A fierce war begins raging in the human organism only days after a bite by a mosquito of the genus Anopheles infected with Plasmodium, a protozoan.
The parasites enter the bloodstream and rapidly reach the liver, invading cells (hepatocytes) and multiplying at breakneck speed. The parasites generated in the liver are released back into the bloodstream, where they infect and destroy red blood cells (erythrocytes).
This scenario is part of a typical case of malaria, an acute febrile illness that kills half a million people every year and against which there are no vaccines.
After infection, the immune system begins a counter-attack. On one flank, antibodies are intensively produced to combat the disease by stopping the invasion of pathogens. On the other, a pro-inflammatory response to the infection is launched. Macrophages go into action, gobbling up (phagocytizing) the red blood cells infected by Plasmodium to control its proliferation in the patient’s bloodstream.
A paper published in PLOS Pathogens based on research conducted in Brazil at the University of São Paulo’s Biomedical Science Institute (ICB–USP) highlights the pivotal role of the P2X7 receptor in the immune response and the importance of a balance between the defense system’s pro-inflammatory and pro-antibody strategies for the war against malaria to succeed.
“We found that in malaria caused by Plasmodium chabaudi, an animal model used for experiments on malaria, it’s important to achieve a balance between the pro-inflammatory response and the production of antibodies. When the cell damage sensor P2X7 is removed, only antibody production remains, and the defense becomes insufficient,” said Érika Salles, first author of the paper and a postdoctoral student at ICB–USP’s Immunology Department with a scholarship from FAPESP.
“P2X7’s role is to tell the immune system that a robust response to the action of the pathogen is needed, comprising not just antibody production but also macrophage activation,” Salles explained.
In the study, red blood cells in mice infected by P. chabaudi released adenosine triphosphate (ATP) into the extracellular medium as a damage signal that can be recognized by P2X7 receptors.
When these receptors detect cell damage or stress in tissue infected by the pathogen, they trigger a pro-inflammatory response in which T CD4+ lymphocytes produce the protein interferon gamma and consequently activate macrophages that will ingest the infected blood cells. The immune response is balanced as a result. Male mice without P2X7 receptors did not survive the infection, whereas females developed a more severe chronic disease.
According to Salles, the need for a balance between the two responses is important input for novel vaccine production strategies. “We know there is polymorphism in humans: some people lack P2X7 receptors, and in others they are strongly activated,” she said.
Despite efforts to develop anti-malarial vaccines and drugs, infection by Plasmodium continues to cause so many deaths above all because the various escape mechanisms for the parasite require an adequate immune response to eliminate the infection.
“Most vaccines induce antibody production very well, but in the case of malaria and several other diseases, it’s also necessary to induce the activation of T lymphocytes and the production of interferon in order to ensure protection,” said Maria Regina D’Império Lima, last author of the article and principal investigator for the Thematic Project “Intervention in signaling pathways associated with the recognition of cellular damage to reduce the pathology of severe forms of malaria and tuberculosis”, supported by FAPESP.
Although the paper describes a conceptual study in immunology, it could have implications for the development of vaccines that involve both strategies and hence ensure a more robust immune response. According to D’Império Lima, tuberculosis is another example of a disease that can be combated only by pro-inflammatory action.
“Against tuberculosis we have only BCG, which protects children from the meningococcal form of the disease but isn’t very effective against the pulmonary form,” she said. “We don’t have efficient vaccines that induce the production of interferon gamma to assist with protection against tuberculosis and malaria, for example. For this reason, it’s worth considering the possibility of developing together with the vaccine a nanoparticle that releases ATP to signal the existence of tissue damage and the need for a robust response.”
According to D’Império Lima, a complete understanding of the mechanisms underlying the acquisition of protective immunity is crucial to vaccination strategies capable of eradicating malaria.
“As we suggest at the end of our article, we could think about including ATP, or non-degradable forms of ATP, in the composition of what we call an adjuvant to try to teach the immune system that when combating something dangerous with major cell damage, the response must also produce interferon gamma so as to activate macrophages,” she said.
Source : By Maria Fernanda Ziegler | Agência FAPESP