FEATURE ARTICLE
Pathogens, Host-Cell Invasion and Disease
Invading pathogens can co-opt even the cells of the immune system. New anti-infective drugs may arise from an understanding of this chemical warfare
Erich Gulbins, Florian Lang
Pushing the Right Buttons
Internalization begins when the invading germ attaches to the host cell's plasma membrane and triggers the host cell to wrap its membrane around the invader. Eventually, when the pathogen is completely wrapped up by the cell membrane, this structure buds off to form a membrane-coated vesicle with the virus, bacterium or other microorganism inside.
Listeria attaches to its target by displaying a so-called InlA (internalin) protein on its surface. InlA is specialized in making contact with a protein called E-cadherin on the surface of epithelial cells in the intestines. This initial contact triggers the movement of other host-cell surface proteins to the binding site; these reinforce the binding of the bacterium to the epithelial cell and help to stimulate the cytoskeleton. Another protein on Listeria's surface, InlB, contacts two surface receptors on the host cell, which in turn activate an enzyme called PI3-kinase in the cell. PI3-kinase starts a series of events in the cell, which eventually induce the changes in the cytoskeleton that are necessary to internalize the attached bacterium. Indeed, this enzyme plays a key role in the Listeria infection process; experiments with an inhibitor of PI3-kinase have shown that the bacterium is unable to enter the cell if the enzyme cannot be activated.
An important factor in this process is the cytoskeleton, a scaffold of various proteins in the cell that define and maintain the cell's form. It is the cytoskeleton that performs the initial ruffling of the plasma membrane and the subsequent changes needed to wrap the membrane around the pathogen. This is an intricate process, so an invading pathogen has to manipulate the host cell's biochemical machinery considerably to induce its internalization. This task is performed by specialized molecules on the bacterium's surface that attach to specific receptor molecules on the host cell's surface. These receptors are molecular switches that react to specific molecules in the outer medium and induce metabolic changes within the cell. By pressing the right buttons, sending the right signals to the target cell, an invading pathogen can thus start the necessary events in the host cell's interior.
Many viruses use similar mechanisms to get into their target cells. The human immunodeficiency virus (HIV) that causes AIDS, for instance, first attaches to several proteins on the host cell's surface, triggering its internalization. After the virus has been taken up by the cell, its hull dissolves and releases the virus's genetic material, which is used by the host cell's biochemical machinery to produce more virus particles.
Several other bacteria have developed an even more sophisticated mechanism for forcing entry into the host cell. They carry needle-like structures on their surface through which they inject into the host cell proteins that eventually trigger internalization of the bacterium. Shigella flexneri uses this mechanism, called a type III secretion system, to inject two proteins that interact with signal-transduction proteins and the host cell's cytoskeleton. The activation of those proteins finally results in the reorganization of the cytoskeleton and the formation of ruffles in the plasma membrane required to internalize the pathogen.
A variation of this process, called phagocytosis, is actually used as a defense mechanism against invading bacteria. Some immune cells, and also epithelial cells in the intestines and the respiratory tract, engulf invading pathogens, take them up and digest them by breaking them down into their constituents. In particular, macrophages are specialized in destroying pathogenic bacteria through this process. Yet some pathogens, such as Listeria or the plague-causing Yersinia pestis, are able to manipulate phagocytosis so that they survive.
For those pathogens, it is important to stop the machinery eventually leading to their digestion. When a macrophage engulfs a cell, the result is a newly created vesicle called a phagosome. The phagosome fuses with a lysosome, another vesicle that contains a high concentration of digestive enzymes specialized in breaking down biological molecules. Several pathogens, such as the tuberculosis-causing Mycobacterium tuberculosis, the leprosy-causing Mycobacterium leprae or Legionella pneumophila, the cause of Legionnaires' disease, have been shown to prevent or slow down the fusion of the phagosome with the lysosome. The ability to redirect the phagosome pathway is presumably important for their survival and replication in the infected cell.
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