Immunological defense mechanism leaves malaria patients vulnerable to deadly infection

Malaria patients are at high risk of developing fatal bacterial infections, especially salmonella infections. This is commonly believed to be due to generalised immunosuppression by malaria, whereby the entire immune system is weakened and compromised.

However, researchers at the London School of Hygiene & Tropical Medicine have discovered that the increased vulnerability to salmonella infections is a side effect of the body's attempts to protect itself from the damaging effects of the malaria infection.

The researchers describe this defence mechanism as a trade-off, where the body fights one enemy but exposes itself to the other. This was demonstrated in their study exploring the connection between malaria and non-typhoid salmonella (NTS)- an infection which is particularly dangerous for children.

Children with malaria can develop anaemia, which puts them at higher risk of developing severe bacterial infections of the blood, caused in up to 70% of the cases by NTS. This infection is fatal in up to 25% of the infected children. To prevent these bacterial infections, or develop an effective treatment, scientists needed to understand the mechanism behind this connection between malaria and salmonella.

Professor Eleanor Riley, one of the lead authors of the study, says: “It is a widespread belief that malaria is an immunosuppressive disease; that once the disease is contracted, the patient will be susceptible to several other infections because of a compromised immune system. However, this study shows that increased susceptibility to salmonella infections is due to a very specific immunological effect which does not affect the immune system as a whole.”

Infection by the malaria parasite periodically causes red blood-cells to burst, releasing the parasite offspring, but also releasing heme – a breakdown product of haemoglobin – which is extremely toxic once outside the red blood cell.

The Medical Research Council (MRC) funded study, published in Nature Medicine, found that in malaria-infected mice (which show exactly the same susceptibility to salmonella as is seen in humans) the body's natural response to defend itself from the dangers of heme, an enzyme that degrades it (heme oxygenase-1 or HO-1), very selectively affects the immune system, crippling the production of white blood-cells (neutrophils) that are essential to fight NTS. These crippled cells are unable to kill the bacteria, allowing them to spread freely.

“The key is in the rupture of the red-blood cells,” says Dr Aubrey Cunnington, Clinical Research Fellow at LSHTM and co-author of the study. “Sickle-cell anaemia patients, where similar red cell damage occurs, are also more susceptible to NTS. But, numerically speaking, malaria is the most common cause of NTS. Where the incidence of malaria is decreasing, so are the salmonella infections.”

The team identified Tin Protoporphyrin (SnPP) as a candidate for the prevention of salmonella infection. SnPP inhibits the activity of the heme oxygenase enzyme, reversing the susceptibility to salmonellosis in malaria infections.

But the authors say that careful testing will be needed before considering SnPP use in humans, as blocking the action of HO-1 may leave the heme free to cause tissue damage.

For further information or to request interviews please contact the press office of the London School of Hygiene & Tropical Medicine by emailing Paula.Fentiman@lshtm.ac.uk or Giorgio.Defaveri@lshtm.ac.uk or calling +44 (0)20 7927 2802.

Notes for Editors

1. Reference Article. A.J. Cunnington, J.B. de Souza, R-M. Walther, E.M.Riley; Malaria impairs resistance to Salmonella through heme- and heme oxygenase–dependent dysfunctional granulocyte mobilization, Nature Medicine, (2011), http://dx.doi.org/10.1038/nm.2601

2. Additional research notes. Although this study was carried out in mice, the team's ongoing (unpublished) studies in The Gambia have confirmed that exactly the same type of neutrophil dysfunction occurs in children with malaria. Importantly, their neutrophil function is impaired for up to two months after treatment of their malaria infection, leaving them at risk of NTS infection for many weeks after recovering from their acute episode of malaria.

3. About LSHTM. The London School of Hygiene & Tropical Medicine (LSHTM) is a renowned research-led postgraduate institution of public health and global health. Its mission is to improve health in the UK and worldwide through the pursuit of excellence in research, postgraduate teaching and advanced training in national and international public health and tropical medicine, and through informing policy and practice in these areas. Part of the University of London, the School is the largest institution of its kind in Europe with a remarkable depth and breadth of expertise encompassing many disciplines associated with public health. www.lshtm.ac.uk

4 – About the MRC. For almost 100 years the Medical Research Council has improved the health of people in the UK and around the world by supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and scientific expertise behind medical breakthroughs, including one of the first antibiotics penicillin, the structure of DNA and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health challenges of the 21st century.