Pathogenesis of Malaria

1. Pathogenesis of Malaria

Mechanisms of Disease and Host Interaction
Presented by [Ritika Sharma]

2. What is Malaria?

Definition
A life—threatening disease caused by Plasmodium parasites,
transmitted by the bite of infected female Anopheles
mosquitoes.
Key Pathogenic Species
P. falciparum: Causes nearly all severe
disease.
P. vivax: Widespread ,can cause relapse.
P. ovale, P. malariae, P. knowlesi.
Pathogenesis occurs entirely during the human asexual
phase.

3. The Malarial Life Cycle: An Overview

Mosquito Phase
Liver Phase
Blood Phase (Disease)
1. Sporogonic
2. Exo-Erythrocytic
3. Erythrocytic
Sexual reproduction occurring
within the mosquito vector.
Ends with sporozoites in
salivary glands.
Initial asymptomatic asexual
Asexual replication in Red
Blood Cells. This is where
pathogenesis and symptoms
occur.
replication within human
hepatocytes (liver cells).

4. Stage 1: The Pre-Erythrocytic Cycle (Liver)

Inoculation & Invasion
Mosquito injects Sporozoites into the
bloodstream. They rapidly travel to and invade
hepatocytes.
This phase is clinically asymptomatic as there
is no inflammatory response yet.
Schizogony & Dormancy
Replication: Parasite multiplies to form a
schizont, releasing 1Ok—3Ok Merozoites.
Hypnozoites: P. v/vax and P. ovale can form
dormant stages in the liver, causing relapse
months later.

5. Stage 2: The Erythrocytic Cycle

1. Release: Merozoites flood into bloodstream from the liver.
2. Invasion: Merozoites invade erythrocytes, using specific receptors.
3. Development: Inside the erythrocytes, they develop form ring forms to
Trophozoites and Schizonts.
4. Rupture: The erythrocytes are ruptured synchronously and releasing
new merozoites and parasite products (like hemozoin and antigens)
5. Pathology Begins: This synchronous rupture triggers cytokine release
(eg. TNF-α, IL-1) from monocytes and other cells, generating the
characteristic paroxysms of fever, chills, and rigors.

6.

7. Anemia: Mechanisms of Destruction

Direct Destruction
Indirect Clearance
Dyserythropoiesis
Lysis of infected RBCs during
the release of merozoites
directly reduces RBC count.
Splenic removal of uninfected
Bone marrow suppression due to
chronic inflammation prevents
new RBC production.
RBCs (bystander effect) and
immune— mediated clearance.

8. Hyper-Inflammation & Immune Response

Hyper-Inflammation & Immune Response
Host Defense
The immune system attempts to control
parasite replication via innate cells
(macrophages, dendritic cells).
Recognition of parasite DNA and hemozoin
triggers response.
Innate Immune Priming
Malaria infection primes the innate immune system,
making it hyperresponsive to both malaria and unrelated
microbial products.
This is due to TLR9 and MyD88-dependent pathways
that boost IL-12 and IFN-γ production, leading to
increased TLR expression and exaggerated cytokine
responses to secondary challenges (like bacterial
endotoxins)
Cytokine Storm
Immune Evasion and Regulation
Excessive release of pro—inflammatory cytokines
(TNF—a, IFN—y).
Consequences: Systemic shock, vascular
endothelium damage, and activation of coagulation
cascades.
Regulatory T cells and other immune modulators
attempt to balance inflammation, but in severe
cases, this regulation may be insufficient, leading to
unchecked hyperinflammation and worse clinical
outcomes.

9. Key Mechanism: Cytoadherence

PfEMP1 & Sequestration
1. P. falciparum infected RBCs express PfEMP1
protein knobs on their surface.
2.Cytoadherence: iRBCs stick to endothelial
receptors (ICAM—1) in microvasculature.
3.Rosetting: Binding to uninfected RBCs.
4.Outcome: Avoidance of splenic clearance and
blockage of blood flow.

10. Cerebral Malaria

1. Vascular Occlusion: Sequestration of
iRBCs completely blocks cerebral capillaries.
2. BBB Disruption: Endothelial activation
leads to Blood— Brain Barrier breakdown and
brain edema.
3. Clinical Picture: Unarousable coma,
seizures, and potential permanent neurological
deficit.

11. Respiratory Distress & Acidosis

Respiratory Distress & Acidosis
Pulmonary Edema (ARDS)
Sequestration in lung capillaries increases vascular
permeability.
Fluid leaks into alveoli, impairing gas exchange and causing
severe respiratory distress.
Inflammatory infiltrates (mainly macrophages and
lymphocytes) further amplify lung injury and impair
oxygenation.
Metabolic Acidosis
Accumulation of lactic acid due to anaerobic
metabolism (host & parasite) and impaired
clearance.
Often the immediate cause of death in severe
cases.

12. Organ Dysfunction: Kidney & Liver

Organ Dysfunction: Kidney & Liver
Acute Kidney Injury
"Blackwater Fever": Massive intravascular hemolysis
leads to hemoglobinuria.
Hemoglobin casts block renal tubules causing acute
tubular necrosis (ATN).
Hepatic Dysfunction
Sequestration impairs liver perfusion.
Resulting in jaundice (high bilirubin) and
dangerous hypoglycemia (impaired
gluconeogenesis).

13. Host Factors & Immunity

Host Factors & Immunity
Genetic Protection
Sickle Cell Trait (HbS): Prevents
severe P. falciparum malaria.
Duffy Negative: Prevents P. vivax
invasion.
G6PD Deficiency: Offers partial protection.
Acquired Immunity
Repeated exposure leads to non—sterilizing immunity,
protecting adults in endemic areas from severe disease.

14. Summary

Stage
Liver Phase
Parasite Form
Liver Phase
Sporozoite
Blood Phase
Merozoite
Severe Malaria
Trophozoite
Key Pathogenic Clinical Result
Event
Hepatocyte
Asymptomatic
invasion and
replication
RBC rupture and Fever, anemia,
toxin release
Sequestration
Coma, Acidosis,
Organ failure.

15. Questions? Thank you for your attention.