From monkeys to people

FIOCRUZ team suggests a sixth form of malaria, transmitted by mosquitoes infected after biting wild primates in the Atlantic Forest

G. ROBERT COATNEY / GERTRUDE H. NICHOLSON / CDC Plasmodium vivax in different stages of development in human red blood cells (left) and P. simium in monkey red blood cells (right). The first cell in each image is not infected.G. ROBERT COATNEY / GERTRUDE H. NICHOLSON / CDC

In 1966, the parasitologist from Pará State Leônidas Deane (1914–1993), who at that time was a professor at the University of São Paulo Medical School (FMUSP), described the first known case of human malaria caused by the protozoa Plasmodium simium. Until then, it was thought that this type of parasite only caused the disease in monkeys. The protozoa had been found in the blood of a park ranger who collected mosquitoes for researchers from the forest canopy at the Horto Florestal Park in the city of São Paulo, a wild area where no case of malaria had been previously recorded. The possibility that mosquitoes which had bitten infected monkeys could transmit this form of malaria to other people could not be demonstrated at the time when the case appeared. Half a century later, a team from the Oswaldo Cruz Foundation (FIOCRUZ) returned to Deane’s hypothesis and proposed a sixth form of human malaria, one transmitted by mosquitoes infected with P. simium after biting contaminated monkeys. This hypothesis has yet to be confirmed by other studies and recognized by international bodies.

Malaria is transmitted to humans by mosquitoes of the genus Anopheles contaminated with infectious agents—protozoa of the genus Plasmodium. The forms of malaria are differentiated by microscopic identification of the species of Plasmodium that multiplies in red blood cells. Although the initial symptoms are similar, involving fever, chills, headache, and body aches, the progress of the disease depends on its causative agent: P. vivax causes a milder form of malaria, and P. falciparum is more severe (see table). One form (caused by P. knowlesi) was described in 1965 in Malaysia as the first type of malaria transmitted to humans by mosquitoes that were infected after biting monkeys; this form is a zoonotic disease involving animals, which function as reservoirs of the infectious agents. P. knowlesi was described in 1932 in monkey blood, and is easily confused with P. malariae and P. falciparum. This variant has been responsible for a growing number of cases in Malaysia (703 in 2011 and 996 in 2013), Thailand, Indonesia, Vietnam, and the Philippines.

The conclusion that monkeys can serve as a reservoir for the protozoa that cause malaria in Brazil came after analysis of blood samples from three animals and 28 residents in the mountain region of Rio de Janeiro. “We initially believed they were cases of malaria caused by P. vivax, the most common form in Brazil and in the region,” says parasitologist Cláudio Tadeu Daniel-Ribeiro, a FIOCRUZ researcher in Rio de Janeiro. “Since the symptoms were slightly different, we considered the possibility it might be the monkey malaria described by Deane.”

P. vivax and P. simium are very similar in microscopic blood tests. The FIOCRUZ team distinguished the two types by identifying two different stretches of the mitochondrial DNA in each species, and considered the possibility that infection by P. simium could explain outbreaks in Rio de Janeiro’s regions of Atlantic Forest. The researchers identified P. simium in 28 of the 49 autochthonous (local) cases of malaria recorded in the region in 2015 and 2016. This work was performed by FIOCRUZ parasitologist Patrícia Brasil and described in an October article published in Lancet Global Health warning of the risk of malaria in areas far from the Amazon, which was the source of 99% of the 131,000 cases recorded from January to September 2017, according to the Brazilian Ministry of Health. The World Health Organization registered 214 million cases of malaria and 438,000 deaths from the disease in 95 countries in 2015.

A FIOCRUZ team in the state of Minas Gerais also used molecular analysis to identify P. simium in nine of a group of 65 brown howler monkeys (Alouatta guiariba) and robust capuchin monkeys (Sapajus spp.) living in captivity or in areas of Atlantic Forest in the city of Indaial, Santa Catarina State, as reported in a 2014 study published in Memórias do Instituto Oswaldo Cruz. The muriqui (Brachyteles spp.) is another primate species which can harbor this parasite; it was identified in 1951 in a monkey from a forest near the city of São Paulo and described for the first time by the parasitologist Flávio Oliveira Ribeiro da Fonseca (1900–1963), a native of Rio de Janeiro State and professor at FM-USP. P. simium has also been found in the blood of monkeys in the states of São Paulo, Espírito Santo, and Paraná, according to biologist Cristiana Ferreira Alves de Brito, a researcher at FIOCRUZ in Belo Horizonte.

“Malaria in humans outside of the Amazon region is much more lethal, because doctors in cities in the south and southeast of the country do not suspect that the high fever and anemia could be symptoms of malaria,” says Brito. “We need to warn doctors and health centers to make the correct diagnosis, because the treatment is efficient.” In November 2010, one traveler from Nigeria and another from Ivory Coast died of malaria in São Paulo after seeking care in hospitals where doctors did not diagnose the disease (see Pesquisa FAPESP, issue No. 186). The São Paulo State Center for Epidemiological Surveillance registered eight autochthonous cases of malaria in humans in 2016 and five as of October 2017, mostly in coastal cities near forest areas.

“Because it is difficult for physicians outside the Amazon region to recognize the disease, the description of malaria cases in Rio de Janeiro as a zoonotic disease is a major challenge for controlling this disease,” says biologist Silvia Di Santi, researcher at the Endemic Diseases Oversight Office (SUCEN) and the Institute of Tropical Medicine at FM-USP. “To better understand this situation, it is essential to broaden the areas of study in regions with the same epidemiological profile, and describe the complete transmission cycle with mosquitoes, monkeys, and infected humans.”

The cases of malaria transmitted in areas of Atlantic Forest along the coast are a benign form of the disease, according to Di Santi. Inhabitants of the mountainous region of Rio de Janeiro State infected with P. simium exhibited similar but milder symptoms caused by P. vivax and responded to treatment with a combination of chloroquine and primaquine. Two patients who were unable to take primaquine received only chloroquine, and had not relapsed 18 months later. According to Ribeiro, the fact that malaria did not reappear in these people is an indication that P. simium, unlike P. vivax, could not maintain dormant forms of the parasite in the liver, which are usually eliminated by primaquine.

According to Ribeiro, the infection could be caused by P. simium or by P. vivax which adapted to the monkey and reached humans via mosquitoes, adding, “We will only know when we have sequenced their complete genomes.” There is no expert consensus on whether P. vivax and P. simium are even different species or variations of the same species. In a 2005 article in PNAS, researchers from the University of California at Irvine argued that there may have been at least two transfers of P. vivax from monkeys to humans or vice versa over the past few thousand years. “In Africa,” says Brito, “vivax and falciparum came from monkeys to humans.”

Scientific articles
BRASIL, P. et al. Outbreak of human malaria caused by Plasmodium simium in the Atlantic Forest in Rio de Janeiro: A molecular epidemiological investigation. Lancet Global Health. V. 5, p. e1038–1046. 2017.
COSTA, D. C. Plasmodium simium/Plasmodium vivax infections in southern brown howler monkeys from the Atlantic Forest. Memórias do Instituto Oswaldo Cruz. V. 109 (5), p. 641–53. 2014.
LIM, C. S. et al. Plasmodium vivax: Recent world expansion and genetic identity to Plasmodium simium. PNAS. V. 102 (43), p. 15523–28. 2005.