-threatening parasitic disease caused by Plasmodium parasites transmitted through the bite
of infected female Anopheles mosquito. Malaria is common in tropical and subtropical countries.

In humans, five major causative agents of Plasmodium species are responsible for malaria infection:

 p. vivax

 p. falciparum

 p. ovale

 p. malariae

 p. knowlesi

Out of the five causative agents; Plasmodium falciparum and Plasmodium vivax are the most dangerous and
predominant species responsible for most case fatality in Africa. Malaria parasite belongs to:

 Phylum: Ampicomplexa

 Class: Sporozoa

 Order: Hemosporida

 Genus: Plasmodium

Phases and Life cycle of malaria parasite (Plasmodium falciparum)

The transmission and the life cycle of malaria parasite primarily occur between the vector; definitive host (Female
Anopheles mosquito) and the intermediate host (Humans). Two phases are involved in the life cycle of plasmodium
falciparum:

The sexual cycle phase: This phase primary occurs in mosquitoes (definitive host). The sexual cycle phase is also known
as the sporogony phase because sporozoites are formed.

Asexual cycle phase: This phase occurs in humans (the intermediate host). The asexual phase is called the schizogony
phase because schizonts are formed.
Life cycle of malaria parasite (plasmodium falciparum)
 An infected female anopheles mosquito injects sporozoites present in its salivary glands into the blood stream during
blood meal.

 The sporozoites migrate to the human liver through the hepatocytes, where it multiplies asexually in the liver cell to
develop and form schizonts.

 The schizonts burst and releases merozoites from the liver cells into the blood stream and infect the red blood cells.

 In the blood stream, the merozoites invade the red blood cells and infect other erythrocytes, then multiply again until
the cells burst.

 Some of the merozoites in the blood cells develop and differentiate into the sexual forms of the parasite called the
gametocytes (Male and female gametocytes).

 When a mosquito bites an infected individual for blood meal, it sucks the gametocytes along with the blood. In the
mosquito, the gametocytes continue the sexual phase of the cycle.

 The fertilized female gametes develop into actively moving ookinetes (the motile zygote of the malarial organism that
penetrates the mosquito stomach to form an oocyst under the outer gut lining).

 Inside the oocyst active sporozoites are developed. The oocyst eventually burst releasing sporozoites that migrate to
the mosquito salivary glands.

 The cycle of the human infection begins again when the infected mosquito bites another person.

Mode of Transmission
Plasmodium parasite in an infected individual can also be transmitted to another individual through:

 infected blood transfusion,

 infected needles

 From mother to her fetus during pregnancy.

Clinical manifestation (signs and symptoms) of malaria parasite

Malaria signs and symptoms typically begin within a few weeks after being bitten by an infected female anopheles
mosquito. However, some types of malaria parasites can lie dormant in the body for up to a year.

Common signs and symptoms of malaria may include:

 fever

 chills

 sweating,

 headache

 Nausea and Vomiting

 Muscular fatigue and pain

 Diarrhea

 confusion

 cough
 Rapid breathing

 bitter taste in the mouth

Risk factors
The greatest risk factor is to live in or to visit areas where the disease is common. The degree of risk depends on the
precautions and the control you take to prevent mosquito bites and infection.

Regions with high risk include the tropical and subtropical regions of:

 South and Southeast Asia

 Pacific Islands

 Sub-Saharan Africa

 Central America and northern South America

Risks of more-severe disease

People at increased risk of serious disease include:

 Young children and infants

 Older adults

 Travelers coming from areas with no malaria

 Pregnant women and their unborn children

Laboratory Diagnosis of malaria parasite

Early diagnosis and treatment of malaria reduces disease, prevents deaths and contributes to reducing transmission. The
primary goal of malaria diagnosis test is not only for the identification or detection of the species present, but to be able
to know the treatment of choice for the specie being identified. WHO recommends that all suspected cases of malaria
be confirmed using parasite-based diagnostic testing (through either microscopy or a rapid diagnostic test).

Treatment
The primary objective of treatment is to ensure the rapid and full elimination of Plasmodium parasites to prevent an
uncomplicated case of malaria from progressing to severe disease or death. Malaria is treated with prescription drugs to
kill the parasite. The types of drugs and the length of treatment will vary, depending on:

 Which type of malaria parasite you have

 The severity of your symptoms

 Your age

 Whether you're pregnant

Medicatons: Anti-malaria Drugs

The most common antimalarial drugs include:

Chloroquine phosphate: Chloroquine is the preferred treatment for any parasite that is sensitive to the drug. But in
many parts of the world, parasites are resistant to chloroquine, and the drug is no longer an effective treatment.
Artemisinin-based combination therapies (ACTs): ACT is a combination of two or more drugs that work against the
malaria parasite in different ways. This is usually the preferred treatment for chloroquine-resistant malaria. Examples
include:

 Artemether +lumenfantrine

 Artesunate + Amodiaquine

 Artesunate + Mefloquine

 Artesunate + sulfadoxine+ Pyrimethamine

 sulfadoxine+ pyrimethamine

 dihydroartemisinin +piperaquine phosphate

 Artemisinin+Piperaquine

 Other common antimalarial drugs include:

 Atovaquone-proguanil (Malarone)

 Quinine sulfate (Qualaquin) with doxycycline (Oracea, Vibramycin, others)

 Primaquine phosphate

 chloroquine phosphate

 proguanil hydrochloride

Malaria Preventive and control Measures

In many countries with high malaria rates, the problem is worsened by lack of access to preventive measures, medical
care and information. Prevention of malaria is currently base on two complementary methods: Chemoprophylaxis and
protection against mosquito bites.

 Chemoprophylaxis: The choice of drugs for prophylaxis depends on individual location, travel destination, duration of
exposure to malaria parasite, efficacy of drug of choice, extent of drug resistance, side effects of the drug, patient
related factors (age, pregnancy, renal or hepatic impairment, and compliance)

 Personal malaria preventive measures and control: The main current measures are focused on reduction of the contact
between mosquitoes and humans through:

 Environmental management and control

 Use of larvicides or mosquito larvae predators

 Use of insecticides treated bed nets

 wearing of clothes that cover most of the body

 use of insect repellent on exposed skin

 MALARIA
Malaria is named after the Italian term “mal’aria”, which means “bad air” to represent the association of the
disease with marshy areas. It is an endemic vector-borne parasitic disease caused by protozoan parasites of the
genus Plasmodium in tropical and subtropical regions worldwide. Plasmodium consists of over 200 species, infecting
mammals, birds, and reptiles, and malaria parasites generally tend to be host-specific. Plasmodium falciparum,
Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, and Plasmodium knowlesi are the five known species of
the genus Plasmodium that causes malaria in humans. Of the five Plasmodium species that cause malaria in humans, P.
falciparum causes severe malaria.

The life cycle of the parasites is a complex process occurring in both vertebrate hosts and a mosquito vector.
Besides, it undergoes both sexual and asexual reproduction mechanisms. This makes the development of drugs and
vaccines challenging.

The first trial to treat malaria dates back to the 2nd century before Christ (168 BC) when China used Qinghai
(Latin Artemisia annua) for the treatment of fever and chills. The next documented trial was in the 16th century when
the Spanish invaders in Peru discovered the Cinchona medications against malaria from the bark of the Cinchona tree
(Latin Cinchona succirubra). The active ingredient of Cinchona succirubra which had been used for many years in
chemoprophylaxis and treatment of malaria was isolated in 1820 by the French chemists Pierre Joseph, Pelletie, and
Joseph Bienaimé Caventou. In 1970, a group of Chinese scientists led by Dr Youyou Tu isolated an active substance
Artemisinin, a compound that has proven activity against malaria, from the plant Artemisia annua.

Although artemisinin and its derivatives are potent treatments for malaria and are being widely used in
combination therapies worldwide, resistance is emerging in some parts of the world. This calls for the need to discover
new anti-malarial agents possessing high therapeutic value with minimal toxicity, and lower cost. 10

Tackling malaria transmission by interrupting parasite transmission or by tackling the insect vector was started in
the late 1800s after Laveran in Algeria discovered the cause of malaria and the Plasmodium parasite around 1880–1882.
In the early 1900s, numerous effective local initiatives were reported in different parts of the world where malaria was
common.11 Later on, DDT (dichloro-diphenyl-trichloroethane), came to the picture. Even though it was synthesized in
1874, it was only in 1939 that its insecticide properties were discovered. It was used extensively during and after World
War II. Due to its high efficacy on malaria vectors, it became the main tool of the malaria eradication campaign launched
in 1955 under the auspices of the League of Nations. But due to failure to meet expectations, it was officially abandoned
in 1978.12 Afterwards, other and costlier insecticides were developed (pyrethroids) for use in the impregnation of bed
nets. However, the impact of long-lasting impregnated nets (LLINs) has been compromised in recent years by several
factors: the emergence of resistance to the insecticide in the mosquito populations, the diversity and changes in the
behavior of Anopheles since some of the species are (or have become) exophagic/exophilic and early biters. 12

Epidemiology of Malaria

Following the second world war, incredible success was achieved with the discoveries of DDT and chloroquine,
lowering the global extents of both P. vivax and P. falciparum, and benefiting enormous parts of the Americas, Europe,
and Asia.13 These tremendous gains in malaria control continued until the first decade of the 21st century, but the
second decade appears to be a bit harder. Malaria incidence has been on the rise in several places since 2014. 14 In 2019,
an estimated 229 million cases were reported worldwide (from 87 malaria-endemic countries). About 94% of the
reported cases (215 million cases) were recorded in the African region. The Southeast Asia region accounted for about
3% of the burden of malaria cases globally. In the same year, an estimated 409,000 deaths from malaria occurred
worldwide of which 94% happened in Africa.15

Malaria affects majorly children under the age of 5 years; with 67% death from the total death in 2019.
Underdeveloped immunity is thought to be the major reason that makes children under 5 years of age vulnerable to
malaria. Aftereffects of fever and illness like reduced appetite, limited social life, and restricted play contribute to
meager growth.16
Etiology of Malaria

Protozoan parasites of the genus Plasmodium originate from photosynthetic protozoa named Dinoflagellates.
About 200 different species of protozoa have been identified so far and among them, at least 13 species are known to
be pathogenic to humans.17 Five of the parasites namely P. falciparum, P. vivax, P. malariae, P. ovale (P. ovale
curtisi and P. ovale wallikeri), and P. knowlesi are well-known etiologies of malaria in humans.18

In Africa, the most prevalent and pathogenic species is P. falciparum. However, malaria infection from most
malaria-endemic regions of Africa shows the presence of multiple sympatric species and co-infection within an individual
human host or mosquito vector.19 P. malariae is the species most commonly found in sympatry with P. falciparum in
malaria-endemic regions of Africa.20

In each endemic area, malaria is transmitted by a specific set of Anopheles species.21 So far, more than 400
different species of Anopheles mosquitoes have been identified. But only 30 of them are known to transmit malaria. All
vectors of malaria undergo the bite between dusk and dawn.22

Stability is observed in the distribution pattern of the mosquito species in malaria-endemic regions of the African
continent. The complete disappearance of a given vector species from a region is unusual and when the non-indigenous
vector is introduced to the area, it is a serious public health concern since it is known to result in devastating epidemics.
Indigenous vectors are hard to eradicate with known vector eradication activities. 21

The Life Cycle of Malaria Parasite

The life cycle of the malaria parasite is a complex process involving an Anopheles mosquito and a vertebrate
host.23 The first stage of the infection is the entrance of the sporozoites in mosquito saliva into the skin and bloodstream
of the human host and then, it invades hepatocytes to undergo asexual replication. 24 During this phase (hepatic or pre-
erythrocytic phase) the rupture of infected hepatocytes results in the release of thousands of merozoites. 25 In the case
of P. vivax and P. ovale infections, some form dormant hypnozoites which remain within hepatocytes for periods of
several months, and even as long as 4 years, before developing and multiplying to initiate a new episode of erythrocytic
infection.26

The erythrocytic infection involves the interaction of the merozoites with the red blood cells (RBC). The
merozoites head orients and adjoin with the erythrocytes membrane by deforming the surface host cell. Then, through
parasite-induced reorganization of the erythrocyte cytoskeleton, the parasite enters the erythrocyte to undergo the
second asexual reproduction.27 While younger erythrocytes are targeted favorably by P. vivax and P. ovale, erythrocytes
of any age are invaded by P. falciparum and P. knowlesi. In contrast, P. malariae prefers senescent erythrocytes.24 After
invading RBC, merozoites reproduce into trophozoites and then into schizonts which erupt from the erythrocytes to
release merozoites and reinvade new RBCs and continue the asexual replication cycle. 27

The sexual reproduction cycle of malaria starts when a portion of trophozoites matures to male and female
sexual progeny or gametocytes.28 The transmission of the malaria parasite from the mammalian host to the mosquito is
mediated by these gametocytes. During the bite of an anopheles mosquito, the matured gametocytes will be taken to
the midgut of the mosquito.29 Inside the midgut, gametocytes get converted into fertile gametes and the next stage
involves the conversion of zygotes into ookinetes which are motile and invasive. 30 The ookinetes in turn get converted
into oocysts in the midgut basal lamina. The oocyst then matures releasing sporozoites, which migrate to the salivary
gland of the mosquito. The parasite is transmitted to another mammalian host through an infected mosquito bite. 31

Pathophysiology of Malaria

The pathophysiology of uncomplicated malaria is characterized by fever 25 secondary to the rupture of

erythrocytes, macrophage ingestion of merozoites, and/or the presence of antigen-presenting trophozoites in the
circulation or spleen which mediates the release of tumor necrosis factor α (TNF-α). 32 Fever associated with malaria
infection is known by its periodicity which differs among different species of the parasite. Tertian fever (“tertian
malaria”) is expected in P. vivax and P. ovale malaria as a progeny of schizonts matures every 48 hours in these species.
In contrast, P. malariae is attributed to quartan fever (“quartan malaria”) which occurs every 72 hours. However, the
fever in falciparum malaria may occur every 48 hours, but is usually irregular, showing no distinct periodicity. 25

The binding of matured infected RBC to host endothelial cells (cytoadherence) is the major player in the
pathogenesis of severe malaria.33 The expression of genes that encode proteins involved in cytoadherence and immune
evasion explains the virulence of P. falciparum when compared with other species. The P. falciparum erythrocyte
membrane protein 1 (PfEMP1), rifin, and stevor proteins are encoded by members of the var, rif, and stevor gene
families, respectively.34 Var gene-encoded PfEMP1 is the best-characterized variant surface antigen which is expressed
on the surface of infected erythrocytes where it mediates binding to endothelial receptors. 35

The PfEMP1 family forms electron-dense protrusions named knobs on the membrane of parasitized RBC (pRBC)
by getting inserted into and protruding from the erythrocyte membrane. Knobs serve as a site by which parasitized
erythrocyte binds to other cell surfaces like normal RBC and endothelium. 36

The adhesion of parasitized erythrocytes to vascular endothelium leads to sequestration, the phenomenon by
which infected RBCs translocated from the peripheral circulation by getting bound to the vascular endothelium, in the
deep microvasculature of various tissues and organs. 37 Host molecules like cluster of differentiation 36 (CD36),
intercellular adhesion molecule-1 (ICAM1), thrombospondin (TSP), P-selectin, chondroitin sulfate A (CSA), and protein C
receptor have been identified as receptor binding for pRBC to the endothelium. 38 For instance, when PfEMP1 on infected
RBCs binds to host receptors such as ICAM-1 and CD36 on brain endothelial cells, it mediates sequestration to cause
cerebral malaria.39

On the other hand, pRBCs can bind to uninfected RBCs and impair microcirculation then cause hypoxia. The
phenomenon is called rosettes, the spontaneous binding of normal RBCs to malaria-infected RBCs. Blood group antigens
A and B, CD36, complement receptor 1 (CR1), and heparan sulfate-like glycosaminoglycans (HS-GAGs) are the five
identified receptors on RBCs implicated in the process of rosettes.37

Parasite-derived molecules called toxins are also implicated in the pathogenesis of severe malaria. 40 Glycolipids
named glycosylphosphatidylinositol (GPI), coupled with protein or free form, induce the overproduction of cytokines:
TNF and interleukin I (ILI) by macrophages. 41 Although cytokines have a physiological role in defending microorganisms
including the malaria parasite when produced in lower amounts, 42 overproduction causes high-grade fever, upregulation
of endothelial receptor expression, and upregulation of nitric oxide production, this in turn may cause local damage and
suppression of erythrocyte production in the bone marrow.37
Parasite incubation (liver cycle):

 P. falciparum: 7-14 days

 P. vivax: 12-17 days (relapse up to 3 years)
 P. ovale: 9-18 days (relapse up to 20 years)
 P. malariae: 13-40 days

Fever intervals match the infecting Plasmodium species:

 P. falciparum: 36-48h (Malignant tertian malaria)

 P. vivax: 48h (Benign tertian malaria)
 P. ovale: 48h (Ovale tertian malaria)
 P. malariae: 72h (Quartan malaria)

Malaria Diagnosis:

1. Medical history
2. Physical exam
3. Lab tests:

 Microscopy: thick/thin blood smears, QBC test

 Immunological: antibody tests (IFAT, ELISA), antigen tests (RDTs)
 Molecular: PCR
Malaria complications by species:

 P. falciparum: cerebral malaria, haemolytic anaemia (blackwater fever), jaundice, hypoglycaemia

 P. vivax: relapse from liver hypnozoites
 P. malariae: nephrotic syndrome
 P. ovale: relapse from liver hypnozoites

Complications of Malaria

 CNS: Cerebral malaria (coma, seizures)

 Kidneys: Hemoglobinuria (blackwater fever), low urine, acute failure
 Blood: Severe anemia, DIC, ARDS
 Metabolic: Low blood sugar, acidosis
 GI/Liver: Diarrhea, jaundice, splenic rupture
 Other: Shock, low blood pressure, high fever Malaria complications

M- Metabolic Acidosis, A- Anemia, L- Lungs (Pulmonary Edema), A- Altered Consciousness, R- Reduce Glucose, I- Infant
Death (Miscarriage), A- Acute Renal Injury