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Report and Opinion 2014; 6(6) http://www.sciencepub.net/report
55
Understanding Human Malaria: Further Review on the Literature, Pathogenesis and Disease Control
Leera Solomon1, Hyacinth Chijioke Okere2 and Victoria Daminabo3.
1&2 Department of Science Laboratory Technology, School of Science and Technology, Rivers State College of Arts
and Science Rumuola, P.M.B. 5936, Port Harcourt, Nigeria.
3Department of Biological Sciences, School of Science and Technology, Rivers State College of Arts and Science
Rumuola, P.M.B. 5936, Port Harcourt, Nigeria.
Sololeera@yahoo.com
Abstract: Human malaria is caused by single-celled parasites from the genus Plasmodium. More than one hundred
different species of Plasmodium exist and produce malaria in many types of animals including birds and humans. A
further review on the four different species of plasmodium parasites implicated in human malaria in the tropics was
undertaken. The pathogenesis, laboratory diagnosis; public health significance, treatment and control strategies
including the new and holistic approaches to fighting the ancient scourge was highlighted. All the manifestations of
malarial illness are caused by the infection of red cells by the asexual forms of the malaria parasite, and this makes
malaria a potentially multisystem disease, as every organ of the body is reached by the blood. The parasite damages
red blood cells using plasmepsin enzymes which are aspartic acid proteases that degrade hemoglobin. Understanding
the molecular biology of the parasite and the sporogonic cycle to aid in re- engineering of the anopheline mosquito
and improved entomological field will help in controlling the disease. The protection of the host from the bite of
mosquito using netting, repellants and elimination of the vector through biological control measures, by introducing
organisms that will feed on their larvae into the site of breeding coupled with prophylactic treatment with anti-
malaria drugs for exposed persons, in theory, would eradicate the disease.
[Solomon, L., Okere, H.C and Daminabo, V. Understanding Human Malaria: Further Review on the
Literature, Pathogenesis and Disease Control. Rep Opinion 2014;6(6):55-63]. (ISSN: 1553-9873).
http://www.sciencepub.net/report. 8
Key words: Anopheline mosquito, plasmodium parasites, human malaria, pathogenesis, public health significance,
holistic approaches, anti-malaria drugs, ancient scourge, multisystem disease, malarial illness, red blood cells.
1. Introduction
Plasmodium is a Eukaryote, an organism
whose cells have a nucleus, but with unusual
features. Chavatt et al. (2007) reported that all the
species examined have 14 chromosomes, one
mitochondrion and one plastid (Martinsen et al.,
2007). The plastid, unlike those found in algae, is not
photosynthetic but there is some evidence that it is
involved in reproduction (Collins et al., 2008).
Malaria was first described in 1885 by Marchiafava
and Celli.
It now contains about 200 species divided
into several subgenera. Current theory suggests that
the genera Plasmodium, Haemocystis, Haemoproteus
and Hepatocystis evolved from leukocytozoon
species (Chavatt et al, 2007). Parasites of the genus
Leukocytozoan are known to infect white blood cells
and are transmitted by ‘black flies’ (Simulium
species), a large genus of flies related to the
mosquitoes (Telfold, 1988).
The parasite is thought to have originated
from Dinoflagellates, a large group of photosynthetic
protozoa (Laudau et al., 2003). Mosquitoes of the
genera Culex (Culex fatigans), Anopheles (Anopheles
albimanus), Mansonia (Mansonia crassippes) and
Aedes (Aedes aegypti) may act as vectors. However,
it was reported by Giovanni Battista Grassi in 2003
that human malaria could only be transmitted by the
female Anopheles mosquitoes.
Every year 300 to 500 million people suffer
from malaria, causing an estimated 1 to 2.7 million
deaths (Gallup and Sachs, 2001). Report has it that 90
percent of these deaths occur in sub-Saharan Africa,
mostly among children younger than five (Sherman,
1998; Philip, 2011). Plasmodium, the malaria-
causing protozoan belonged to the class sporozoa,
family Plasmodiidae, order Haemosporidia, and
phylum Apicomplexa (Telfold, 1988). Organisms in
the class, sporozoa are all obligate parasites;
therefore, there are no free-living representatives
(John et al., 2006; Hay et al., 2009). Plasmodium
lack locomotive organelles and multiply by spore
formation.
Malaria accounts for 9 to10 percent of
Africa’s entire disease burden with severe economic
consequences (Craig et al., 1999; Anyido et al.,
2010). Countries with a high incidence of malaria can
suffer a 1.3 percent annual loss of economic growth.
A Harvard/World Health Organization study suggests
that if malaria had been eliminated 35 years ago,
Sub-Saharan Africa’s gross domestic product could
be $100 billion greater (Gallup and Sachs, 2001).
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Malaria thrives in the tropical areas of Asia,
Central and South America, where it strikes millions
of people (Cohen et al., 2009; Decastro et al., 2004;
Bomblies et al., 2008). Each year 350 to 500 million
cases of malaria occur worldwide. The understanding
of malaria pathogenesis can inform how best to
defeat malaria and contain the rising cases of infant
mortality and morbidity associated with the ancient
global scourge.
The present review aims at creating a
flexible framework for a better understanding of the
human malaria. A further review on the stages and
development of plasmodium parasites coupled with
possible new tools in the control, treatment and
eradication of the disease was re-examined.
1.1. Disease transmission
Malaria is transmitted by the blood feeding
of infectious female Anopheles mosquitoes. There
are about 100 species of Anopheles genus, but only
50–60 can transmit malaria. Examples include
Anopheles stephensi and A. gambiae (Clement,
2000). In rare cases, a person may contract malaria
through contaminated blood, or a fetus may become
infected by its mother during pregnancy.
Because the malaria parasite is found in red
blood cells, malaria can also be transmitted through
blood transfusion, organ transplant, or the shared use
of needles or syringes contaminated with blood
(Kileen et al., 2006). Malaria also may be transmitted
from a mother to her fetus before or during delivery.
This is known as “congenital” malaria.
Malaria is endemic to over 100 nations and
territories in Africa, Asia, Latin America, the Middle
East, and the South Pacific. At least 10 species of
Plasmodium infect humans; other species infect other
animals, including birds, reptiles and rodents, while
29 species infect non-human primates (Chavatt et al.,
2007; Yotoko and Elisei, 2006). The only known host
of P. falciparium and P. malaria is humans. P. vivax,
however, has been reported to infect chimpanzees
and orangutans (Reid et al., 2006).
P. ovale are said to have an unusual
distribution, being found in Africa, the Philippines
and New Guinea and can be transmitted to
chimpanzees and other animals (Sullivan and
Galland, 1994) as well.
1.2. Species of plasmodium that infect humans
Four species of Plasmodium commonly
infect humans. They include Plasmodium falciparum
(the cause of malignant tertian malaria), Plasmodium
malariae (the cause of benign quartian malaria),
Plasmodium ovale (the other, less frequent, cause of
benign tertian malaria), and Plasmodium vivax (the
most frequent cause of benign tertian malaria).
Plasmodium (P.) falciparum is by far the deadliest of
the four human malarial species; P. vivax is the most
widespread. P. malariae and P. ovale, although also
significant, cause fewer cases and less severe forms
of the disease (Depinay et al., 2004; Nester et al.,
1998; Sullivan and Galland, 1994).
Plasmodium ovale is rare, can cause
relapses, and generally occurs in West Africa. Nearly
all human deaths from malaria are caused by
Plasmodium falciparum, mainly in sub-Saharan
Africa (Obi, 2013). In addition to being the deadliest
form of malaria, P. falciparum destroys red blood
cells, which can cause acute anemia. Compared to
P.vivax, P. falciparum is less widespread.
Adherence to cells in certain tissues may
cause problems within those organs, such as the
lungs, kidneys and brain (Baier, 1998). Plasmodium
vivax, the most geographically widespread of the
species, produces less severe symptoms. Relapses,
however, can occur for up to three years, and chronic
disease is debilitating.
Plasmodium malariae infections not only
produce typical malaria symptoms but also can
persist in the blood for very long periods, possibly
decades, without ever producing symptoms (Yotoko
and Elisei, 2006). A person with asymptomatic (no
symptom) P. malariae, however, can infect others,
either through blood donation or mosquito bites.
Although, P. malariae has been wiped out from
temperate climates, it persists in African sub-region.
1.3. Life Cycle
All types of malaria have a similar life cycle
.The malaria parasite exhibits a complex life cycle
(Richard, 2007) involving two very different hosts:
an insect vector (mosquito) and a vertebrate host
(human) as shown in Figure 1. They have a sexual
cycle, in which spores are formed, and an asexual
cycle. The sexual cycle takes place in the gut and
abdominal wall of the female of some species of
mosquito in the genus Anopheles while the asexual
cycle takes place in the liver and erythrocytes of
humans and causes the symptoms of the disease (Obi,
2013).
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During the sexual cycle, in the mosquito's
stomach a "male" gametocyte fertilizes a "female" to
form an egg, or oocyst, which matures into thousands
of sporozoites that swim to the mosquito's salivary
glands to be injected into another human at the next
bite (Trager et al., 197). An organism such as the
malaria parasite (Plasmodium) must alternate sexual
and asexual cycles (alternation of generation) in order
to continue to exist (Sacci et al., 2006). Both the
intracellular as well as extracellular stages must be
accomplished in both the human host and mosquito
vector, respectively.
Figure 1. Life cycle of Plasmodium parasite (Source: Richard, 2007)
1.4. Pathogenesis
The disease remains one of the major killers
of humans worldwide, threatening the lives of more
than one-third of the world’s population (Smith and
McKenzie, 2004). Humans contact malaria from the
bite of a plasmodial-infected female Anopheline
mosquito (Killeen et al., 2000). As the mosquito
inserts its proboscis into a human to take its blood
meal, it injects the plasmodial sporozoite at the same
time through its saliva (Killeen et al., 2006). The
sporozoite begins the asexual cycle by the pre-
erythrocytic development of merozoites in the
parenchymal cells of the liver (Tsuji et al., 1994).
The merozoites can repeat the pre-erythrocytic cycle
in the liver cells, or they can enter the erytrocytic
cycle. Once the merozoites penetrate the
erythrocytes, the parasite undergoes several
morphological changes, as shown in Figure 2. First, a
ring form develops, which enlarges to become a
mature amoeboid trophozoite filling most of the
parasitized red blood cell (Philip, 2011). Next,
asexual multiplication takes place by the splitting of
nuclear material and cytoplasm of the amoeboid-
appearing parasite to form more merozoites.
Figure 2. Stages of the plasmodium life cycle in blood smears (Source: Sherman, 1998)
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Depending on the species, this multiple
fission (schizogony) results in 6 to 36 new
merozoites per parasitized erythrocyte. As the
erythrocyte ruptures, the merozoites are freed into the
blood plasma to infect many other erythrocytes.
During the erythrocytic cycle, some merozoites
differentiate as male and female gametocytes (Sortt et
al., 1951; Zhu and Hollingdale, 1991).
Figure 3 is a simplified presentation of the
asexual cycle as seen in humans. Each merozoite
invades a red blood cell, and for two days multiplies
into more merozoites. The red blood cell full of
merozoites ruptures to release more merozoites. It is
this stage of the life cycle that causes disease and, too
often, death. Some merozoites change into the form
called gametocytes, which do not cause disease but
remain in the blood until they are cleared by drugs or
the immune system, or taken up by the bite of a
mosquito. For the sexual cycle to evolve, the
gametocytes of both sexes must be ingested in the
blood meal of another female Anopheles mosquito, as
shown in Figure 4. In the gut of the mosquito, the
male gametocyte forms spermatozoa, and the female
forms an ovum. Fertilization of the ovum takes place,
and the resting zygote changes shape, becomes
motile, and invades the gut wall.
Next, in the tissues of the gut wall,
sporogony of the parasite takes place. That is, there is
multiple fission of parasitic content, and numerous
sporozoites are formed. The sporozoites migrate
through the tissues of the mosquito to the salivary
glands where they wait to be injected into another
unsuspecting human host when the mosquito takes its
next blood meal (Saul et al., 1990; WHO, 1999;
Clement, 2000). The asexual cycle begins again, and
malaria is established in a new host.
Figure 3. Asexual cycle in humans (Source: Sullivan and Galland, 1994)
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Figure 4. Sexual cycle in gut of mosquito (Source: Beier, 1998)
At the completion of schizogony within the
red blood cells, each cycle lasting 24 to 72 hours
depending on the species of the infecting parasite,
newly developed merozoites are released by the lyses
of infected red cells accompanied by waste
substances, such as red cell membrane products,
hemozoin pigment, and other toxic factors such as
glycosylphosphatidylinositol (GPI). These products,
particularly the GPI, activate macrophages and
endothelial cells to secrete cytokines and
inflammatory mediators such as tumor necrosis factor
(TNF), IFN-ƴ, interleukin 1 (IL-1), IL-6, IL-8,
macrophage colony-stimulating factor, and
lymphotoxin, as well as superoxide and nitric oxide
(Nardin et al., 1982; Obi, 2013). The GPI tail was
reported to be common to several merozoite surface
proteins such as MSP-1, MSP-2, and MSP-4, as a key
parasite toxin (Clement, 2000).
1.5. Geographical classification of malaria
Geographical areas classified by intensity of
transmission (based upon percent of children, age 2–
9, with enlarged spleens and malaria parasitemia) are
as presented in Table 1.
Table 1: GEOGRAPHICAL AREAS CLASSIFIED BY INTENSITY OF TRANSMISSION
S/NO. Geographical areas Intensity of transmission
1 Holo-endemic Intense transmission with continuing high EIRs where everyone is
infected with malaria parasites all the time. In older children and adults,
parasites difficult to detect because of high levels of immunity, but
sufficient search will generally reveal the presence of parasites. Criteria:
Spleen and parasite rates of over 75%.
2 Hyper-endemic Regular, often seasonal transmission to all, but immunity in some
does not confer continuing protection at all times. Criteria: Spleen
and parasite rates from 50–75%.
3 Meso-endemic Transmission fairly regularly but at much lower levels. Danger is
occasional epidemics involving those with little immunity resulting in
fairly high mortality. Criteria: Spleen and parasite rates from 10–50%.
4 Hypo-endemic
Limited malaria
transmission and population with little or no immunity. Danger is
severe malaria epidemics involving all age groups. Criteria: Spleen and parasite
rates less than 10%.
Source: Richard (2007)
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1.6. Signs and symptoms
Human shows symptoms, usually about 10
days after being bitten by the infected mosquito
(Murphy and Breman, 2004). Malaria typically
produces a string of recurrent attacks, or paroxysms,
each of which has three stages such as chills,
followed by fever, and then sweating. The chill and
fever symptoms of malaria are associated with the
almost simultaneous release of many merozoites into
the bloodstream. The chill may last as long as one
hour.
The patient usually experiences headache,
fever, nausea and vomiting, diarrhea, anorexia,
tiredness, aching joints and muscle,
thrombocytopenia, immunosuppression,
coagulopathy, and central nervous system
manifestations during this time. These systemic
manifestations have been largely attributed to the
various cytokines released in response to the parasite
and red cell membrane products (Hoffman, 1996).
1.7. Laboratory diagnosis
Health care providers should suspect malaria
in anyone who has been in the tropics recently or
received a blood transfusion, and who develops a
fever and other signs that resemble the flu.
Laboratory examination of the malaria parasite is
usually done through microscopic inspection of
stained blood smear for the different stages of the
Plasmodium parasite. The thick film is often stained
with Giemsa stained (Cheesbrough, 2005) and
examined using x100 objective to view the inside of
the erythrocytes (Sacci et al., 2006). The common
features used to identify the malaria parasite on
Giemsa stained blood smears are dark red chromatin
bodies, pale purplish-blue cytoplasm, black pigments,
and rings that are usually in marginal location. The
ring form is the most common stage. The three
structures of the ring form of the parasite that are
commonly seen are the nucleus, cytoplasm and
vacuole. The infected erythrocytes contain a
developing trophozoite with a distinctive chromatin
dot.
1.8. Public health significance
Public health significance of a disease
equals the incidence and consequent disability and
death. In low-transmission areas this is a useful
formulation but in high-transmission holo-endemic
Africa, however, everyone is infected all the time and
neither incidence nor prevalence has much meaning
(Decastro et al., 2004). Malaria has continued to be a
major health problem in many parts of the world,
with over 2400 million people in about 100 countries
at risk of infection.
Nearly all the people who live in endemic
areas are exposed to infection repeatedly. Those who
survive malaria in childhood gradually build up some
immunity (U.S. Department of Health and Human
Services, National Institutes of Health, National
Institute of Allergy and Infectious Diseases, 2007). In
other areas, where the infection rate is low, people do
not develop immunity because they rarely are
exposed to the disease. The enormous loss of life,
days of labour, absenteeism in schools; the cost of
treatment of patients and the negative impact of the
disease on the socio-economic growth of a nation
makes malaria a major social and economic burden
(WHO, 1995; Hermsen et al., 2004).
1.9. Control strategies
Control strategies geared toward prevention of
the disease include general infrastructure, community
and household empowerment including the role of
vector control and environmental improvements to
reduce breeding. Residual insecticide (role for DDT),
bed-nets impregnated and personal protection.
Household use of anti-malarial for under-fives by
mothers; intermittent preventive therapy for pregnant
women and for under-fives.
Monitoring for anti-malarial resistance
everywhere; the protection of the host from the bite
of the mosquito using netting and repellants.
Treatment and prophylaxis using quinine, quinidine,
chloroquine, amodiaquine, and relatives;
Pyrimethamine. Others are Proquanil and
chlorproguanil, Mefloquine, Halofantrine,
Artemisinin and derivatives (qinghaosu). Antibiotics
such as tetracycline, clindamycin, rifampicin and
Primaquine are recommended. Traditional first-line
treatments using choloroquine, Sulphadoxine and /or
Pyrimethamine have lost much of their effectiveness
in many countries. This has led to the need for new
and more expensive antimalarial drugs, including
artemisinin combination therapy–ACT, now being
introduced by some governments (Okell et al., 2008;
Hoffman, 1996).
1.10. Holistic approach to fighting malaria
Key challenges right now are to produce
clinical-grade vaccines against malaria. Vaccine
development, especially asexual phase, but perhaps
sporozoite with new developments. Several different
malaria vaccine approaches, using the latest advances
in technology, are now in human clinical trials in
Report and Opinion 2014; 6(6) http://www.sciencepub.net/report
61
Africa, Asia, Europe, and the United States (Prescott
et al., 2005; Philip, 2011). Malaria vaccines could
save millions of lives and are likely to be hugely
cost-effective.
Much progress has been made in
understanding the immune mechanisms and in
identifying potential vaccine targets. Although
vaccine development is reaching maturity, it is still a
challenge and could be ten years before an effective
vaccine could be licensed and introduced. Methods
for better understanding of micro-epidemiological
variation and factors that contribute to its spread and
better diagnostic tests that rapidly and inexpensively
indicate drug resistance are necessary.
The new tools included drug development
and acceleration of those in the pipeline,
understanding of the molecular biology of the
parasite. Better understanding of the sporogonic cycle
to aid in re- engineering of the anopheline, improved
entomological field methods for better understanding
of micro-epidemiological variation and
understanding of the mechanism of drug resistance
and factors that contribute to its spread coupled with
better diagnostic tests that rapidly and inexpensively
indicate drug resistance.
Conclusion
A major turning point in recent years is the
development and implementation of a vaccine against
malaria which are critical to the long-term solution to
this age-old killer. Vaccines are directed against
sporozoites (plus), asexual forms (patarroyo) and
gametocytes (plus). This is referred to as
“transmission-blocking” Campaigns must address the
ecology and behaviour of local mosquito populations
in order to ensure that sufficient resources with broad
enough effects for all relevant components of the
local mosquito populations are introduced. A one-
size-fits-all campaign is not optimal, being wasteful
in some circumstances and insufficient in others;
local tailoring and design are important.
Correspondence to:
Solomon, leera, M.Sc., MNSM.
Department of Science Laboratory Technology,
School of Science and Technology, Rivers State
College of Arts and Science Rumuola,
P.M.B. 5936, Port Harcourt, Nigeria.
Tel.: +2348067973111
Email: sololeera@yahoo.com
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