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
Nurturing the Parasite
The infection of a cell allows pathogens to take over the cell's biochemical machinery and produce offspring by using the nutrients that it finds in the host cell. Eventually, the production requires the delivery of additional nutrients at a rate that far exceeds the normal demand of a noninfected cell. Thus the pathogen has to manipulate the host cell's transport systems in the plasma membrane, not only to allow for this additional uptake of nutrients, but also to dispose of waste products that accumulate through the intense activity.
This manipulation is particularly obvious during the infection of red blood cells by the malaria-causing protozoan Plasmodium. Before infection, an erythrocyte is little more than a sack of hemoglobin proteins with a very low need for nutrients. Its membrane mainly contains transporter proteins that exchange bicarbonate ions, HCO3–, with the surrounding medium and maintain the cell volume through the exchange of other ions. Since the cell does not synthesize proteins, DNA or membranes, it has no need for amino acids, nucleic acids, lipids, vitamins and so forth. The replicating malaria pathogen, however, has an excessive requirement for all these nutrients. Furthermore, to fuel the replication process, Plasmodium needs large amounts of glucose; indeed, an infected erythrocyte takes up 40 to 100 times more glucose than a noninfected cell.
To gain access to the necessary nutrients, Plasmodium forces the host cell to alter the transport properties of its membrane by inducing the so-called new permeability pathway. The pathogen forces the infected cell to activate additional transport proteins in its plasma membrane that carry sugars, nucleic acids, membrane components and other substances from the intercellular medium into the cell. The necessity of the new permeability pathway for Plasmodium's survival and replication is illustrated by the fact that several inhibitors of this pathway eventually kill the pathogen while it still remains in the erythrocyte.
The essential nature of the new permeability pathway is not yet clear and is being intensely studied. Theoretically, the pathogen could express the respective transport systems itself and insert the proteins into the host-cell membrane. The advantage of this approach is that Plasmodium would not depend for its survival on the presence of adequate host-cell membrane proteins. The disadvantage, however, is that its proteins would be exposed at the membrane and thus would be recognized as alien structures by antibodies. Using the antibodies as markers, immune cells would sweep in and destroy the infected cell and the pathogen in it.
Alternatively, Plasmodium could modify existing host-cell membrane proteins to turn them into the new permeability pathway. The advantage of this mechanism is that the cell would remain undetected by the immune system. Indeed, recent experiments indicate that at least part of the new permeability pathway results from modification of existing cell-membrane proteins by the pathogen. Because Plasmodium depends on creation of the new permeability pathway to proliferate in the infected cell, investigators are hoping to find new malaria drugs to block this pathway. There is little doubt that other pathogens that rapidly proliferate inside infected host cells have to modify the transport properties of these cells in order to gain access to nutrients. But not much is known so far about the changes in nutrient transport that these pathogens induce in their host cells.
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