Micro - human pathogens

What protist is malaria caused by?

• Caused by the protozoa Plasmodium species

• Transmitted by the female anopheles mosquito

• Infects red blood cells causing cycles of fever

• Severe disease includes anaemia and small capillaries becoming blocked by infected red blood cells

• Kills approximately 1,200 children per day in sub-Saharan Africa

How do apicomplexans play a role in malaria?

• Contain an apical complex that facilitates host invasion

• Often have complex life cycles with multiple hosts

• More than 200 Plasmodium species are known to infect vertebrates

What is the epidemiological importance of malaria?

• Global deaths from malaria in 2022 was estimated to be 608,000

• More than 50% of deaths occurred in 4 countries

• Most victims (55%) are sub-Saharan children infected with cerebral malaria

What are the four life stages of the malarial parasite?

• Skin infection

• Liver-stage development

• Blood-stage development

• Mosquito-stage development

How does the skin infection stage of the malarial infection occur?

• Sporozoites residing within the malarian salivary gland are injected into the skin - motile infective form

How does the liver-stage of the lifecycle occur?

• Sporozoites invade liver cells within 30-60 minutes via engulfing by a modified host cell membrane

• Divide asexually within hepatocytes forming schizonts after 6/7 days

• P. vivax can form a non-replicating hypnozoite - enables long term survival of the parasite leading to relapses of disease years after initial infection

• Each schizont produces thousands of merozoites that are released into the blood from ruptured hepatocytes

• Merozoites actively invade red blood cells

How does the blood-stage of the lifecycle occur?

• Merozoites bind receptors on red blood cells and are internalised

• Differentiate into trophozoites and ingest the cytoplasm of the red blood cell

• Rupture of haemocyte schizont in the blood releases malaria endotoxins (haemozoin and parasite DNA)

• Induces the host to produce high levels of pro-inflammatory cytokines that induce fever-like symptoms - can lead to severe anaemia

• P. falciparium proteins are expressed on the surface of infected red blood cells enabling attachment to the endothelium and can cause rosetting and capillary obstruction

• Asexual reproduction in host red blood cells results in either many merozoites or some reproduce sexually and produce gametocytes

How does the mosquito-stage of the lifecycle occur?

• Female anopheles mosquitos pick up gametocytes from the host blood

• Male and female gametocytes undergo gamecytogenesis within the midgut of the mosquito - forms a zygote and motile ookinetes

• Cross the midgut to form oocytes that release thousands of sporozoites - migrate to the salivary gland

How can immunity be obtained against malaria?

• Immune system produces antibodies to malarial proteins expressed on the surface of infected red blood cells

• Main antigen is PfEMP1 in P. falciparum - undergoes antigenic variation to evade the immune system

How can immunity to malaria be provided through vaccination?

• RTS,S - world’s first licensed malaria vaccine that has been recommended since 2021, undergoing pilot trials in select countries and is hoped to protect in future

• R21/Matrix-M - has been recommended for use since 2023

What is Chagas disease caused by and how does it affect people?

• Caused by Trypanosoma cruzi

• Transmitted by the triatomine bug

• Affects 6-7 million people in Latin America

• Acute symptoms: fever, fatigue, headache and rash

• Chronic symptoms: severe cardiac and intestinal lesions

What is Trypaosomiasis caused by and how does it affect people?

• Caused by Trypanosoma brucei

• Transmitted by the tsetse fly

• Affects <1000 people in sub-Saharan Africa

• Acute symptoms: skin lesions

• Chronic symptoms: severe sleep disturbance leading to coma/death

What is the trypanosome life cycle?

• Acute phase of 2-8 weeks - amplified by binary fission

• Chronic phase after up to 10-30 years symptom free

• T. cruzi spends the intracellular stage in the smooth muscle

• T. brucei spends the intercellular stage in the CNS

How does T. cruzi evade the immune system?

• Intracellular growth in macrophages

• Differentiates into amastigotes

How does T. brucei evade the immune system?

• Antigenic variation

• Variable surface glycoproteins (VSGs)

• Genome contains 2000 VSG-encoding genes - only one is expressed at a time

What are the gastrointestinal symptoms of intestinal protists?

• Diarrhoea

• Gastroenteritis - condition involving nausea, vomiting, diarrhoea and abdominal distress

• Dysentery - involves blood and mucus in the stool, results from damage to the large intestine

What are types of intestinal pathogenic protists?

• Giardia

• Cryptosporidium

How is Giardia an intestinal pathogen?

• Most common protozoal parasite isolated

• Often asymptomatic and non-fatal in developed countries

• Exhibits antigenic variation via single variant surface proteins (VSPs) - expression switching occurs once every 10 generations

What is Giardia’s life cycle?

• Adherence to the intestinal cell via an adhesive disc

• Replication on the intestinal cells

• Encystation

• Cyst stage

• Excystation

How does Cryptosporidium act as an intestinal pathogen?

• First recorded case in 1976

• Two main pathogens - C. hominis and C. parvum

• Outbreaks are common

• Can be fatal to the immunocompromised

What is the life cycle of Cryptosporidium?

• Excystation

• Autoinfection: 3x asexual replication, sexual commitment, fertilisation

• Faecal shedding: oocyst formation and release

What is the pathology of Cryptosporidium?

• Inflammation around intestinal epithelial cells

• Impacts normal nutrient and ion adsorption leading to diarrhoea

• Prolonged infection in children - malnutrition and death in the very young (<5 years old)

• Infection lasts 1-2 weeks in healthy adults and usually self limiting - can be fatal in the immunocompromised

How can Cryptosporidium be prevented and treated?

• Oocysts are resistant to chlorine - removed from water by filtration

• Most diarrhoeal diseases can be prevented by good sanitation and access to clean water

• Disease is usually self-limiting and can be treated with low-osmolarity oral rehydration salts (ORS) and zinc tablets