MST1

Why is clinical malaria described as a "disease of the blood stage"?

Clinical symptoms (fever, chills, organ failure) only occur during the asexual replication and rupture of red blood cells.

What is the primary evolutionary reason P. falciparum sequesters in the microvasculature?

Spleen Avoidance: The spleen filters out rigid or damaged cells; by sticking to vessel walls, the parasite avoids passing through the spleen and being destroyed.

Define the role of PfEMP1 in the context of parasite survival.

It acts as the "ligand" or glue that allows infected RBCs to stick to the vascular endothelium (cytoadherence).

How many var genes does a single P. falciparum parasite typically possess, and how many are expressed at once?

~60 genes per genome; only one is expressed at a time.

Explain the concept of "singular expression" in var gene regulation.

A mechanism where 59 genes are silenced and 1 is active, allowing the parasite to change its "coat" and evade the immune system.

Where are silent var genes physically located within the parasite nucleus?

In heterochromatic clusters at the nuclear periphery.

What must happen physically to a var gene for it to become transcriptionally active?

The gene must move from the periphery to a transcriptionally permissive "active zone."

What is the PEXEL motif, and what is its specific amino acid sequence?

A "passport" sequence: RxLxE/Q/D (Arginine, any aa, Leucine, any aa, Glutamate/Glutamine/Aspartate).

What is the function of Plasmepsin V in the protein export pathway?

An aspartyl protease in the ER that cleaves the PEXEL motif to license the protein for export.

Identify the three core proteins that make up the PTEX translocon.

EXP2, HSP101, and PTEX150.

Which component of the PTEX complex acts as the "motor" to unfold proteins?

HSP101 (the AAA+ ATPase).

What is the specific role of EXP2 within the PTEX machinery?

It forms the actual pore in the parasitophorous vacuole membrane (PVM).

How does the parasite neutralize the toxic heme released during hemoglobin digestion?

Polymerizes toxic heme into non-toxic hemozoin crystals.

What structural feature on the RBC surface is required to anchor PfEMP1, and which protein is essential for its formation?

Knobs: KAHRP (Knob-Associated Histidine-Rich Protein) is essential to form the "knobs" that anchor PfEMP1.

Define cytoadherence and name one host receptor it involves (excluding the placenta).

Cytoadherence Receptor: CD36 (most common) or ICAM-1.

Why are children under five in endemic areas the most vulnerable to malaria mortality?

They have not yet built up "clinical immunity" through repeated exposure to different PfEMP1 variants.

Explain why women in their first pregnancy (primigravidae) are at high risk for malaria.

They lack antibodies against the specific PfEMP1 variant (VAR2CSA) that binds to the placenta.

What is the specific ligand and receptor interaction involved in Pregnancy-Associated Malaria (PAM)?

VAR2CSA (ligand) binding to Chondroitin Sulphate A (CSA) (receptor) in the placenta.

Why do women become less susceptible to PAM in their second and third pregnancies?

Women develop specific antibodies against VAR2CSA from their first exposure, providing immunity.

What is "Invasion Slowing" and how does it assist the immune system?

Slowing the entry into RBCs to give host antibodies more time to recognize and neutralize the parasite.

Why is RH5 considered a high-priority vaccine candidate?

It is an obligatory (essential) and highly conserved protein for RBC invasion, making it an ideal vaccine target.

Define "Diagnostic Escape" in the context of HRP2.

Parasites deleting the HRP2 gene so they aren't detected by Rapid Diagnostic Tests (RDTs).

What is the significance of the sub-telomeric location of var and HRP2 genes?

Being at the ends of chromosomes makes these genes prone to high rates of recombination and deletion.

Which stage of the life cycle does the RTS,S vaccine target?

The sporozoite (pre-erythrocytic/liver stage).

Describe the biological purpose of gametocytes.

The reproductive stages of the parasite that must be taken up by a mosquito to continue the cycle.

What is the difference between a sporozoite and a merozoite?

Sporozoites are injected by mosquitoes to infect the liver; Merozoites emerge from the liver/RBCs to infect RBCs.

How does the sickle cell trait (HbAS) provide a survival advantage against malaria?

HbAS (heterozygotes) are significantly protected against severe malaria and death.

What is the role of the Anopheles mosquito in the malaria life cycle?

The vector where sexual reproduction occurs and which transmits sporozoites to humans.

Why is P. falciparum more virulent than other human malaria species?

Due to its unique ability to sequester in deep tissues, causing organ-specific complications.

What is the clinical significance of cerebral malaria?

Severe complication where parasites sequester in the brain, leading to coma or death.

How does malaria contribute to the "poverty trap" in tropical regions?

Malaria causes high healthcare costs and massive loss of productivity (absenteeism), keeping regions economically stagnant.

What does the term "antigenic variation" mean in the context of var genes?

The ability to switch which PfEMP1 is displayed, staying one step ahead of the host's antibody response.

What is the function of the parasitophorous vacuole membrane (PVM)?

A membrane envelope that protects the parasite while it grows inside the RBC.

How is hemozoin used as a diagnostic tool?

It is a diagnostic marker of infection and can be seen under a microscope or detected by its magnetic properties.

Name the host receptor associated with cerebral malaria adherence.

ICAM-1

What is the "bottleneck" in the malaria life cycle that vaccines try to exploit?

The transition between stages (e.g., sporozoite to liver) where parasite numbers are at their lowest.

Describe the transition from the liver stage to the blood stage.

Parasites replicate in liver cells for ~7 days, then burst out as thousands of merozoites to start the blood stage.

What happens to the RBC membrane's rigidity during a malaria infection?

Infected RBCs become more rigid, which would normally lead to their destruction in the spleen if not for sequestration.

Why is the deletion of the HRP2 gene a major public health threat in Africa?

It leads to "hidden" infections that go untreated, allowing the disease to spread and kill despite available testing.

What is the ultimate goal of "block and lock" strategies in infectious disease (applied here to malaria's persistence)?

Pushing a pathogen into a permanent state of "deep latency" or silencing so it can never reactivate.

On which chromosome is the CFTR gene located?

Chromosome 7 (7q31.2)

CFTR is a member of which protein superfamily?

ABC Transporter (ATP-Binding Cassette)

Unlike other ABC transporters, what is the specific function of CFTR?

It is a cAMP-gated chloride channel, not an active pump

List the five domains of the CFTR protein.

MSD1, MSD2, NBD1, NBD2, and the R (Regulatory) domain

What is required to activate the Regulatory (R) domain of CFTR?

Phosphorylation by Protein Kinase A (PKA)

Describe the inheritance pattern of Cystic Fibrosis.

Autosomal Recessive

What is the most common CF-causing mutation worldwide?

F508del (Phe508del)

Define Class I CFTR mutations and provide an example.

No protein is made (e.g., G542X nonsense mutation)

What is the molecular hallmark of a Class II mutation?

Defective processing/folding; protein is trapped and degraded in the ER

Why does the F508del protein fail to reach the cell surface?

The cell’s "quality control" (chaperones) recognizes the misfolded protein and sends it to the proteasome for destruction

Describe a Class III mutation (e.g., G551D).

Protein reaches the surface but the "gate" doesn't open properly (e.g., G551D)

What is the difference between Class IV and Class V mutations?

Class IV has reduced conductance (narrower channel); Class V has reduced quantity (splicing errors)

Explain the "Gold Standard" test for diagnosing CF.

Sweat Chloride Test (measures high salt in sweat)

Why is IRT used in newborn screening, and what does it indicate?

Immunoreactive Trypsinogen; indicates pancreatic duct blockage/stress in newborns.

How does CFTR dysfunction lead to dehydrated Airway Surface Liquid (ASL)?

Without chloride/bicarbonate secretion, water isn't drawn out to the cell surface, leaving mucus dry and sticky.

What is the primary cause of death in 90% of CF patients?

Respiratory failure due to progressive lung disease.

Describe the impact of CF on the pancreas.

Mucus blocks ducts, leading to exocrine pancreatic insufficiency and malabsorption.

What is Meconium Ileus, and what percentage of CF newborns experience it?

Bowel obstruction in newborns; affects ~15-20% of CF babies.

Why are most males with CF infertile?

Due to CBAVD (Congenital Bilateral Absence of the Vas Deferens).

What is Aquagenic Wrinkling of the Palms?

Rapid "pruning" of palms in water; a sign of CFTR dysfunction in the skin.

Define CFTR Modulators.

Small molecules that target the specific underlying protein defect rather than just symptoms.

What is the specific function of a "Potentiator" (e.g., Ivacaftor)?

Increases the activity/gating of CFTR already at the surface (e.g., Ivacaftor).

What is the specific function of a "Corrector" (e.g., Tezacaftor)?

Helps misfolded CFTR fold correctly and reach the surface (e.g., Tezacaftor).

Which three drugs make up Trikafta?

Elexacaftor, Tezacaftor, and Ivacaftor.

What are Genetic Modifiers, and how do they affect the CF phenotype?

Other genes (not CFTR) that influence how severe symptoms like lung disease or meconium ileus will be.

Provide an example of an environmental modifier that worsens CF outcomes.

Tobacco smoke or lower socioeconomic status.

Why is a high-calorie, high-fat diet recommended for CF patients?

To compensate for high energy expenditure from lung infections and nutrient malabsorption.

What is PERT, and when must it be taken?

Pancreatic Enzyme Replacement Therapy; must be taken with every meal/snack containing fat/protein.

Describe the role of Bicarbonate transport by CFTR.

Essential for neutralizing acid and allowing mucus to expand/unfold properly.

How does thick mucus affect mucociliary clearance?

Thick mucus "collapses" the cilia, preventing them from beating and clearing bacteria/dust.

What is the role of the Multidisciplinary Team (MDT) in CF care?

Provides holistic care (physio, nutrition, medical, psychosocial) needed for a multi-system disease.

Name a common bacterial pathogen that chronically infects CF lungs.

Pseudomonas aeruginosa (or Staph. aureus).

What is Airway Clearance Technique (ACT)?

Airway Clearance Techniques (physical therapy to move mucus).

Why is salt supplementation often necessary for CF patients?

CF patients lose excessive salt in their sweat, especially in hot weather or during exercise.

What is the significance of the "Vest" (HFCWO) in CF treatment compared to manual physio?

Commonly used in the US, but found in head-to-head trials to be less effective than manual techniques.

Describe the "Class VI" mutation mechanism.

Accelerated turnover; protein reaches the surface but is unstable and removed too quickly.

How has life expectancy for CF patients changed since the 1950s?

Increased from ~5 years in the 1950s to ~40-55 years today.

What is positional cloning, and how does it relate to the discovery of CFTR?

Finding a gene based on its location in the genome rather than its function (used to find CFTR in 1989).

What is the impact of CF on the sweat duct specifically?

CFTR normally reabsorbs chloride from sweat; in CF, chloride stays in the sweat and is excreted.

What is the future goal of Gene Editing (CRISPR) in CF research?

Permanent correction of the DNA mutation to provide a one-time cure.

What type of virus is HIV, and what is its most defining characteristic regarding the host genome?

HIV is a retrovirus. Its defining characteristic is its ability to integrate its viral DNA into the host cell's genome, where it can persist indefinitely.

Which region of the world carries the highest burden of people living with HIV?

Sub-Saharan Africa (specifically Eastern and Southern Africa), with over 25 million people living with the virus.

What are the two primary "key receptors" HIV uses to enter a target cell?

The CD4 receptor (primary) and a chemokine co-receptor, either CCR5 or CXCR4.

What is the significance of the CCR5-delta32 mutation?

It is a natural genetic mutation that makes individuals highly resistant to HIV infection because the virus cannot use the defective CCR5 receptor to enter cells.

Name the three essential enzymes HIV carries within its capsid for replication.

Reverse Transcriptase, Integrase, and Protease.

What is the role of the HIV Capsid, and which new class of drugs targets it?

The capsid protects the viral genome and coordinates delivery to the nucleus. It is targeted by Capsid Inhibitors (e.g., Lenacapavir).

What is the "hallmark" of HIV pathogenesis?

The progressive loss of CD4+ T cells, leading to profound immune deficiency.

Describe the "Eclipse Period" in HIV infection.

The short interval (approx. 10 days) after infection where the virus is replicating but cannot yet be detected in the plasma by standard tests.

What defines the transition from HIV infection to AIDS?

When the CD4 T cell count drops below 200 cells/μL or the individual develops an AIDS-defining opportunistic infection.

What is Immune Activation, and why is it a problem for patients on ART?

It is a state of chronic "inflammation" caused by the virus. Even when the virus is suppressed by drugs, this persistent activation can lead to non-AIDS complications like cardiovascular disease.

What is the primary goal of Antiretroviral Therapy (ART)?

To suppress the viral load to undetectable levels, allowing the immune system to recover and preventing transmission.

Which two classes of drugs are currently the most commonly used in modern ART regimens?

NRTIs (Nucleoside Reverse Transcriptase Inhibitors) and Integrase Inhibitors (InSTIs).

What does the phrase "U=U" stand for in HIV public health?

Undetectable = Untransmittable. A person with an undetectable viral load cannot sexually transmit the virus to others.

Define PrEP and its efficacy.

Pre-Exposure Prophylaxis; it involves HIV-negative people taking antiretroviral medication to prevent infection. It is near 100% effective when taken as prescribed.

What is the difference between PrEP and PEP?

PrEP is taken before potential exposure; PEP (Post-Exposure Prophylaxis) is taken after a potential exposure and must be started within 72 hours.

What is a significant advantage of long-acting antivirals like Lenacapavir?

They can be administered as infrequently as every 6 months, which improves adherence compared to daily pills.

Why is "Treatment as Prevention" (TasP) a key pillar in ending the epidemic?

By treating everyone who is positive, we reduce the overall "community viral load," which stops new infections from occurring.

Why do patients need to take ART for the rest of their lives?

Because ART only stops active replication; it cannot eliminate the latent reservoir of virus integrated into long-lived resting cells.

What are the three pillars of the "Ending HIV" campaign in Australia?

Test More, Treat Early, and Stay Safe.

Name one class of HIV drugs that is now "rarely used" due to side effects or better alternatives.

Protease Inhibitors or Fusion Inhibitors (though still used in salvage therapy, they are no longer first-line).