……thy cunning seeds, Oh, million-thy cunning seeds, Oh, million-murdering Death.murdering Death.

……thy cunning seeds, Oh, million-thy cunning seeds, Oh, million-murdering Death.murdering Death.

Malaria…Malaria…Malaria…Malaria…

--Ronald RossRonald Ross

MalariaMalariaMalariaMalaria From the Italian “mal aria” - Bad Air

Also known as ague, marsh disease Descriptions of malaria go as far back as

3550 B.C. Caused by species of the genus

Plasmodium. There are nine sub-genera.

Three occur in mammals Four occur in birds Two occur in lizards

From the Italian “mal aria” - Bad Air Also known as ague, marsh disease Descriptions of malaria go as far back as

3550 B.C. Caused by species of the genus

Plasmodium. There are nine sub-genera.

Three occur in mammals Four occur in birds Two occur in lizards

TaxonomyTaxonomy

Kingdom: Animalia Phylum: Apicomplexa Class: Coccidia Order: Haemosporidia Genus: Plasmodium Species: vivax, falciparum, ovale &

malariae

Kingdom: Animalia Phylum: Apicomplexa Class: Coccidia Order: Haemosporidia Genus: Plasmodium Species: vivax, falciparum, ovale &

malariae

Parasitic Human MalariasParasitic Human Malarias

Of the nine sub-genera, there are four that are typically parasitic to humans P. falciparum P. vivax P. malariae P. ovale

Each is more closely related to other Plasmodium lineages than each other

Of the nine sub-genera, there are four that are typically parasitic to humans P. falciparum P. vivax P. malariae P. ovale

Each is more closely related to other Plasmodium lineages than each other

Hosts of PlasmodiumHosts of Plasmodium

Plasmodium requires two types of host Vertebrate and Invertebrate

Definitive host is the invertebrate (Anopheles spp.)

Sexual reproduction occurs

Intermediate host is the vertebrate (Humans)

Asexual reproduction occurs

Plasmodium requires two types of host Vertebrate and Invertebrate

Definitive host is the invertebrate (Anopheles spp.)

Sexual reproduction occurs

Intermediate host is the vertebrate (Humans)

Asexual reproduction occurs

Reproduction and maturation in definitive

host

Reproduction and maturation in definitive

host Anopheles spp. ingest erythrocytes containing

Plasmodium gametocytes If an unsuitable species of mosquito ingests Plasmodium

gametocytes, they are digested Macrogametocytes and Microgametocytes are

released from erythrocytes Macrogametocyte matures into macrogamete (Nucleus

shift) Microgametocyte matures into microgamete

(exflagellation) Microgametes fertilize macrogametes

Diploid zygote becomes a motile ookinete

Anopheles spp. ingest erythrocytes containing Plasmodium gametocytes If an unsuitable species of mosquito ingests Plasmodium

gametocytes, they are digested Macrogametocytes and Microgametocytes are

released from erythrocytes Macrogametocyte matures into macrogamete (Nucleus

shift) Microgametocyte matures into microgamete

(exflagellation) Microgametes fertilize macrogametes

Diploid zygote becomes a motile ookinete

Reproduction and maturation in definitive host, cont’d

Reproduction and maturation in definitive host, cont’d

The motile ookinete penetrates the stomach lining of the mosquito Once there, the ookinete begins to form an oocyst

Sporoblasts begin to form within the oocyst Sporoblasts divide repeatedly to form sporozoites

Sporozoites break out of the oocyst and migrate throughout the body of the mosquito This entire process (from ookinete to sporozite) can take from

10-21 days Some sporozoites end up in the salivary gland of

Anopheles, where they are transmitted when the mosquito takes a blood meal

The motile ookinete penetrates the stomach lining of the mosquito Once there, the ookinete begins to form an oocyst

Sporoblasts begin to form within the oocyst Sporoblasts divide repeatedly to form sporozoites

Sporozoites break out of the oocyst and migrate throughout the body of the mosquito This entire process (from ookinete to sporozite) can take from

10-21 days Some sporozoites end up in the salivary gland of

Anopheles, where they are transmitted when the mosquito takes a blood meal

Life cycle illustrationLife cycle illustration

Reproduction and maturation in the intermediate host

Reproduction and maturation in the intermediate host

Sporozoites injected by Anopheles migrate to liver from the bloodstream Covered in a protein that aids in access to

hepatocytes Entry into hepatocytes is the beginning

of the pre-erythrocytic cycle Upon entry into hepatocytes, sporozoites

become feeding trophozoites Some sporozoites go dormant indefinitely

(depending on Plasmodium spp) After a week, trophozoites are mature

At this point, trophozoites undergo schizogony

Sporozoites injected by Anopheles migrate to liver from the bloodstream Covered in a protein that aids in access to

hepatocytes Entry into hepatocytes is the beginning

of the pre-erythrocytic cycle Upon entry into hepatocytes, sporozoites

become feeding trophozoites Some sporozoites go dormant indefinitely

(depending on Plasmodium spp) After a week, trophozoites are mature

At this point, trophozoites undergo schizogony

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

Reproduction and maturation in the intermediate host,

cont’d

Reproduction and maturation in the intermediate host,

cont’d Merozoites re-enter the blood from the liver and penetrate red blood cells Upon entry, merozoites become trophozoites again

At this stage, trophozoites display distinctive “signet-ring” appearance, feed on hemoglobin

After maturing in the RBC, trophozoites again form a schizont, creating more merozoites

RBC ruptures, releasing merozoites, and parasite metabolic wastes, which causes many of the symptoms of malaria One of these, hemozoin, a byproduct of parasitic

consumption of hemoglobin, is toxic, and causes inhibition of macrophages

After a number of generations, some merozoites become macro and microgametocytes Ingestion of gametes causes infection in

Anopheles If not ingested, gametes are phagocytized

Merozoites re-enter the blood from the liver and penetrate red blood cells Upon entry, merozoites become trophozoites again

At this stage, trophozoites display distinctive “signet-ring” appearance, feed on hemoglobin

After maturing in the RBC, trophozoites again form a schizont, creating more merozoites

RBC ruptures, releasing merozoites, and parasite metabolic wastes, which causes many of the symptoms of malaria One of these, hemozoin, a byproduct of parasitic

consumption of hemoglobin, is toxic, and causes inhibition of macrophages

After a number of generations, some merozoites become macro and microgametocytes Ingestion of gametes causes infection in

Anopheles If not ingested, gametes are phagocytized

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

Human cycleHuman cycle

P. falciparumP. falciparum Is the most dangerous of the malaria parasites

Accounts for 50 % of all malaria cases Causes malignant tertian malaria Symptoms appear 9 to 14 days after initial infection Parasitemia levels are extremely high

Up to 65% of erythrocytes infected Schizonts grow in liver cells

Schizont ruptures in 5 1/2 days, releasing 30,000 merozoites

Schizonts are more asymmetrical than other Plasmodium spp.

Infected RBCs can attach to uninfected RBCs, forming rosettes Rosettes can clog venules

Falciparum trophozoites secrete proteins that cause deformations of erythrocytes

Falciparum trophozoites extend pseudopodia, but are not as active as P.vivax trophozoites

Falciparum gametocytes are crescent shaped

Is the most dangerous of the malaria parasites Accounts for 50 % of all malaria cases Causes malignant tertian malaria Symptoms appear 9 to 14 days after initial infection Parasitemia levels are extremely high

Up to 65% of erythrocytes infected Schizonts grow in liver cells

Schizont ruptures in 5 1/2 days, releasing 30,000 merozoites

Schizonts are more asymmetrical than other Plasmodium spp.

Infected RBCs can attach to uninfected RBCs, forming rosettes Rosettes can clog venules

Falciparum trophozoites secrete proteins that cause deformations of erythrocytes

Falciparum trophozoites extend pseudopodia, but are not as active as P.vivax trophozoites

Falciparum gametocytes are crescent shaped

P.vivaxP.vivax Trophozoites of P.vivax are much more motile than other

plasmodium spp. This motility caused Italian researchers to nickname it “vivace”,

Italian for “quick and lively” P.vivax flourishes in temperate zones

Most cases of P.vivax malaria now occur in Asia P.vivax is common in North Africa, but not in tropical Africa

Africans have a natural resistance to this form of malaria Schizonts are formed in the liver parenchyma and release 10,000

merozoites upon maturation Trophozoites cannot penetrate mature red cells

In addition, merozoites can only penetrate RBCs with mediated receptor sites Receptor sites are genetically determined, conferring

resistance A defining characteristic of P.vivax is the development of

hypnozoites Hypnozoites cause relapse of malarial infection

Trophozoites of P.vivax are much more motile than other plasmodium spp. This motility caused Italian researchers to nickname it “vivace”,

Italian for “quick and lively” P.vivax flourishes in temperate zones

Most cases of P.vivax malaria now occur in Asia P.vivax is common in North Africa, but not in tropical Africa

Africans have a natural resistance to this form of malaria Schizonts are formed in the liver parenchyma and release 10,000

merozoites upon maturation Trophozoites cannot penetrate mature red cells

In addition, merozoites can only penetrate RBCs with mediated receptor sites Receptor sites are genetically determined, conferring

resistance A defining characteristic of P.vivax is the development of

hypnozoites Hypnozoites cause relapse of malarial infection

P.vivax, cont’dP.vivax, cont’d

P.vivax gametocytes are rounded It appears that P.vivax gametocytes do not require

several generations to appear Causes benign tertian malaria Symptoms appear between 12 and 18 days after

initial infection

P.vivax gametocytes are rounded It appears that P.vivax gametocytes do not require

several generations to appear Causes benign tertian malaria Symptoms appear between 12 and 18 days after

initial infection

P. MalariaeP. Malariae Causes quartan malaria

Causes paroxysms every 72 hours

Is cosmopolitan, but does not have continuous distribution Is found in many regions of tropical Africa, Asia,

South America, and even Europe

Is thought to be the only Plasmodium organism that lives in wild animals

Parasitemia levels are low One parasite per 20,000 red cells

Symptoms appear between 18 and 40 days after initial infection

Causes quartan malaria Causes paroxysms every 72 hours

Is cosmopolitan, but does not have continuous distribution Is found in many regions of tropical Africa, Asia,

South America, and even Europe

Is thought to be the only Plasmodium organism that lives in wild animals

Parasitemia levels are low One parasite per 20,000 red cells

Symptoms appear between 18 and 40 days after initial infection

P. OvaleP. Ovale

Rarest of the four malaria parasites Causes tertian malaria Symptoms appear between 12 and 18 days after initial

infection Common to western coastal Africa, also found in India,

the Philippines, New Guinea, and Vietnam Difficult to diagnose due to its similarity to P.vivax Gametocytes take longer to appear in blood than those

of other species

Rarest of the four malaria parasites Causes tertian malaria Symptoms appear between 12 and 18 days after initial

infection Common to western coastal Africa, also found in India,

the Philippines, New Guinea, and Vietnam Difficult to diagnose due to its similarity to P.vivax Gametocytes take longer to appear in blood than those

of other species

SymptomsSymptoms Common symptoms

Fever Chills Headache Sweats Fatigue Nausea and vomiting

P.falciparum Causes Cerebral Malaria, which accounts for 10 % of hospital

admitted malaria cases and 80% Mild jaundince Enlarged liver Increased respiratory rate Pulmonary edema

P.vivax P.ovale P.malariae

Common symptoms Fever Chills Headache Sweats Fatigue Nausea and vomiting

P.falciparum Causes Cerebral Malaria, which accounts for 10 % of hospital

admitted malaria cases and 80% Mild jaundince Enlarged liver Increased respiratory rate Pulmonary edema

P.vivax P.ovale P.malariae

PathogenesisPathogenesis

Clinical signs of malaria can be attributed to two factors Host inflammatory response

Produces chills and fever Correlated with maturation of merozoites, rupture

of RBCs Toxins released from burst RBCs can stimulate

secretion of TNF by macrophages TNF overproduction and toxicity can cause most

or all of malaria symptoms Anemia

Caused by destruction of RBCs

Clinical signs of malaria can be attributed to two factors Host inflammatory response

Produces chills and fever Correlated with maturation of merozoites, rupture

of RBCs Toxins released from burst RBCs can stimulate

secretion of TNF by macrophages TNF overproduction and toxicity can cause most

or all of malaria symptoms Anemia

Caused by destruction of RBCs

ControlControl

DiagnosisDiagnosis Diagnosis of malaria can be difficult, because

many symptoms are general Demonstration of the parasites in peripheral

blood is important to a diagnosis Individuals with very low parasitemias can often

be overlooked Several effective methods for diagnosis have

been developed Fluorescent dye staining DNA probe specific for P.falciparum PCR diagnostics ELISA detection of P.falciparum antigen

Diagnosis of malaria can be difficult, because many symptoms are general

Demonstration of the parasites in peripheral blood is important to a diagnosis

Individuals with very low parasitemias can often be overlooked

Several effective methods for diagnosis have been developed Fluorescent dye staining DNA probe specific for P.falciparum PCR diagnostics ELISA detection of P.falciparum antigen

TreatmentTreatment Treatment of malaria focuses on eradication of the

blood parasites Several drugs can be administered, such as

Chloroquine Quinine Doxycycline Malarone Lariam Fansidar

Treatment is dependent on several factors, including: Type of malaria Drug-resistance

Nearly all strains of P.falciparum are now chloroquine resistant, in addition to developing resistance to nearly all other currently available antimalarial drugs

P.vivax has also developed resistance to chloroquine and primaquine, though they are not as widespread as P.falciparum

Treatment of malaria focuses on eradication of the blood parasites Several drugs can be administered, such as

Chloroquine Quinine Doxycycline Malarone Lariam Fansidar

Treatment is dependent on several factors, including: Type of malaria Drug-resistance

Nearly all strains of P.falciparum are now chloroquine resistant, in addition to developing resistance to nearly all other currently available antimalarial drugs

P.vivax has also developed resistance to chloroquine and primaquine, though they are not as widespread as P.falciparum

Impact of malariaImpact of malaria According to the WHO - World Malaria Report 2005:

At the end of 2004, some 3.2 billion people lived in areas at risk of malaria transmission in 107 countries and territories.

Between 350 and 500 million clinical episodes of malaria occur every year.

At least one million deaths occur every year due to malaria.

About 60% of the cases of malaria worldwide and more than 80% of the malaria deaths worldwide occur in Africa south of the Sahara. In 1995, 990,000 deaths reported in some African countries where

malaria infection is high (2,700 deaths per day) In 2000, 84% of the blood transfusion given in Kinshasa, Congo

were for anemia caused by malaria

According to the WHO - World Malaria Report 2005: At the end of 2004, some 3.2 billion people lived in areas

at risk of malaria transmission in 107 countries and territories.

Between 350 and 500 million clinical episodes of malaria occur every year.

At least one million deaths occur every year due to malaria.

About 60% of the cases of malaria worldwide and more than 80% of the malaria deaths worldwide occur in Africa south of the Sahara. In 1995, 990,000 deaths reported in some African countries where

malaria infection is high (2,700 deaths per day) In 2000, 84% of the blood transfusion given in Kinshasa, Congo

were for anemia caused by malaria