Miguel Prudêncio

Researcher. Biological Sciences. Malaria

Index

Research Interests

Our research interests span a wide range of topics within the malaria field, with particular emphasis on the hepatic stage of infection by Plasmodium parasites. We are interested in elucidating novel aspects of the biology of Plasmodium infection and host-parasite interactions, investigating co-infections between Plasmodium and other pathogens, developing new drug- and vaccine-based anti-malarial strategies, and developing new experimental strategies to study the different stages of Plasmodium infection.

 

Our current research focuses on:

  • Investigating the reciprocal influence of Plasmodium and viral or parasitic co-infections.
  • Developing and evaluating the activity of novel antiplasmodial compounds.
  • Addressing current bottlenecks and knowledge gaps in whole-sporozoite vaccination against malaria.
  • Investigating immunomodulation strategies for enhancement of vaccine efficacy.
  • Developing a novel whole-sporozoite vaccination strategy.
  • Generating monoclonal antibodies against human Plasmodium parasites.
  • Developing novel strategies for assessment of Plasmodium hepatic infection.

About Malaria

Malaria is an infectious disease caused by parasites called Plasmodium spp., belonging to the parasitic phylum Apicomplexa. There are five identified species of this parasite causing human malaria, namely, P. vivax, P. falciparum, P. ovale, P. malariae and P. knowlesi. It is a mosquito-borne disease, transmitted by female Anopheles mosquitoes. Malaria is the fifth cause of death from infectious diseases worldwide (after respiratory infections, HIV/AIDS, diarrhoeal diseases, and tuberculosis) and the second in Africa, after HIV/AIDS. The disease causes widespread premature death and suffering, imposes financial hardship on poor households, and holds back economic growth and improvements in living standards. Malaria is the most common disease in Africa. It is also the number one cause of death among young children and a significant cause of miscarriages among pregnant mothers. A significant amount of suffering, complications and death due to malaria can be prevented through prompt and correct treatment and prevention measures. 

Burden

According to the World Malaria Report 2021, malaria is prevalent in more than 80 countries of the tropical and semitropical world (Africa; Amazon, central and southern America; central, south and south-east Asia; Pacific) that are home to more than half of the world’s people. In most of these areas malaria is a perennial problem. The estimates of malaria burden vary; every year, malaria is reported to cause more than 200 million infections and more than a 600.000 (mostly among African children). 

In most areas, malaria and poverty co-exist, with the average GDP and average growth of per capita GDP in malarious countries being about one fifth of those in non-malarious countries. Malaria dramatically inhibits economic growth by restricting individual worker productivity, tourism, foreign investment, and transportation. Furthermore, the macroeconomic toll is severe, particularly in sub-Saharan Africa, since malaria may cost more than one percentage point of economic growth every year. The social and economic toll imposes substantial costs to individuals and governments. Such costs can add substantially to the economic burden of malaria particularly in endemic countries and strongly impedes their economic growth.

The economic burden of malaria is huge, estimated to be $12 billion a year in Africa alone. But the global spending on malaria control is only meager, with US$ 652 million disbursed in 2007 and US$ 1.7 billion committed in 2009. (In comparison, in the year 2008, HIV/AIDS accounted for 33.4 million case prevalence, 2 million deaths and a total global spending of US $13.7 billion).

History

Malaria has infected humans for over 50,000 years, and ”Plasmodium” may have been a human pathogen for the entire history of the species. Close relatives of the human malaria parasites remain common in chimpanzees. References to the unique periodic fevers of malaria are found throughout recorded history, beginning in 2700 BC in China. The term malaria originates from Medieval Italian: ”mala aria”—”bad air”; and the disease was formerly called ”ague” or ”marsh fever” due to its association with swamps and marshland. Malaria was once common in most of Europe and North America, where it is no longer endemic, though imported cases do occur.

Scientific studies on malaria made their first significant advance in 1880, when a French army doctor working in the military hospital of Constantine in Algeria named Charles Louis Alphonse Laveran observed parasites for the first time, inside the red blood cells of people suffering from malaria. He, therefore, proposed that malaria is caused by this organism, the first time a protist was identified as causing disease. For this and later discoveries, he was awarded the 1907 Nobel Prize for Physiology or Medicine. The malarial parasite was called ”Plasmodium” by the Italian scientists Ettore Marchiafava and Angelo Celli. A year later, Carlos Finlay, a Cuban doctor treating patients with yellow fever in Havana, provided strong evidence that mosquitoes were transmitting disease to and from humans. This work followed earlier suggestions by Josiah C. Nott, and work by Patrick Manson on the transmission of filariasis.

However, it was Britain’s Sir Ronald Ross working in the Presidency General Hospital in Calcutta who finally proved in 1898 that malaria is transmitted by mosquitoes. He did this by showing that certain mosquito species transmit malaria to birds and isolating malaria parasites from the salivary glands of mosquitoes that had fed on infected birds. For this work Ross received the 1902 Nobel Prize in Medicine. 

In 1948, Shortt & Garnham solved a centuries-old mystery — the source of malaria’s parasitaemic relapses. P.G. Shute and Sir Gordon Covell, placed the discovery of the exoerythrocytic (EE) hepatic phase of mammalian malaria parasites in the following historical context: “Just as the name of Ross will forever be associated with the discovery that mosquitoes transmit malaria, so too, will the names of Shortt and Garnham be remembered in connection with the primary tissue phase of the parasite.” 

The first effective treatment for malaria came from the bark of cinchona tree, which contains quinine. This tree grows on the slopes of the Andes, mainly in Peru. A tincture made of this natural product was used by the inhabitants of Peru to control malaria, and the Jesuits introduced this practice to Europe during the 1640s, where it was rapidly accepted. However, it was not until 1820 that the active ingredient, quinine, was extracted from the bark, isolated and named by the French chemists Pierre Joseph Pelletier and Joseph Bienaimé Caventou.

In 1973 human protection from malaria by vaccination was first reported. However, the vaccination consisted of the bites of about a thousand mosquitoes infected with malaria parasites that had been X irradiated. For about 20 years, progress occurred mainly in experimental models rather than in human vaccine trials. During the past 5 years, many candidate vaccine approaches have been tested in clinical trials.

The genome sequences of Anopheles gambiae and Plasmodium falciparum were published in 2002, and those of P. vivax and P. knowlesi in 2008.

Symptoms

Symptoms of malaria include fever, shivering, arthralgia (joint pain), vomiting, anemia (caused by hemolysis), hemoglobinuria, retinal damage, and convulsions. The classic symptom of malaria is cyclical occurrence of sudden coldness followed by rigor and then fever and sweating lasting four to six hours, occurring every two days in P. vivax and P. ovale infections, while every three for P. malariae. P. falciparum can have recurrent fever every 36–48 hours or a less pronounced and almost continuous fever. For reasons that are poorly understood, but that may be related to high intracranial pressure, children with malaria frequently exhibit abnormal posturing, a sign indicating severe brain damage. Malaria has been found to cause cognitive impairments, especially in children. It causes widespread anemia during a period of rapid brain development and also direct brain damage. This neurologic damage results from cerebral malaria to which children are more vulnerable. Cerebral malaria is associated with retinal whitening, which may be a useful clinical sign in distinguishing malaria from other causes of fever.

Severe malaria is almost exclusively caused by P. falciparum infection and usually arises 6–14 days after infection. Consequences of severe malaria include coma and death if untreated—young children and pregnant women are especially vulnerable. Splenomegaly (enlarged spleen), severe headache, cerebral ischemia, hepatomegaly (enlarged liver), hypoglycemia, and hemoglobinuria with renal failure may occur. Renal failure may cause blackwater fever, where hemoglobin from lysed red blood cells leaks into the urine. Severe malaria can progress extremely rapidly and cause death within hours or days. In endemic areas, treatment is often less satisfactory and the overall fatality rate for all cases of malaria can be as high as one in ten. Over the longer term, developmental impairments have been documented in children who have suffered episodes of severe malaria.

Chronic malaria is seen in both P. vivax and P. ovale, but not in P. falciparum. Here, the disease can relapse months or years after exposure, due to the presence of latent parasites in the liver. Describing a case of malaria as cured by observing the disappearance of parasites from the bloodstream can, therefore, be deceptive. The longest incubation period reported for a P. vivax infection is 30 years.

Links

The Life Cycle of the Plasmodium Parasite

Malaria infection is initiated when Plasmodium sporozoites enter the mammalian host through the bite of an infected female Anopheles mosquito. During a blood meal, an average of 15–123 sporozoites has been reported to be deposited under the skin of the host, which migrate to the liver. There, sporozoites traverse a few hepatocytes and eventually productively invade one, with formation of a parasitophorous vacuole.  Inside this vacuole, the parasites replicate extensively and develop into merozoites. Between 2 and 16 days later, depending on the Plasmodium species, thousands of merozoites per invading sporozoite are released into the bloodstream. Each merozoite will invade an erythrocyte, initiating a replication cycle that ends with the release of new merozoites from the mature infected erythrocyte (schizont), which go on to infect other erythrocytes. Malaria- associated pathology only occurs during the blood stage of infection. The Plasmodium life cycle continues when some merozoites develop into the sexual parasite stages, the male and female gametocytes, which can be taken up by mosquitoes during blood meals. Gametocytes undergo fertilization and maturation in the mosquito midgut, forming an infective ookinete form that migrates through the mosquito midgut into the hemocele, developing into the oocyst in which sporozoites are formed. When fully matured, the oocysts burst and release sporozoites, which migrate into the mosquito’s salivary glands, ready for the next transmission step.

Videos

The life cycle of Plasmodium parasites
Mosquito infected with fluorescent Plasmodium
Plasmodium-infected mosquito salivary gland
Plasmodium sporozoites