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Anticipated death

Virologists discover how the agent that causes yellow fever destroys liver cells

In the interior of the Amazonian Rainforest a dark blue mosquito of 4 millimeters in length keeps an extremely lethal virus in circulation: that of yellow fever, an infection that each year strikes around 200,000 people in tropical countries and kills in 10% of the cases. Inoffensive to this insect, the Haemagogus janthinomys, this virus is capable of killing  within only a few days human beings that venture into the jungle.

For some time now it has been known that this virus seriously damages the liver, which stops working. A recent finding, however, opens up a pathway for therapies capable of avoiding this situation. On analyzing liver samples from 53 people who died as a result of yellow fever, researchers from the States of Para and Sao Paulo have identified and accounted for the type of damage that the virus that causes this illness brings about in the liver cells. It had been believed that the cells underwent necrosis, a violent process in which a cell breaks down and liberates toxic compounds that kill its neighbors, in a reaction that widens into a chain reaction. Now a team from the Federal University of Para (UFPA), the Evandro Chagas Institute (IEC) and the University of Sao Paulo (USP) has shown that necrosis is not the most important phenomenon. The yellow fever virus may well produce necrosis in the liver, but very little.

It may well appear to be an excess of detail, but among cells there are deaths and deaths. Biochemical examinations and electron microscope analysis have revealed that the virus liberates chemical signals that cause death by apoptosis, described Juarez Quaresma, from  UFPA, and Maria Irma Seixas Duarte, from USP, in two recent articles, one of them published During May in Acta Tropica. The apoptosis – or programmed cellular death – is a natural process for the elimination of old or sick cells. Instead of bringing about a chemical imbalance that would make the cells swell up until they explode, the apoptosis leads the cells to shrink without liberating their content, before being digested by defense system cells. The problem in the case of yellow fever is that the apoptosis occurs to an exaggerated extent, as if the virus were making the hands of a clock rotate rapidly, thus anticipating the death of the liver cells.

With these discoveries, the possibility of testing compounds capable of slowing down the apoptosis has come about as well as protecting the liver in the most serious cases of yellow fever, whose mortality rate can reach 50%. “Now we can think about mechanisms that protect the liver”, advised researcher Maria Irma, who coordinated this study, carried out in collaboration with Pedro da Costa Vasconcelos and Vera Barros, both from the Evandro Chagas Institute in the city of Belém.

The importance of this result is greater than one might think. Since 1942 yellow fever has been restricted to the forest areas of eleven states in the north and northeast, as well as the state of Maranhão, where 30 million people live. Even at that, one cannot discard the risk that the infection could return and spread throughout the country. Over the last ten years the number of registered cases in human beings has grown, reaching a peak of 85 cases during 2000. The yellow fever virus has gone on to also be found in parts of the states of Piaui,  Bahia, Minas Gerais, Sao Paulo and the southern region states. If the case were to be that the virus continues to spread towards the most eastern states, it could reach an area inhabited by 120 million people, in which the level of vaccination against yellow fever is practically nil.

There is another worrying motive. In urban areas the yellow fever virus is not transmitted by mosquitoes of the genre Haemagogus, from a wild habitat, but by the Aedes aegypti, the urban mosquito that also transmits the breakbone fever virus and is found from the north to the south of the country. An aggravating factor: many cases of yellow fever are only confirmed after the death of the victim. This is because the symptoms’ fever, muscular pains, bleeding, vomiting and a yellowing of the skin – are common among other viral illnesses that affect the liver, and very often yellow fever passes unperceived even in areas in which the infection is endemic. As the organism sets itself up to combat the virus in a mild form of the illness, there is the risk of dissemination being sly, helped by the human being himself. “It’s probable that the light forms are more common than is imagined and go unperceived by doctors and health authorities”, suggested researcher Vasconcelos.

Recently he studied how this virus, which originated in Africa, has evolved in Brazil and Latin America. He compared 117 samples collected in seven Latin countries with 19 samples from African countries. Published in March of this year in the magazine Journal of Virology, the results showed that the yellow fever virus has evolved since it reached America almost four centuries ago. But is has not become more aggressive nor has it lost its capacity to infect mosquitoes and to cause the illness, according to the study financed by the Lancet International Fellowship Award.

In another study, Dr. Vasconcelos evaluated the genetic characteristics of 79 samples of the virus collected in 12 Brazilian states between 1935 and 2001. His conclusion: the virus in circulation in the country belongs to a unique type, the South American1, formed by five groups (A, B, C, D and Old Para). The viruses detected over the past seven years belong to group D, which has been dispersing in a southerly direction: in 1998 they were found in Para; in 1999 and in 2000, in Bahia, Tocantins and Goias; and in 2001, in Minas Gerais. Dr. Vasconcelos attributes this dissemination in part to the migration of asymtomatic carriers of the virus to the southeast and south. He also suspects a further factor: the trafficking of wild animals, especially monkeys.