In a groundbreaking study published in the December 4 issue of the scientific journal Cell, an investigation team led by Miguel Soares, from the Gulbenkian Institute of Science (IGC), found that specific components of bacteria residing in the gut can trigger a natural defense mechanism that protects against the transmission of malaria.
Over the past few years, the scientific community has become more aware of the fact that humans live in a constant symbiotic relationship with the vast community of bacteria and other microbes that reside in our gut.
This community of microbes, called the gut microbiota, does not necessarily cause disease. Rather, the microbiota can influence a variety of physiological functions necessary to maintain human health.
Some of these microbes, including strains of Escherichia coli (E. coli) that normally inhabit the human intestine, express on their surface sugar molecules known as carbohydrates or glycans. These glycans can be recognized by the human immune system, resulting in the production of high levels of natural antibodies present in the bloodstream of adult individuals.
It is speculated that natural antibodies directed against sugar molecules expressed by gut bacteria may also recognize other similar sugar molecules expressed by pathogens, that is, by parasites that can cause disease in humans.
Bahtiyar Yilmaz, a PhD student at the IGC in Miguel Soares' laboratory, discovered that the parasite Plasmodium, the agent responsible for malaria, expresses a sugar molecule called α-gal (alpha-gal) that is also expressed on the surface of a strain of E. coli existing in the human gut microbiota.
Through experiments carried out in rats, Bahtiyar Yilmaz discovered that the expression of α-gal by these bacteria, when residing in the intestine, is sufficient to induce the production of natural anti-α-gal antibodies that recognize the same sugar molecule on the surface of the intestine. Plasmodium.
Bahtiyar then found that these antibodies bind to the α-gal on the surface of the parasite immediately after its inoculation into the skin by the mosquito that transmits malaria. When this occurs, the anti-α-gal antibodies activate an additional mechanism of the immune system – the complement – which causes small holes in the Plasmodium killing the parasite before it can get out of the skin.
The protective effect is such that, when present at high levels at the time of the mosquito bite, anti-α-gal antibodies are able to prevent the parasite from passing from the skin to the bloodstream and, in doing so, block the transmission of malaria .
Before these studies, it was already known that only a fraction of all adult individuals who are confronted with a mosquito bite in malaria-endemic areas become infected with the parasite. Plasmodium and eventually develop malaria.
This supports the theory that adults may have a natural defense mechanism against malaria transmission, which contrasts sharply with what is seen in children under 3 to 5 years of age who are much more susceptible to contracting malaria.
When individuals from a malaria endemic area in Mali were analyzed, the team led by Miguel Soares, in collaboration with a team led by Peter D. Crompton of National Institute of Allergy and Infectious Diseases (Maryland, USA) and University of Sciences, Techniques and Technologies of Bamako (Bamako, Mali) established that individuals who have the lowest levels of circulating anti-α-gal antibodies are also the most susceptible to malaria.
In contrast, individuals with higher levels of circulating anti-α-gal antibodies are less likely to become infected and develop malaria. The researchers concluded that the reason younger children are so susceptible to malaria is probably because they have not yet generated enough natural antibodies directed against the α-gal sugar molecule.
In order to overcome this gap, Bahtiyar Yilmaz found that when mice were vaccinated against a synthetic α-gal molecule, which is relatively easy to produce and inexpensive, they produced high levels of highly protective anti-α-gal antibodies against α-gal. transmission of malaria by mosquitoes.
Whether this “trick” can be applied to humans, particularly younger children, in order to protect them against malaria transmission, is a pressing question that remains to be answered.
An estimated 3,4 billion people are at risk of contracting malaria, and 2012 WHO data indicate that around 460 African children died before their fifth birthday. The present study argues that if we manage to induce the production of antibodies against α-gal in these children, we can reverse these worrying numbers.
Miguel Soares comments: “We observed that children under 3 years of age do not have sufficient levels of anti-α-gal antibodies, which may be one of the reasons for their greater susceptibility to malaria. One of the wonders of the protective mechanism we've now discovered is that it can be induced through a standard vaccination protocol, leading to the production of high levels of anti-α-gal antibodies that can bind and kill the parasite. Plasmodium. If we can vaccinate these young children against α-gal, many lives can be saved.”
This study was developed at the IGC in collaboration with the National Institute of Allergy and Infectious Diseases (Maryland; USA), Institute of Hygiene and Tropical Medicine (Lisbon, Portugal), St Vincent's Hospital e University of Melbourne (Victoria, Australia), University of Chicago (Chicago, USA), and University of Sciences, Techniques and Technologies of Bamako (Bamako, Mali).
This investigation was funded by Bill and Melinda Gates Foundation (USA), by the Foundation for Science and Technology (FCT, Portugal), and by the European Research Council (ERC).
Article reference: Bahtiyar Yilmaz, Silvia Portugal, Tuan M. Tran, Raffaella Gozzelino, Susana Ramos, Joana Gomes, Ana Regalado, Peter J. Cowan, Anthony JF d'Apice, Anita S. Chong, Ogobara K. Doumbo, Boubacar Traore , Peter D. Crompton, Henrique Silveira, and Miguel P. Soares. (2014). Gut Microbiota Elicits a Protective Immune Response against Malaria Transmission. Cell 159. Doi: http://dx.doi.org/10.1016/j.cell.2014.10.053
Ana Mena (IGC)
Author Ana Mena | Science in the Regional Press – Ciência Viva
Photo caption: Research team led by Miguel Soares at Instituto Gulbenkian de Ciência. Credits: Roberto Keller (IGC).
Comments