Parasitology Part 5: Plasmodium

Plasmodium vivax Pathology 1. Duffy blood groups (a) What are they? (b) Two alleles code for RBC receptors (c) One allele codes for a lack of RBC receptors (d) Common (≥40%) in people of West African descent 2. Recently shown to cause cerebral malaria and severe anemia 3. Periodicity. Symptoms? 4. Duffy glycoprotein (a) What is this? 5. Limitation?

(1a) Certain RBC receptors required for merozoite penetration 3. Fever/chills episodes every 48 hours 4. - Receptor for chemicals secreted by blood cells during inflammation - Receptor for Plasmodium vivax 5. RBCs that lack Duffy antigens relatively resistant to invasion by P. vivax. Many of them don't have duffy blood group. Without this, vivax cannot enter and this makes host immune to this parasite. This benefits the host and is selected for

Plasmodium vivax 1. Distribution (a) Where does it occur? (b) Where were eradication programs successful? (c) Where does it mainly occur? 2. Prevalence?

(1a) Occurs in temperate zones more than tropical - Once the most widespread as far north as Siberia (1b) Eradication programs in temperate zones successful (1c) in Asia and North Africa 2. Causes 43% of malaria

Plasmodium falciparum Acute malaria 1. Sequestration (a) Which form produces certain proteins? (b) What does this cause? (c) What do knobs cause? (d) Result? 2. Recrudescences. What occurs? 3. Jaundice. What occurs? Sequestration associated with adhesion proteins that allow it to stick. Associated with slower movement of RBCs

(1a) Trophozoites (1b) deformations of RBC membrane called knobs (1c) Knobs cause RBCs to adhere to vein endothelium (1d) - Only see ring stages or gametocytes in blood (gametocytes produce no knobs) - May prevent clearance of infected RBCs by spleen - Infected RBCs form rosettes - Infected RBCs may bind to uninfected RBCs - Clog venules 2. Small populations of parasites remain in RBCs - Leads to recrudescences 1-3 years later - Usually 1 year 3. (icterus) Breakdown of RBC leads to high bilirubin levels - causes yellow bile to show in skin and eyes

Plasmodium spp. Epidemiology 1. Each year 350-500 million cases of malaria occur worldwide (2016 - 216 million) (a) How many people die of malaria each year? 2. Highest transmission rates are found in countries in? 3. ~41% of the world's population lives in areas where malaria is transmitted (e.g., parts of Africa, Asia, the Middle East, Central and South America, Hispaniola, and Oceania) 4. Malaria is no longer endemic in the U.S. (a) ~1200 cases reported each year (b) That number has increased to 1700 cases (c) Most cases in U.S. occur after?

(1a) ~ million people die of malaria each year. 75% of deaths are African children 2. sub-Saharan Africa (4c) travel to countries that have endemic malaria

3 cyclic forms of malaria:

- Liver is exoerythrocytic cycle - Blood is erythrocytic cycle - Taken up by female mosquito is sporogonic cycle

What are the 3 cyclic forms of malaria?

- Liver is exoerythrocytic cycle - Blood is erythrocytic cycle - Taken up by female mosquito is sporogonic cycle

Plasmodium spp. Three basic types of malaria 1. Benign tertian. Species? Symptoms? 2. Benign quartan. Species? Symptoms? 3. Malignant tertian. Species? Symptoms? 4. What two species of Plasmodium can remain in the liver, if not treated properly? What can result? Case study example: If you have a fever every 2nd day, you can eliminate P. malariae.

1. (P vivax and P ovale) with a fever every 2nd day (e.g., Monday; fever, Tuesday; no fever, Wednesday; fever) 2. (P malariae) with a fever every 3rd day (e.g., Monday; fever, Tuesday; no fever, Wednesday; no fever, Thursday; fever). Cyclic process of mirozoites replicating and rupturing RBCs 3. (P falciparum), in which the cold stage is less pronounced and the fever stage is more prolonged and intensified (if the fever is recurring it occurs every 2nd day). Most common. More severe 4. P vivax and P ovale - The organisms leave the liver and re-infect erythrocytes, causing the recurring symptoms. - Relapsing malaria occurs when there are relapses many years after the initial episode of malarial disease.

Plasmodium spp. Epidemiology 1. Describe P. falciparum 2. Describe P. malariae 3. Describe P. ovale 4. Describe P. vivax 5. Which two species cause relapsing malaria?

1. - #1 cause of Malaria - Found in tropical regions - Causes most severe and fatal disease - Most common species of malarial parasite diagnosed in the U.S., followed by P vivax, P malariae, and then P ovale 2. - Limited entirely to subtropical regions - Less common than P falciparum or P vivax 3. - Least common malarial species - Endemic in Africa 4. - Most common species outside of sub-Saharan Africa - 2nd Most common cause of malaria - Most common cause of malaria in Asia - Found in subtropical and temperate areas of the world 5. P. vivax and P. ovale

Periodicity of signs 1. Cold phase (chills). Symptoms? 2. Hot phase (fever). Symptoms? 3. Periodicity and relapse. Describe what is occurring 4. What is causing relapse? Know relapse and why it is important to malaria!

1. - Feeling of intense cold - Rapid rise in body temp (104-106 F) - Teeth chatter, bed rattles from shivering - Nausea and vomiting - Pale skin 2. - Begins 30-60 minutes after cold phase - Intense headache - Feeling of intense heat - Flushed skin - Mild delirium - Copious perspiration: signals end of episode (normal temp 2-3 hours later) 3. Symptoms appear in cycles - Cycles coincide with RBC lysis and merozoite release (Erythrocytic cycle) - Length of cycles varies by species - May take a few cycles for merozoite release to synchronize 4. Hypnozoites (dormant schizonts) in liver cells remain dormant for years; can release merozoites months or years later

Plasmodium falciparum Severe malaria 1. Cerebral malaria. Symptoms? 2. Severe anemia. Symptoms? 3. What is erythropoietin?

1. - Gradual or rapid onset - Headache followed by coma - Uncontrollable rise in body temp (108 F and above) - Psychotic symptoms - Convulsions - Death within hours: 1% of cases = millions of deaths - Can recover with or without neurological complications - Exact mechanism unknown: Induce apoptosis to cross BBB; blockage of capillaries; immune response 2. Inadequate reduction of RBCs - Shock - Impaired consciousness - Respiratory distress - Mechanism: Spleen removes infected and uninfected RBCs. Body cannot use iron in hemozoin. Bones cannot keep up with RBC production: inadequate erythropoietic response 3. a glycoprotein hormone secreted by the kidney in the adult and by the liver in the fetus, which acts on stem cells of the bone marrow to stimulate red blood cell production (erythropoiesis).

Anopheles mosquitoes 1. Like all mosquitoes, adult anophelines have slender bodies with 3 sections: 2. Which gender takes a blood meal? 3. Which gender has plumose palps? 4. How can Anopheles mosquitoes be distinguished from other mosquitoes? 5. How is adult Anopheles easily identified? Very complex life cycle! Recognize what is occurring in all 3 cycles. All the details!

1. - Head - Thorax - Abdomen 2. Females 3. males 4. - Palps are as long as proboscis - Discrete blocks of black and white scales on wings 5. by typical resting position - Abdomens sticking up in the air

Plasmodium ovale Epidemiology 1. Distribution? 2. Prevalence? 3. Diagnosis? 4. Life cycle?

1. - Most common on west coast of Africa - Also in Sub-saharan Africa, Western Pacific - Confined to tropics 2. Rarest form of malaria 3. Difficult to diagnose - Very similar to P. vivax morphologically 4. (a) Schizonts - 4-16 merozoites formed (usually 8) (b) Gametocytes - Take longer to appear in blood

1. How is Plasmodium ovale treated? 2. What medicinal tree is used? (exam question)

1. - Must treat people with disease - Must have prophylactic treatment for people traveling to endemic regions 2. Extract of quinine and other compounds from Cinchona pubescens

Plasmodium falciparum 1. Distribution? 2. Prevalence? 3. Pathogenicity?

1. - Once nearly worldwide - Now eradicated in US, Balkans, Mediterranean - Now in Sub-saharan Africa, SE Asia, and S. America. This species represents 99% in these regions 2. 50% of malaria cases 3. - Most virulent form (most severe) - The #1 killer of humans in tropics

Plasmodium spp. Treatment 1. What is used to treat P. vivax and P. ovale? 2. What is used to treat P. malariae? 3. What is used to treat P. falciparum? 4. What is used for prophylactic treatment?

1. - Primiquine - Chloroquine 2. Chloroquinone 3. Artemisinin 4. - Artemisinin - Mefloquinone

Plasmodium falciparum Complications 1. Pulmonary edema 2. Algid Malaria 3. Blackwater Fever (clearing of RBCs) Be aware of severity of these cases bc we won't see this in other strains

1. - Result of overuse of IV fluids - Difficulty breathing - Death in hours 2. - Shock = low blood pressure - Circulatory system collapse - Constricted veins - Cold and clammy skin 3. - Acute, massive lysis of RBC - High levels of free hemoglobin in blood. Filtered by kidneys - Dark urine, fever, jaundice, persistent fever - Renal failure ® death - Associated with P. falciparum patients who had inadequate treatment (exact cause unknown) - 20-50% mortality

How are mosquitos controlled? Exam question

1. Destruction of breeding areas - May not be possible or practical 2. Introduction of mosquito predators - Gambusia (fish) eats mosquito larvae 3. Insecticides. DDT: spray over brush and water - Cheap and effective - Major environmental impact - Some mosquitoes becoming resistant 4. Indoor insecticides - Spray on walls - Mosquito nets

Plasmodium falciparum Life cycle 1. How do they contain recrudescences? 2. What is recrudescence?

1. Higher levels of parasitemia than other species 2. The infection recurs from persistent blood stages of the malaria parasite. This is different from relapse. It is not associated with the hypnozoites. It is a lack of clearance of the parasite not associated with a dormant form.

Life cycle 1. Is it direct or indirect? 2. What is the definitive host? 3. What is the intermediate host?

1. Indirect 2. Definitive Host (sexual reproduction): Invertebrate animal - Anopheles spp. (mosquito) 3. Intermediate host (asexual reproduction): Vertebrate animal - Mammals - Birds - Reptiles

Describe each step in the Malaria life cycle Plasmodium spp. Study this cycle for exam! Be prepared to answer every step! - Pay attention to unaffected mosquito taking blood meal! - Sexual maturity occurs in gut of mosquito. - Recognize that hypnozoite is a dormant liver form and it is only related to two species (Step 9 and 10) macro and microgametocyte forms ookinete. Ookinete is the actively moving zygote of the malarial organism that penetrates the mosquito stomach that will eventually form the oocyst. DO NOT give word zygote; make sure to understand. (step 11) Oocyst is produced when male and female gametes combine. It is between the ookinete and the sporozoite

1. Mosquito takes a blood meal (injects sporozoites). Infective stage. Sporozoites travel to liver cell 2. Infected liver cell 3. Schizont 4. Merozoites 5. Red blood cell → immature trophozoite → mature trophozoite (diagnostic stage) → schizont (diagnostic stage) → ruptured shizont (step 6) OR immature trophozoite becomes gametocyte 6. Ruptured shizont 7. Immature trophozoite becomes Gametocytes. (diagnostic stage) 8. Mosquito takes a blood meal (ingests gametocytes) 9. Macrogametocyte/ Microgametocyte 10. Ookinete 11. Oocyst 12. Ruptured oocyst. Release of sporozoites - Exoerythrocytic cycle (human liver stages): step 2-4 - Erythrocytic cycle (human blood stages): step 5-7 - Sporogonic cycle (mosquito stages): step 8-12

Plasmodium spp. Current Recommendations 1. What medication treats hypnozoites and is effective against all forms and species of Plasmodium? 2. What medication has many resistant strains in Asia, Africa, South America? 3. What medication is useful for Chloroquine resistant strains?

1. Primaquine 2. Chloroquine 3. Artemisinin - Neurotoxic at high doses and prolonged exposure - Some resistant strains reported

Plasmodium 1. Plasmodium vivax and P. ovale. What are they? (a) What stage may persist in liver? (b) How are relapses caused? 2. Which stage is responsible for clinical manifestations? 3. How long do mosquitos remain infective? 4. How does infection affect mosquitos? 5. Intermediate hosts (humans) may also be infected by? Benign tertian is only associated w/ terminology of P. vivax and P. ovale with a fever every other day

1. They are two species that have the hypnozoite form (dormant liver form only) (1a) Dormant stage (hypnozoites) may persist in liver - Hypnozoites (dormant schizonts) in liver cells remain dormant for years; can release merozoites months or years later. This is the complexity of malaria that makes it difficult to eradicate! (1b) by invading bloodstream weeks, or even years later 2. Blood stage parasites 3. for life 4. Infection stimulates mosquitoes to feed more frequently: infecting more hosts - This is the second host parasite interaction that affects the parasite's behavior. The mosquito is more likely to infect an individual because it wants to take blood meal 5. - Blood transfusion - Syringe inoculation - Congenital infection (very rare)

Plasmodium malariae 1. Distribution? 2. Prevalence? 3. Infective to? 4. Relatively benign

1. Worldwide, but discontinuous - Tropical Africa, Asia, Europe, Americas. Not common anywhere 2. 7% of malaria cases (least prevalent) 3. Chimpanzees. They are not an important reservoir host for human infections

Global spread of malaria 1. Coincided with development of? 2. Africa 3. China 4. Spread to New World by 15th century 5. Spread to entire world by 19th century 6. What occurred in the 1950s? 7. Ancient history - Killed many people trying to invade Rome - Vatican moved to higher ground 8. Recent history - Killed more soldiers than combat - Revolutionary War, Civil War - WWI, WWII, Korean War, Vietnam War, Iraq War 9. Panama Canal - Severely impacted development

1. agriculture 6. Eradicated or nearly eradicated from North America and Europe

Plasmodium spp. Clinical manifestations 1. Disease caused by? Major clinical signs: 2. Fever and chills (paroxysms) (a) Correlates with? (b) Release of? (c) Waste products stimulate host inflammatory response (especially TNF- alpha) 3. Anemia (a) Caused by? (b) Inability to use iron in? (c) Lack of erythropoietic response. What is this? (d) Coagulopathy. What is this? 4. Slow onset. What are symptoms? 5. Rapid onset. What are symptoms?

1. bloodstream forms in intermediate hosts (2a) rupture of RBC following merogony (2b) merozoites and waste products (3a) destruction of infected and uninfected RBC (3b) hemozoin (3c) ability to replenish RBC (3d) Affects clotting ability - uncontrolled bleeding 4. Early prodromal symptoms: - Malaise - Muscle pain - Headache - Loss of appetite - Slight fever 5. No early symptoms

Plasmodium spp. Immunity & Relapse 1. Immunity 2. Premunition. What is this? 3. Relapse (hypnozoites (reactivation of dormant forms getting into blood and going through cyclic process)). What species undergo relapse? 4. Recrudescence (ineffective treatment). What species undergo recrudescence? 5. Relapse/recrudescence. - Symptoms lessened - Parasitemia higher Malaria gives some immunity. There are multiple species that can cause malaria. Typically, those that are exposed do have some immunity and they don't have as much vulnerability as those under 5.

2. (resistance to superinfection) A state of existing resistance of a host to infection or reinfection with a parasite; used especially in malaria epidemiology. 3. - P. ovale - P. vivax 4. - P. falciparum - P. malariae

Quinine 1. Discovered in 16th century 2. Derived from? 3. Drug of choice for centuries 4. WWII - Capture of Cinchona plantations - Had to develop new drugs

2. bark of tree (Cinchona sp.)

Plasmodium malariae Life cycle 1. Pre-erythrocytic cycle completed 13-16 dpi 2. Merozoites only infect? 3. What happens to erythrocytic forms? 4. Trophozoite forms? 5. Schizont forms? (a) Schizont very symmetric (b) Called? 6. Gametocytes develop in? 7. Recrudescences (a) May occur over 50 years later (b) Small populations of parasites remain in blood 8. Most common cause of malaria via?

2. old RBCs - Quickly eliminated by spleen 3. Erythrocytic forms build slowly in blood - Symptoms may appear before blood forms seen 4. ring stage then elongated band form 5. 6-12 merozoites after 72 hours (5b) rosette or daisy-head 6. internal organs - Only immature forms seen in blood 8. blood transfusion

What is hemozoin?

A disposal product formed from the digestion of blood by some blood-feeding parasites, e.g., hematophagous organisms such as Malaria parasites (Plasmodium spp. ) - Hemoglobin digestion by Plasmodium sp. leads to the production of heme which is polymerized into a less toxic form, hemozoin

Algid malaria

A form of falciparum malaria chiefly involving the gut and other abdominal viscera; gastric algid malaria is characterized by persistent vomiting; dysenteric algid malaria is characterized by bloody diarrheic stools in which enormous numbers of infected red blood cells are found.

What are Schuffner's dots?

Any of the fine, round, uniformly red or red-yellow staining dots occurring in red blood cells infected with Plasmodium vivax or P. ovale. Also called Schüffner's granule.

What are hypnozoites?

Exoerythrocytic schizozoite of Plasmodium vivax or P. ovale in the human liver, characterized by delayed primary development; thought to be responsible for malarial relapse.

What occurs from the immature trophozoite?

From the immature trophozoite: can mature into schizont to create more merozoites (it is creating more RBCs) or it can turn into sexual gametes (macro and microgametocytes). Precursors of sexual forms of malaria parasite that, once taken up, differentiate into male or female gametes within stomach of mosquitos. (TEST QUESTION): Uninfected mosquito ingests gametocytes. DO NOT give word zygote; make sure to understand

Schizont

Infects the hepatozites (liver form or exoerythrocytic form (meaning outside the blood)). The mature form of the malaria parasite that will release merozoites.

What are the characteristics of premunition?

It is not a sterilizing type of immunity, chronic infections persist, although the max load reached is low. It keeps the pathogen below the threshold of capacity

Merozoites

The form that infects the RBCs. They are then formed into a trophozoite (ring stage; looks like a signant ring

Sporozoites

This is what is injected by an infected mosquito. Infectious actively moving form of malaria parasite. At the sporozoite that is injected moved from midgut to salivary glands And then injected into human host. Sporozoites transfer to hepatozoites

What are paroxysms? (Exam question!)

a sudden attack or increase of symptoms of a disease (such as pain, coughing, shaking, etc.) that often occurs again and again

What is prodrome? (Exam question!)

an early symptom (or set of symptoms) that might indicate the start of a disease before specific symptoms occur