Plasmodium And Malaria Basics

Front 1

Describe the life cycle of plasmodium and name labeled parts

Back 1

The malaria parasite life cycle involves two hosts. During a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the human host . Sporozoites infect liver cells and mature into schizonts , which rupture and release merozoites . (Of note, in P. vivax and P. ovale a dormant stage [hypnozoites] can persist in the liver and cause relapses by invading the bloodstream weeks, or even years later.) After this initial replication in the liver (exo-erythrocytic schizogony ), the parasites undergo asexual multiplication in the erythrocytes (erythrocytic schizogony ). Merozoites infect red blood cells . The ring stage trophozoites mature into schizonts, which rupture releasing merozoites . Some parasites differentiate into sexual erythrocytic stages (gametocytes) . Blood stage parasites are responsible for the clinical manifestations of the disease.

The gametocytes, male (microgametocytes) and female (macrogametocytes), are ingested by an Anopheles mosquito during a blood meal . The parasites’ multiplication in the mosquito is known as the sporogonic cycle . While in the mosquito's stomach, the microgametes penetrate the macrogametes generating zygotes . The zygotes in turn become motile and elongated (ookinetes) which invade the midgut wall of the mosquito where they develop into oocysts . The oocysts grow, rupture, and release sporozoites , which make their way to the mosquito's salivary glands. Inoculation of the sporozoites into a new human host perpetuates the malaria life cycle.

Front 2

what is shizogony?

Back 2

Following invasion of a liver cell
the parasite first undergoes a round of asexual replication called merogony,
or schizogony, followed by multiple rounds of merogony in the erythrocytes

Front 3

What is another name for schizogony?

Back 3

merogony

Front 4

What is gametogony and where does it occur?

Back 4

the formation of sexual forms, begins
within the erythrocytes of the vertebrate host and is completed within the
mosquito

Front 5

What is sporogony and where does it occur?

Back 5

within the mosquito another round of asexual replication called sporogony takes place

Front 6

Compare the nomenclature of generalized apicomplexan life cycles to plasmodium

Back 6

- merogony in Plasmodium species is almost always referred to as schizogony

gametogony in Plasmodium is usually separated into two phases called gametocytogenesis and gametogenesis.

Front 7

where do you find sporozoites?

Back 7

Sporozoites are injected with the saliva during mosquito feeding and are
carried to the liver via the circulatory system.

Within 30–60 minutes the
sporozoites find the liver and invade a liver cell. The sporozoites gain access
to the hepatocytes by first invading and traversing a macrophage within the
liver called a Kupffer cell.

Front 8

what is an exoerythrocytic schizont

Back 8

(or pre-erythrocytic)

After exiting the Kupffer
cell, the sporozoite can traverse several hepatocytes before developing into an exoerythrocytic (or pre-erythrocytic) schizont

Front 9

What is schizogony?

Back 9

Schizogony refers
to an asexual replicative process in which the parasite undergoes multiple
rounds of nuclear division without cytoplasmic division followed by a budding, or segmentation

Front 10

When schizogony ends, what does it form? where do you find them?

Back 10

merozoites. The merozoites
are released into the circulatory system following rupture of the host hepatocytes.

Front 11

what is the hypnozoite stage?
What zoite is involved in the hypnozoite stage?

Back 11

sporozoites do not immediately
undergo asexual replication, but enter a dormant phase known as the hypnozoite
stage. The hypnozoite can reactivate and undergo schizogony at a
later time resulting in a relapse.

Front 12

what species can enter the hypnozoite stage?

Back 12

In P. vivax and P. ovale some of the sporozoites do not immediately
undergo asexual replication, but enter a dormant phase known as the hypnozoite stage.

Front 13

describe relapse

Back 13

Relapse has a specific meaning in regard to malaria and refers to the reactivation of the infection via hypnozoites.

Front 14

describe recrudescence

Back 14

Recrudescence is used to describe the situation in which parasitemia in
the blood falls below detectable levels and then later increases to a patent
parasitemia.

Front 15

what zoite invades erythrocytes?

Back 15

Merozoites released from the infected liver cells invade erythrocytes

Front 16

what is the invasion mechanism?

Back 16

During the invasion process the invasive forms (e.g., merozoites and sporozoites) of most apicomplexan species orientate themselves
so that the apical end is juxtaposed to the host cell.

The contents of the rhoptries, micronemes, and dense granules are expelled as the parasite
invades. Experiments in Toxoplasma gondii indicate that the micronemes
are expelled first and the expulsion occurs with initial contact between
the parasite and host. The rhoptries are discharged immediately after the
micronemes and dense granule contents are released last.

Many dense granules are extruded after the parasite has completed its entry, and thus probably play a role in modifying the host cell.

Front 17

Describe the invasion mechanism

Back 17

During the invasion process the invasive forms (e.g.,
merozoites and sporozoites) of most apicomplexan species orientate themselves
so that the apical end is juxtaposed to the host cell. The contents of
the rhoptries, micronemes, and dense granules are expelled as the parasite
invades. Experiments in Toxoplasma gondii indicate that the micronemes are expelled first and the expulsion occurs with initial contact between the parasite and host.

The rhoptries are discharged immediately after the micronemes and dense granule contents are released last.

Many dense granules are extruded after the parasite has completed its entry, and thus probably play a role in modifying the host cell.

Front 18

What is the trophic period

Back 18

intracellular parasite undergoes trophic phase

young trophozoite called ‘ring form’

ingests host hemoglobin
- cytostome
- food vacuole
- hemozoin (malarial pigment)

After entering the erythrocyte the parasite undergoes a trophic period
followed by an asexual replication. The young trophozoite is often called a
ring form due to its morphology in Giemsa-stained blood smears (Figure
15.2). As the parasite increases in size this ring morphology disappears and it is called a trophozoite.

During the trophic period the parasite ingests the
host cell cytoplasm and breaks down the hemoglobin into amino acids.

Front 19

What is hemozoin?

Back 19

A by-product of the hemoglobin digestion is the malaria pigment, or hemozoin.

golden-brown to black granules

Front 20

What are th blood stages of a malaria parasite?

Back 20

(A) Ring stage of P. falciparum.

(B) Trophozoite of P. vivax. Note the stippling
known as Schüffner’s granules within the
infected erythrocyte.

(C) Multinucleated
schizont stage of P. malariae.

Front 21

What marks the end of the trophozoite stage?

What stage is it now?

Back 21

Nuclear division marks the end of the trophozoite stage and the beginning
of the schizont stage.

Front 22

What is erythrocytic schizogony?

Back 22

nuclear division = begin schizont stage

6-40 nuclei

budding merozoites = segmenter

erythrocyte rupture releases merozoites

Erythrocytic schizogony consists of three to
five rounds (depending on species) of nuclear replication followed by a
budding process. Budding involves the migration of the nuclei and other
organelles to the plasma membrane where they are incorporated into the
forming merozoite. Late stage schizonts in which the individual merozoites
become discernable are called segmenters. The host erythrocyte ruptures
and releases the merozoites.

Front 23

What causes the intermittent fever paroxysms?

Back 23

The blood-stage parasites within a host usually undergo a synchronous schizogony resulting in a simultaneous
rupture of the infected erythrocytes and release of merozoites.

The concomitant release of antigens and waste products with the rupture of the infected erythrocyte accounts for the intermittent fever paroxysms associated
with malaria.

Front 24

what is gametocytogenesis?

Back 24

As an alternative to schizogony some of the parasites will undergo a
sexual cycle and differentiate into either micro- or macrogametocytes.
Gametocytes circulate in the peripheral blood stream and are capable of
forming gametes if ingested by a mosquito. They do not cause pathology in the human host and will disappear from the circulation if not taken up by a mosquito.

The factors involved in the induction of gametocytogenesis
are not known.

Host immunity and drug treatment may result in a higher proportion of gametocytes as compared with asexual forms.

Front 25

What is gametogenesis?

Back 25

The next step in sexual development is gametogenesis, or the formation
of micro- and macrogametes. After ingestion by the mosquito, the gametocytes
escape from the erythrocyte and undergo gametogenesis within the
mosquito gut.

Front 26

what are microgametes?

Back 26

The microgametocyte
undergoes three rounds of nuclear replication. Then these eight nuclei
become associated with flagella that emerge from the body of the microgametocyte
to form the microgametes. This process is readily observable by
light microscopy due to the thrashing flagella and is called exflagellation.

Front 27

What are macrogametes?

Back 27

the macrogametocytes mature into macrogametes. However, at
the morphological level this is much less dramatic than the exflagellation
exhibited by the microgametocytes

Front 28

What is exflagellation?

Back 28

Flagella that emerge from the body of the microgametocyte to form the microgametes. This process is readily observable by light microscopy due to the thrashing flagella and is called exflagellation.

Exflagellation occurs spontaneously when infected blood is exposed
to air.

Front 29

What are the critical factors involved in the induction of gametogenesis?

Back 29

Critical factors involved in the induction of this gametogenesis are
1) a decrease in temperature

2) decrease in the dissolved carbon dioxide

3) the subsequent increase in pH to above 8.0
1-3 all occur spontaneously after expoure to air.

4) decrease in pH: a mosquito-derived exflagellation factor also promotes the formation
of gametes at a lower pH.

Front 30

What does xanthurenic acid do?

Back 30

mosquito-derived exflagellation factor has been identified as xanthurenic acid, a metabolite from insects.

Xanthurenic acid lowers the permissive pH
for exflagellation and is probably a biological cue for the parasite to undergo
gametogenesis.

Front 31

Summarize gametogenesis

Back 31

occurs in mosquito gut

‘exflagellation’ most obvious
- 3X nuclear replication
- 8 microgametes formed

one macrogamete

exposure to air induces
- decreased temperature (2-3oC)
- increased pH (8-8.3)
- result of decreased pCO2

gametocyte activating factor in mosquito
- xanthurenic acid

Front 32

What am I?

Back 32

Exflagellation

Front 33

Summarize gametocytogenesis

Back 33

alternative to asexual replication

induction factors not known
- drug treatment increase #'s
- immune response increases #'s

ring --> gametocyte
- Pf : ~10 days
- others: ~same as schizogony

sexual dimorphism
- microgametocytes (♂)
- macrogametocytes (♀)

no pathology

no replication

infective stage for mosquito

Front 34

Summarize ookinete formation

Back 34

fusion of micro- and macrogametes

zygote --> ookinete (~24 hr)

ookinete transverses gut

epithelium ('trans-invasion')

Front 35

summarize sporogony

Back 35

summarize sporogony

ookinete --> oocyst
between epithelium and basal lamina

asexual replication --> sporozoites

sporozoites released

sporozoites migrate through hemocoel

sporozoites 'invade' salivary glands

9-21 days (gametes --> sporozoites)

Front 36

What is an ookinete?

Back 36

gamete fusion (i.e., fertilization), the resulting
zygote develops into an ookinete.

The ookinete is a motile and invasive stage which can traverse both the peritrophic membrane and the midgut epithelium of the mosquito.

Traversing the peritrophic membrane probably
involves secretion of chitinases.

Penetration of the midgut epithelium involves invading and exiting several epithelial cells before emerging on
the basal side of the epithelium.

Front 37

What is sporogony?

Back 37

After the ookinete reaches the extracellular space between the epithelial cells and the basal lamina, the ookinete develops into an oocyst.

Oocysts undergo an asexual replication, called sporogony, which culminates in the production of several thousand sporozoites.

After finding the salivary glands, the sporozoites invade and traverse the salivary gland epithelial cells and come to lie within its lumen. These sporozoites are expelled into the vertebrate host as the mosquito takes a blood meal.

Front 38

What are the three distinct invasive malaria life cycle stages?

Back 38

three distinct invasive stages: sporozoites,
merozoites, and ookinetes.

Sporozoites traverse the salivary glands and
invade hepatocytes;

merozoites invade erythrocytes;

ookinetes traverse
the mosquito gut epithelium.

All invasive stages are characterized by apical
organelles and can invade or pass through host cells.

Front 39

What are the two distinct merogony types obsevrved in malaria life cycle?

Back 39

The first, called exoerythrocytic schizogony, occurs in the liver and is initiated by the sporozoite.

Second, the resulting merozoites then invade erythrocytes and undergo repeated rounds of merogony called
erythrocytic schizogony.

Some of the merozoites produced from the erythrocytic schizogony will undergo gametogony.

Front 40

Describe the two plasmodium gametogony phases

Back 40

1) gametocytogenesis occurring in the bloodstream
of the vertebrate host,

2) gametogenesis taking place in the mosquito gut.

The gametes fuse to become a zygote which first develops into an ookinete
and then becomes an oocyst where sporogony takes place.

Front 41

Summarize the invasive stages

Back 41

Invasive Stages

Merozoite -->
erythrocytes

Sporozoite --> salivary glands and hepatocytes

Ookinete --> epithelium

Front 42

Malaria epi info

Back 42

causative agent = Plasmodium species
40% of world’s population lives in endemic areas
3-500 million clinical cases per year
1.5-2.7 million deaths (90% Africa)

Front 43

Who identified malaria

Back 43

Laveran 1880

Front 44

Who demonstrated malaria's mosqutito transmission

Back 44

Ross 1898

Front 45

Who described malaria's liver stage?

Back 45

Garnham 1940s

Front 46

What stage are most of the pathology and clinical manifestations associated with malaria found?

Back 46

the asexual erythrocytic stage parasites. Tissue
schizonts and gametocytes cause little, if any, pathology

Front 47

The severity of malaria attacks are dependent onw what factors?

Back 47

manifestations and severity depend on parasite species and host status: immunity, general health, nutritional state, genetics

Front 48

How long do recrudenseces or relapses occur?

Back 48

recrudescences or relapses can occur over months or years

Front 49

What are the three ways you can get malaria?

Back 49

natural (sporozoites/Anopheles)

blood transfusions

congenital : relatively rare although placenta is heavily infected

Front 50

What is different about malaria that was transmitted via blood transfusions?

Back 50

shorter incubation period
fatality risk (P. falciparum)
no relapses possible (vivax/ovale)

Mechanical transmission of infected blood via blood
transfusions or sharing syringes will result in a shorter incubation period
because there is no liver stage. There is also an increased risk of fatality with mechanically transmitted P. falciparum. The lack of the liver stage infection
as a result of mechanical transmission also precludes relapses in P. vivax or P. ovale infections.
Table

Front 51

what are the prepatent periods for Pf, Pv, Po, Pm?

Back 51

Prepatent period (days)
Pf, Pv, Po, Pm
6–9, 8–12, 10–14, and 15–18, respectively

Front 52

What are the incubation periods for Pf, Pv, Po, and Pm?

Back 52

Incubation period (days)
Pf, Pv, Po, and Pm?
7–14, 12–17, 16–18, 18–40, respectively

Front 53

What are the merozoite maturation (days) for Pf, Pv, Po, and Pm?

Back 53

Merozoite maturation (days)
Pf, Pv, Po, and Pm
5–7, 6–8, 9, 12–16, respectively

Front 54

How many merozoits are produced for Pf, Pv, Po, and Pm?

Back 54

Merozoites produced
Pf, Pv, Po, and Pm
40,000; 10,000; 15,000; 2000, respectively

Front 55

What are the prodromal symptoms and when do they occur?

Back 55

All four species can exhibit nonspecific prodromal symptoms a few days
before the first febrile attack.

These prodromal symptoms are generally
described as flu-like and include: headache, slight fever, muscle pain, anorexia, nausea, and lassitude.

The symptoms tend to correlate with increasing
numbers of parasites in the blood.

Front 56

What are malaria paroxysms?

Back 56

Febrile Attack (Malaria Paroxysm)

prodromal symptoms will be
followed by febrile attacks also known as malarial paroxysms. These paroxysms
exhibit periodicities of 48 hours for P. vivax, P. ovale, and P. falciparum,
and a 72-hour periodicity for P. malariae.

periodic febrile episodes every 48 or 72 hours alternating with symptom-free periods

initially fever may be irregular before developing periodicity

may be accompanied by splenomegaly, hepato-megaly (slight jaundice), hemolytic anemia

Front 57

What is the malaria paroxysm cold stage?

Back 57

The malarial paroxysm usually lasts 4–8 hours and begins
with a sudden onset of chills in which the patient experiences an intense
feeling of cold despite having an elevated temperature.

Cold stage:
Feeling of intense cold
Vigorous shivering
Lasts 15–60 minutes

Front 58

What is the malaria paroxysm hot stage?

Back 58

Immediately following this cold stage is the hot stage. The patient feels an intense heat accompanied by severe headache.
Fatigue, dizziness, anorexia, myalgia, and nausea will often be associated with the hot stage.

Hot stage:
Intense heat
Dry burning skin
Throbbing headache
Lasts 2–6 hours

Front 59

What is the malaria paroxysm sweating stage?

Back 59

Next a period of profuse sweating will ensue and the fever will start to decline. The
patient is exhausted and weak and will usually fall asleep. Upon awakening
the patient generally feels well, other than being tired, and does not exhibit
symptoms until the onset of the next paroxysm.

Sweating stage:
Profuse sweating
Declining temperature
Exhausted and weak --> sleep
Lasts 2–4 hours

Front 60

What are the malaria paraxysms associated with?

Back 60

paroxysms associated with synchrony of merozoite release
between paroxysms temperature is normal and patient feels well
falciparum may not exhi-bit classic paroxysms
continuous fever
24 hr periodicity

Front 61

What species are tertian verses quartan malaria?

Back 61

Pf, Pv, Po - tertian
Pm - quartan

Front 62

name the species fever pattern

Back 62

Pf, Pv/Po, Pm

Front 63

What is the relationship between fever and TNF-alpha levels?

Back 63

Body temperature (circles) and serum TNF-a levels (triangles) were measured during the malarial paroxysm. The hatched box denotes the period of intense shivering, the black box the hot stage and the gray box denotes profuse sweating.

Presumably antigens or toxins are released into the bloodstream and tissues when the infected erythrocyte ruptures.

These released parasite products then stimulate macrophages and other immune effector cells to produce TNF-a and
other cytokines leading to the febrile attacks.

It has been suggested that a major component of this presumptive toxin might be glycosylphosphatidylinositol derived from various parasite proteins.

Front 64

Describe the severity of initial paroxysms for Pv, Po, Pm, and Pf

Back 64

Pv: Moderate to severe
Po: Mild
Pm:Mild to moderate
Pf: Severe

Front 65

What is the average parasiemia (mm3) for Pv, Po, Pm, and Pf?

Back 65

Pv: 20,000
Po: 9,000
Pm: 6,000
Pf: 50,000–500,000

Front 66

What is the maximum parasiemia (mm3) for Pv, Po, Pm, and Pf?

Back 66

Pv: 50,000
Po: 30,000
Pm: 20,000
Pf: 2,500,000(half of all RBCs are infected)

Front 67

What is the symptom duration (untreated) for Pv, Po, Pm, and Pf

Back 67

Pv: 3–8+ weeks
Po: 2–3 weeks
Pm: 3–24 weeks
Pf: 2–3 weeks

Front 68

What is the maximum infection duration (untreated) for Pv, Po, Pm, and Pf

Back 68

the maximum infection duration (untreated)
Pv: 5–8 years*
Po: 12–20 months*
Pm: 20–50+ years
Pf: 6–17 months

* Includes relapses from the hypnozoite stage.

Relapses due to the activation of P. vivax hypnozoites can occur for several years. P. ovale is the most benign in that the paroxysms tend to be mild and of short duration and relapses seldom occur more than one year after the initial infection.

Front 69

What is the level of anemia for Pv, Po, Pm, and Pf

Back 69

Pv: ++
Po: +
Pm: ++
Pf: ++++

Front 70

Which species has renal complications?

Back 70

Pm

P. malariae is the most chronic, though, and recrudescences have
been documented several decades after the initial infection. This chronicity
is sometimes associated with renal complications, which are probably
due to the deposition of antigen–antibody complexes in the glomeruli of the kidney.

Front 71

Which species has cerebral complications

Back 71

Pf

P. falciparum can produce serious disease with mortal consequences. This increased morbidity and mortality is due in large part to the high parasitemias associated with P. falciparum infections. These potentially high parasitemias are partly the result of the large number of merozoites produced and the ability of P. falciparum to invade all erythrocytes.

Front 72

What RBCs do the different species prefer?

Back 72

P. falciparum to
invade all erythrocytes.

P. vivax and P. ovale prefer reticulocytes (i.e., immature erythrocytes)

P. malariae prefers senescent erythrocytes.

Front 73

What is associated with higher parasitemias in Pf?

Back 73

Higher parasitemias are also associated with the cytoadherence and sequestration of P. falciparum.

This sequestration in
the tissues minimizes removal of infected erythrocytes by the spleen and can be viewed as an avoidance of the immune system. In addition, the
cytoadherence to the endothelial cells of the capillaries allows for a more efficient erythrocyte invasion because the blood flow is much slower.

The low oxygen tension found in the deep tissues is also metabolically favorable for parasite growth.

Front 74

Describe anti-malarial immunity

Back 74

P. falciparum can be lethal in non-immune (eg., children, expatriates)

paroxysms become less severe and irregular as infection progresses

semi-immune may exhibit little (1-2 days fever) or no symptoms

Immunity against malaria is slow to develop and requires multiple exposures.

- slow to develop
- short lived
- - - ‘premunition’
- non-sterilizing
- - - lower parasitemia
- - - less symptoms

Front 75

What is anti-parasite immunity?

Back 75

immune response prevents merozoite invasion, eliminates infected erythrocytes, etc.

the “antiparasite” immunity which lowers the parasitemia

Front 76

What is anti-disease immunity?

Back 76

eg., neutralization of exo-antigens or toxic effects

The observation that asymptomatic individuals can exhibit high levels
of parasitemia has led to the concept of “antidisease” immunity.

antigens or toxins released by the infected erythrocyte might stimulate the
production of proinflammatory cytokines. Antibodies against these exoantigens
could neutralize their toxic effects and thus lead to an antidisease immunity.

People from endemic areas develop antibodies specific for the parasite glycosylphosphatidylinositol, a proposed parasite toxin, and some studies show a correlation between these antibodies and improved clinical
outcomes.