July 27, 2011
By Fábio de Castro
Agência FAPESP – Various pathogens employ a treacherous strategy to invade a host cell: they subvert existing mechanisms in the main cell membrane to have access to the cytoplasm
A group of Brazilian researchers have just shown that Trypanosoma cruzi, which causes Chagas disease, uses this type of subterfuge, taking advantage of the cell membrane repair mechanism as a resource for invasion.
The study, published in Journal of Experimental Medicine, originated in research lines developed by Norma Andrews, of the Department of Cell Biology and Molecular Genetics at the University of Maryland, and Renata Mortara of the Microbiology, Immunology and Parasitology Department at Universidade Federal de São Paulo (Unifesp).
The study was highlighted in editorials published by the magazines Cell and Nature Reviews in Microbiology. The first author of the article, Maria Cecília Fernandes, concluded her doctorate in 2007 with a FAPESP fellowship in Mortara’s lab at Unifesp and prepared the study during her post-doctoral research at Andrews’ laboratory in the United States. The other authors are Mauro Cortez, Andrew Flannery and Christina Tam, all of the University of Maryland.
Andrews has studied the interaction between Trypanosoma cruzi and host cells since she did her doctorate at the Biochemistry Department at Universidade de São Paulo (USP), also with a FAPESP fellowship, under the orientation of Walter Colli.
The Brazilian researcher who is now based in the United States conducted her post-doctoral studies with Victor Nussenzweig at the New York University. She was also a professor and researcher at Yale University before transferring to the University of Maryland.
Mortara received FAPESP funding to do an internship at Andrews’ laboratory under the Thematic Project “Molecular studies on Trypanosoma cruzi and its interaction with cells and factors from the host in vitro and in vivo”, coordinated by José Franco da Silveira Filho, also of Unifesp.
While Mortara develops studies on cellular invasion by the parasite, Andrews has given special attention studying the plasma membrane repair in eukaryotic cells. According to Mortara, through her work Fernandes has managed to demonstrate the meeting of two important biological areas: cell invasion by the parasite and membrane repair.
“The article had major repercussions because it demonstrates that Trypanosoma cruzi is one more microorganism capable of exploring a constitutive mechanism, in addition to offering a detailed description of the mechanism that it uses to do so,” Mortara told Agência FAPESP.
Andrews’ laboratory has developed studies on the functions of lysosomes – cellular organelles responsible for degrading particles from extracellular material – in membrane repair. According to Mortara, scientists already knew that when a cell membrane is damaged, the lysosomes are recruited and release their contents, which are fused with the membrane, repairing the lesion.
“The Maryland group recently observed that this repair mechanism has two stages. When the lysosome fuses with the membrane, the cell still continues to rupture. Then part of the membrane is internalized by the cell, incorporating the lesion. The rupture is englobed by this type of ‘bubble’, moving inside the cell and preserving the membrane’s properties,” she explains.
Fernandes coupled knowledge about the parasite’s invasion mechanism with membrane repair. The researcher observed that the parasite causes damage to the membrane, inducing the lesion internalization process. “As the parasite remains close to the lesion, the process ends up taking it inside the cell,” tells Mortara.
When the parasite damages the membrane, the damage itself does not directly provoke its entry to the cytoplasm. But it does initiate the mobilization of lysosomes, which in addition to fusing its contents with the cell surface, also release lysosomal enzyme acid sphingomyelinase (ASMase), which is dependent on calcium.
“The study shows that cells with reduced ASM are resistant to infection and that treating cells with extracellular enzymes is enough to mediate the entry of the parasite. Increased ASM stimulate endocytosis, giving the parasite the chance to enter the cell,” she explains.
According to the study, Trypanosoma cruzi’s use of the membrane repair mechanism can help explain why these parasites tend to infect smooth muscles and cardiomiocytes – tissues in which these repair mechanisms are especially active.
The article “Trypanosoma cruzi subverts the sphingomyelinase-mediated plasma membrane repair pathway for cell invasion (doi:10.1084/jem.20102518), by Maria Cecília Fernandes et al, can be read by subscribers of the Journal of Experimental Medicine at: jem.rupress.org/content/early/2011/04/27/jem.20102518.abstract.Republish
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