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Received September 9, 1998
The role of reactive oxygen species (ROS) participating in antiviral host defense is considered. Unlike antibacterial defense, when ROS and their derivatives act as biological weapons killing pathogenic bacteria, the function of ROS in the antiviral defense is assumed to be mediated by apoptosis. It is suggested that a cell activates generation of superoxide and hydrogen peroxide by xanthine oxidase as well as by intracellular NADPH-oxidase in response to appearance of a virus in its cytoplasm. Increase in ROS level turns on the process of programmed cell death in the infected cells. Moreover, H2O2 diffuses into the adjacent cells (due to its high membrane permeability), also inducing apoptosis (death of bystander cells). So, the infected cell and its neighbors (which are the most likely to be infected) are eliminated, thus blocking the spreading of the viral infection.
KEY WORDS: reactive oxygen species, hydrogen peroxide, virus, antiviral defense
ROS can be dangerous to the cell. For example, hydroxyl radical (OH·) can rapidly and irreversibly oxidize virtually any biological compound, thus altering its function. It is not a big surprise that the cell has a well-organized system of anti-ROS defense. The system includes several specific mechanisms blocking the formation of ROS or inactivating accidentally generated ROS [1, 2].
Altered cellular activity can result in dysfunctions of the complex antioxidant system, thus increasing the concentration of ROS. Hence, the cell can control its state by monitoring the level of ROS, similar to people who diagnose the onset of a disease by measuring the body temperature.
At least two systems sensitive to the concentration of ROS are known in bacteria. In one system, the receptor SoxRS responds to the level of O2-· [3-5] and in another system, oxyR measures the level of H2O2 [3, 6]. In both cases the signal is transduced to genome inducing coordinated changes in the function of multiple genes. Additional resources of antioxidant defense of the cell are thus mobilized.
Higher animals and humans also possess certain mechanisms monitoring the concentration of ROS. For example, increased O2-· level in the blood induces narrowing of the vessels and capillaries [7]. This effect can lower the content of O2 in the cells and tissues, thus inhibiting the formation of O2-· [2].
The list of pathologies associated with dramatic increase in the level of ROS includes viral infections [8]. This is not limited to the altered balance between the parasite reactions generating ROS and ROS inactivation processes. Maeda et al. [8-10] demonstrated that infection of mice with influenza virus induces strong activation of xanthine oxidase in the lung (the rate of the xanthine oxidase reaction in increased by 2-3 orders of magnitude). A similar effect was also detected in animals infected with cytomegalovirus.
Xanthine oxidase is the enzyme which catalyzes oxidation of xanthine and hypoxanthine by molecular oxygen. Unlike most oxidases which generate water from O2, xanthine oxidase converts O2 into O2-· and H2O2. So, it is similar to NADPH-oxidase of the plasma membrane of phagocytes, which reduces oxygen to superoxide [11].
In the case of phagocytes, O2-· is their biological weaponry used to defend against pathogenic bacteria. Apparently, ROS play a different role in case of viral infection. It was shown that the outburst of xanthine oxidase by itself does not suppress the production of the viruses [8, 12]. However, the virus can consider increased [ROS] as something dangerous. Certain viruses possess specific mechanisms preventing an increase in the level of ROS during infection. For example, human T-lymphotropic virus stimulates the formation of thioredoxin that is an important component of the antioxidant defense in the cell [13].
The herpes virus genome encodes for a specific protein ICP-4 which blocks apoptosis (programmed cell death) [14]. A similar situation is described in Sendai virus [15]. On the other hand, ROS are known to actively induce apoptosis [2, 16] and apoptosis is one of the ways to defend against viral infection; infected cells commit suicide, thus killing the viruses [17].
So, the following hypothesis is suggested to explain the role of xanthine oxidase activation and increase in ROS during viral infection.
The initial relationship between ROS and viral infection (infection --> disbalance of antioxidant defense --> increase in [ROS] --> elimination of infected cells by ROS-induced apoptosis) was probably modified during evolution so that the cell considers the appearance of a virus in the cytoplasm as a signal for ROS production. This results in increase in [ROS] long before this increase becomes inevitable due to cellular pathology occurring during intensive replication of the virus inside the cell. Increase in [ROS] should induce apoptosis in the infected cell before it becomes a source of massive infection for its neighbors. Another important consequence of the suggested mechanism should include a possibility of induction of apoptosis in the adjacent cells which directly contact with the infected cell and which are especially prone to infection. This can result from the diffusion of one ROS, namely H2O2. H2O2 is a small neutral molecule that easily penetrates through the biological membrane similarly to H2O. Evidently, the front of elevated concentration of H2O2 would spread significantly faster around the infected cell than the front of viral particles formed in the very same cell. Hence, an apoptotic zone would be formed around the cell which is a potential source of viral infection. This explains the phenomenon of bystanders, i.e., the cells that are not infected with the virus but adjacent to the infected cells and that are eliminated together with the latter.
Apoptosis can be transformed to necrosis during vigorous development of infection, and necrotic plaques appear that are specific symptoms of viral infection in plants infected with tobacco mosaic virus. In humans and animals, superproduction of H2O2 by xanthine oxidase in response to intensive viral infection can be so potent that it induces pathological effects by itself, and the virus plays only the trigger role. Administration of allopurinol, a specific inhibitor of xanthine oxidase, relieves the symptoms [8-10], whereas administration of adenosine, precursor of xanthine, worsens the disease [10].
The hypothesis that the cell detects a virus and responds by an outburst of enzymatic generation of ROS is based in particular on a work of Falciani et al. [18] who described induction by alpha-interferon of transcription of xanthine dehydrogenase, an enzyme that becomes xanthine oxidase during viral infection [8]. This effect can be an additional mechanism of antiviral defense mediated by interferon.
Interestingly, a healthy uninfected cell tends to maintain the rate of the xanthine oxidase reaction at a low but constant level. For example, this activity should be lowered by decreasing oxygen concentration. However, the data of Terada et al. [19] indicate that such effect is not detected because hypoxia turns on some regulatory mechanisms resulting in 6-fold potentiation of xanthine oxidase. Hyperoxia lowers the activity by several orders of magnitude. Variations of activity of xanthine oxidase ([O2]-dependent) apparently result from changes in enzyme activity and amount. Thus, the cell constantly keeps its xanthine oxidase mechanism at hand.
Apart from xanthine oxidase, intracellular NADPH-oxidase can participate in ROS generation during viral infection; this enzyme is homologous but not identical to a phagocyte analog. The main functional difference from the phagocyte enzyme is that generated superoxide appears on the inside the cell but not on the outside [20]. Participation of intracellular NADH-oxidase activity generating superoxide should not be neglected. Unfortunately, the nature of this activity remains unknown. On the other hand, parasite reactions of O2-· generation by the mitochondrial respiratory chain or cytochrome P450 are unlikely to generate ROS during viral infection because in this case ROS are side products of completely different functionally important processes.
Participation of ROS in apoptosis induced by viral infection was demonstrated for HIV [21, 22] and type I human T cell leukoma virus [23-25]. In the latter case, infected cells are significantly more susceptible to ROS than normal ones [23, 26]. An inducer of apoptosis, 13-cys-retinoic acid, induced apoptosis the cultured cells from leukemia patients, whereas in the cells from the healthy donors this effect was not detected. Considering this, it is especially important that apoptosis of leukemia cells was significantly suppressed in the presence of catalase, an H2O2-decomposing enzyme [24].
The hypothesis could resolve the issue that was previously discussed in our journal concerning whether ROS are mediators of signal transduction in the cell and organism. The scientists supporting this regulatory role list the examples of regulatory responses of cells towards ROS [27, 28], whereas their opponents emphasize the toxicity of ROS and suggest that these dangerous compounds could be hardly selected by evolution to mediate any useful function [29]. I think that one ROS, namely H2O2, is a real signal mediator but its role is limited to "bad news"; H2O2 informs the cell that it should commit suicide. In such situation, any danger of H2O2 as a precursor of toxic hydroxyl radicals seems unimportant because the cell is supposed to die in any case.
Also, another evolutionary aspect of the problem should be considered. Apparently, detection of even low concentrations of O2-· and H2O2 was initially used by the cell exclusively for mobilization of the antioxidant system. However, the very same mechanism could be used to achieve some other goal due to switching of a metabolic response that is included into the antioxidant system. For example, stimulation of cell proliferation in response to the increasing levels of ROS makes sense as a mechanism stimulating repair to correct possible oxidative damage of DNA [17]. On the other hand, considering that such device was invented by evolution, it could be used to turn on proliferation in situations which are not associated with the anti-ROS defense. For instance, ROS induce proliferation of aortic smooth muscle cells, and this fact is apparently not related to the antioxidant system [20].
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