A new study led by Maria Manuel Mota, group leader at Instituto de Medicina Molecular João Lobo Antunes (iMM; Portugal), now shows that malaria parasites secrete the protein EXP2 that is required for their entry into hepatocytes.
Plasmodium parasites are the causative agents of malaria, one of the most prevalent infectious diseases, that still infect yearly over 200 million people worldwide. After being transmitted, Plasmodium parasites travel to the liver, where they infect its cells, called hepatocytes. It is still largely unknown how parasites invade hepatocytes and consequently, few therapies are available to prevent this initial step.
Findings of a study shedding light on this were published in the scientific journal Nature Communications, opening a new avenue for prophylactic anti-malarial strategies, since blocking or decreasing the infection of the liver can prevent the disease.
The research team led by Maria Manuel Mota at iMM discovered that malaria parasites secrete a protein named EXP2, before invading the hepatocyte, creating pores in the host cell's membrane.
PhD student and the study’s first author, João Mello-Vieira, explained that they observed that the Plasmodium parasites, that are called sporozoites at this stage, secrete EXP2 molecules before entering the cell and this protein creates pores in the outer membrane of hepatocytes, facilitating parasite entry.
EXP2 had been widely studied during the blood stage of infection, where it has a crucial role only after the parasite has established itself inside the red blood cell. However, its role during the liver infection was unclear.
The research team observed that sporozoites that lack EXP2, are not able to invade hepatocytes. When it is added to the cell, the parasites that lack EXP2 were able to enter cells normally.
“This created another question: the pores created by EXP2 are not big enough for the parasite to go through them. So, how is EXP2 facilitating invasion?” Said Vanessa Zuzarte Luis, senior author of the work.
Other pathogens, such as adenoviruses, bacteria and another parasite (Trypanosoma cruzi) have been shown to invade using this type of pore-forming proteins. In such cases, the secreted pore-forming proteins, induce a damage in the membrane of the cell, so that the cell actively engulfs the pathogen, as it is repairing the pore.
“We hypothesized that Plasmodium sporozoites induce a similar response. In fact, if we block the key human enzyme for this repair process, acid sphingomyelinase, we can reduce invasion of hepatocytes by sporozoites,” said Vanessa Zuzarte Luis.
“Our results hint at the convergent evolution of different pathogens, that evolved a common strategy to hitchhike their way into the cells. It also creates an opportunity for prophylactic interventions. If we are able to block parasite proteins or the repair process, we are able to prevent infection of the liver by Plasmodium parasites, preventing malaria before the parasite can cause any harm. Moreover, if we are able to block EXP2, we might be able to prevent the development of the parasite in the ensuing blood stage.” Said Maria Manuel Mota.