Scientists Reveal Malaria Parasites' Tactics For Outwitting Our Immune Systems

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Also Included In: Tropical Diseases
Article Date: 01 Dec 2009 - 6:00 PST

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Malaria parasites are able to disguise themselves to avoid the host's immune system, according to research funded by the Wellcome Trust and published recently in the journal Proceedings of the National Academy of Sciences.

Malaria is one of the world's biggest killers, responsible for over a million deaths every year, mainly in children and pregnant women in Africa and South-east Asia. It is caused by the malaria parasite, which is injected into the bloodstream from the salivary glands of infected mosquitoes. There are a number of different species of parasite, but the deadliest is the Plasmodium falciparum parasite, which accounts for 90 per cent of deaths from malaria.

The malaria parasite infects healthy red blood cells, where it reproduces. The P. falciparum parasite generates a family of molecules, known as PfEMP1, that are inserted into the surface of the infected red blood cells. The cells become sticky and adhere to the walls of blood vessels in tissues such as the brain. This prevents the cells being flushed through the spleen, where the parasites would be destroyed by the body's immune system, but also restricts blood supply to vital organs.

Symptoms can differ greatly between young and older children depending on previous exposure to the parasite. In young children, the disease can be extremely serious and potentially fatal if untreated; older children and adults who have grown up in endemic areas are resistant to severe malaria but rarely develop the ability to rid their bodies of the parasite.

Each parasite has 'recipes' for around sixty different types of PfEMP1 molecule written into its genes. However, the exact recipes differ from parasite to parasite, so every new infection may carry a set of molecules that the immune system has not previously encountered. This has meant that in the past, researchers have ruled out the molecules as vaccine candidates. However there appear to be at least two main classes of PfEMP1 types within every parasite, suggesting different broad tactical approaches to infecting the host. The most efficient tactic or combination of tactics to use may depend on the host's immunity.

Now, Dr George Warimwe and colleagues from the Kenya Medical Research Institute (KEMRI)-Wellcome Trust Programme and the Wellcome Trust Sanger Institute, have shown that the parasites adapt their molecules depending on which antibodies it encounters in the host's immune response. They have also found evidence to suggest that there may be a limit to the number of molecular types that are actually associated with severe disease.

"The malaria parasite is very complex, so our immune system mounts many different responses, some more effective than others and many not effective at all," explains Dr Peter Bull from the KEMRI-Wellcome Trust Programme and the University of Oxford, who led the research. "We know that our bodies have great difficulty in completely clearing infections, which begs the question: how does the parasite manage to outwit our immune response? We have shown that, as children begin to develop antibodies to parasites, the malaria parasite changes its tactics to adapt to our defences."

The researchers at the KEMRI-Wellcome Trust Programme studied malaria parasites in blood samples from 217 Kenyan children with malaria. They found that a group of genes coding for a particular class of PfEMP1 molecule called Cys-2 tended to be switched on when the children had a low immunity to the parasite; as immunity develops, the parasite switches on a different set of genes, effectively disguising it so that immune system cannot clear the infection

Dr Warimwe and colleagues also found an independent association between activity in Cys-2 genes and severe malaria in the children, suggesting that specific forms of the molecule may be more likely to trigger specific disease symptoms. This supports a previous study in Mali which suggested that the same class of PfEMP1 molecule was associated with cerebral malaria.

The findings could suggest a new approach to tackling malaria, in terms of both vaccine development and drug interventions, argues Dr Bull.

"If there exists a limited class of severe disease-causing variants that naturally-exposed children learn to recognise readily, this opens up the possibility of designing a vaccine against severe malaria that mimics an adult's immune response, making the infections less dangerous. But this would still be an enormous task.

"Similarly, if we can establish what the particular class of molecules are doing, then we may be able to develop a drug to modify this function and relieve symptoms of severe disease."

Malaria Mistreated in Nearly Two Thirds of Cases in Kenya

Authors and Disclosures

Information from IndustryAssess clinically focused product information on Medscape.
Click Here for Product Infosites – Information from Industry. November 26, 2009 (Washington, DC) — Results from a study conducted in 2 health facilities in Kenya show that the mistreatment of malaria might be as high as 66%. The findings, presented here at the American Society of Tropical Medicine and Hygiene 58th Annual Meeting by Yaw A. Afrane, MB, from the Kenya Medical Research Institute in Kisumu, confirm those from other studies about the mistreatment of malaria in certain regions.

Intensive malaria control programs have been implemented in sub-Saharan Africa; however, the reliability of hospital data on diagnosis and treatment has been questioned.

To determine if or how much misdiagnosis was occurring, Dr. Afrane and colleagues conducted both passive clinic-based and active community-based case surveillance in the communities of Kakamega, Vihega, and Emuhaya. Malaria is endemic in these communities, which are situated in the western highlands of Kenya.

The catchment populations for the passive clinic-based surveillance ranged from 21,000 to 26,085 patients; for the active community-based surveillance, the sampled populations ranged from 1789 to 1954. Mosquitoes, which breed during the wet weather, transmit malaria, so disease prevalence varies by season.

As expected, the active surveillance found a typical peak prevalence of 6% to 7% from May to July, the rainy season, and of 2% to 3% during the nonrainy season. However, when Dr. Afrane put the curve for the passive surveillance pattern against the active one, no seasonality pattern emerged.

"When we saw this discrepancy in the number of cases between one method and another, we wanted to see what was going on," Dr. Afrane said during an interview with Medscape Infectious Diseases. "You wouldn't expect to see a difference with a seasonally occurring disease like malaria." Several factors could explain such a difference, including overtreatment, misdiagnosis, presumptive treatment, and underreporting.

To study this, random blood slides were made from patients referred for malaria testing. Slides were analyzed by Dr. Afrane's research team and by hospital technicians. All readings were done in a masked fashion; readers did not know how the others had interpreted the slides.

Blood slides were obtained from patients who were presumptively treated for malaria because of the symptoms they showed. A questionnaire was designed to collect information from these patients, and clinicians were asked how they made their diagnosis of malaria.

The findings were quite striking, Dr. Afrane said. Among the 2544 outpatients (close to half were children younger than 5 years), 42% were diagnosed with clinical malaria and 85% presented with a fever.

According to Dr. Afrane, clinical malaria is diagnosed by the presence of fever, parasitemia (by microscopy), and other related symptoms, such as vomiting, headache, nausea, and diarrhea. However, microscopy didn't bear these findings out.

Of the 2544 patients, microscopy showed the "true positive" rate to be 35% (n = 914) and the "true negative" rate to be 64% (n = 1630). Among the 914 cases of true positives, the clinic diagnosed 54% as positive. All these subjects received antimalarial treatment.

For the 45.7% diagnosed as negative by the clinic, more than half (57%) received antimalarial treatment. Treatment of the true negatives shed even more light on what was going on, Dr. Afrane explained. Among these 1630 patients, the clinic diagnosed 28% as positive by microscopy. All these patients received antimalarial treatment. Among the nearly 72% that were deemed negative by the clinic, 68% received treatment.

The difficulty lies in the reliability of the microscopy test. "There are several reasons for the unreliability of microscopy," said Meredith McMorrow, MD, MPH, FAAP, from the Centers for Disease Control and Prevention's Malaria Branch in Atlanta, Georgia, and chair of the session. "Limited resources probably play a big role in terms of having good equipment, but high staff turnover and limited opportunities for training may also play a role."

Dr. Afrane agreed that this is a big part of the problem. "Some of the misdiagnosis problems can also come from cases where parasite levels are low, and therefore more difficult to accurately detect," Dr. Afrane told Medscape Infectious Diseases. "So what happens is that clinicians end up not trusting the test and make the decision to treat people based on clinical judgment."

Dr. Afrane and his team also studied data from 784 outpatients who did not receive diagnostic testing at the clinic visit, 37% of whom had a clinical diagnosis of malaria. The reasons for the diagnosis varied; 45% of patients refused testing because of lack of money, fear of having their blood drawn, or believing it wasn't necessary. Physicians did not request laboratory confirmation of malaria in approximately half the cases because they considered it unnecessary.

The Kenyan investigator reported that 63% of patients ended up being overprescribed malaria drugs, mostly artemisinin-combination therapy (ACT). ACT is now considered the best therapy for malaria caused by Plasmodium falciparum.

"There is a very big debate about whether presumptive treatment is or isn't good," said Dr. Afrane. "It's very hard for clinicians to see sick patients and not treat them." This challenge is compounded when a reliable diagnostic test is not available.

However, the misuse of drugs — as demonstrated in this study — always generates concern about the early onset of resistance, Dr. Afrane explained. In addition, the unreliability of hospital-based data makes accurate evaluation of malaria programs difficult.

But there is light on the horizon, he said. Rapid diagnostic tests (RDTs) for malaria detect specific antigens produced by malaria parasites that are present in the blood of infected individuals. Some RDTs also test for the presence of antibodies. "RDTs are being rolled out now for use in settings like this," noted Dr. McMorrow. "There are still some technical challenges, like stability under varying field conditions and educating staff about these new tools, but we think these are very promising in terms of improving diagnostic accuracy."

The study was funding by National Institutes of Health grants. The authors have disclosed no relevant financial relationships.

American Society of Tropical Medicine and Hygiene (ASTMH) 58th Annual Meeting: Abstract 679. Presented November 20, 2009.

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Authors and Disclosures
Journalist
Maria Sgambati, MD
Maria Sgambati, MD is a freelancer for Medscape.

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Scientists reveal malaria parasites' tactics for outwitting our immune systems

IMAGE: This is an Anopheles gambiae mosquito sucking blood from human skin. This mosquito is the vector for malaria in Africa.


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Malaria parasites are able to disguise themselves to avoid the host's immune system, according to research funded by the Wellcome Trust and published today in the journal Proceedings of the National Academy of Sciences.

Malaria is one of the world's biggest killers, responsible for over a million deaths every year, mainly in children and pregnant women in Africa and South-east Asia. It is caused by the malaria parasite, which is injected into the bloodstream from the salivary glands of infected mosquitoes. There are a number of different species of parasite, but the deadliest is the Plasmodium falciparum parasite, which accounts for 90 per cent of deaths from malaria.

The malaria parasite infects healthy red blood cells, where it reproduces. The P. falciparum parasite generates a family of molecules, known as PfEMP1, that are inserted into the surface of the infected red blood cells. The cells become sticky and adhere to the walls of blood vessels in tissues such as the brain. This prevents the cells being flushed through the spleen, where the parasites would be destroyed by the body's immune system, but also restricts blood supply to vital organs.

Symptoms can differ greatly between young and older children depending on previous exposure to the parasite. In young children, the disease can be extremely serious and potentially fatal if untreated; older children and adults who have grown up in endemic areas are resistant to severe malaria but rarely develop the ability to rid their bodies of the parasite.

Each parasite has 'recipes' for around sixty different types of PfEMP1 molecule written into its genes. However, the exact recipes differ from parasite to parasite, so every new infection may carry a set of molecules that the immune system has not previously encountered. This has meant that in the past, researchers have ruled out the molecules as vaccine candidates. However there appear to be at least two main classes of PfEMP1 types within every parasite, suggesting different broad tactical approaches to infecting the host. The most efficient tactic or combination of tactics to use may depend on the host's immunity.

Now, Dr George Warimwe and colleagues from the Kenya Medical Research Institute (KEMRI)-Wellcome Trust Programme and the Wellcome Trust Sanger Institute, have shown that the parasites adapt their molecules depending on which antibodies it encounters in the host's immune response. They have also found evidence to suggest that there may be a limit to the number of molecular types that are actually associated with severe disease.

"The malaria parasite is very complex, so our immune system mounts many different responses, some more effective than others and many not effective at all," explains Dr Peter Bull from the KEMRI-Wellcome Trust Programme and the University of Oxford, who led the research. "We know that our bodies have great difficulty in completely clearing infections, which begs the question: how does the parasite manage to outwit our immune response? We have shown that, as children begin to develop antibodies to parasites, the malaria parasite changes its tactics to adapt to our defences."

The researchers at the KEMRI-Wellcome Trust Programme studied malaria parasites in blood samples from 217 Kenyan children with malaria. They found that a group of genes coding for a particular class of PfEMP1 molecule called Cys-2 tended to be switched on when the children had a low immunity to the parasite; as immunity develops, the parasite switches on a different set of genes, effectively disguising it so that immune system cannot clear the infection

Dr Warimwe and colleagues also found an independent association between activity in Cys-2 genes and severe malaria in the children, suggesting that specific forms of the molecule may be more likely to trigger specific disease symptoms. This supports a previous study in Mali which suggested that the same class of PfEMP1 molecule was associated with cerebral malaria.

The findings could suggest a new approach to tackling malaria, in terms of both vaccine development and drug interventions, argues Dr Bull.

"If there exists a limited class of severe disease-causing variants that naturally-exposed children learn to recognise readily, this opens up the possibility of designing a vaccine against severe malaria that mimics an adult's immune response, making the infections less dangerous. But this would still be an enormous task.

"Similarly, if we can establish what the particular class of molecules are doing, then we may be able to develop a drug to modify this function and relieve symptoms of severe disease."


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