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Oxidative stress is implicated in the pathogenesis of several viral infections, including hepatitis, influenza, and AIDS. Dietary oxidative stress due to either selenium or vitamin E deficiency increases cardiac damage in mice infected with a myocarditic strain of coxsackievirus B3. Such dietary oxidative stress also allows a normally benign (i.e. amyocarditic) coxsackievirus B3 to convert to virulence and cause heart damage. This conversion to virulence is due to a nucleotide sequence change in the genome of the benign virus, which then resembles more closely the nucleotide sequence of virulent strains. Although it has been known for many years that poor nutrition can affect host response to infection, this is the first report of host nutrition affecting the genetic sequence of a pathogen. Further research is needed to determine whether poor host nutrition plays any role in the emergence of new vital diseases via alterations in the genotype of an infectious agent.

Under appropriate conditions, deficiencies of certain minerals and vitamins as well as high intakes of dietary fat increase the toxicity of a given dose of lead in experimental animals. The severity of lead poisoning can also be increased by the consumption of either deficient or excessive levels of protein. Mineral deficiencies appear to have some of the most profound effects on lead toxicity, since the consequences of plumbism can be exaggerated by feeding diets low in calcium, phosphorus, iron, zinc, and, in some cases, copper. Evidence for an antagonism between lead and nutritional levels of selenium is inconclusive. Vitamin E deficiency and lead poisoning interact to produce an anemia in rats that is more severe than that caused by either treatment alone. Lead apparently exerts a pro-oxidant stress on the red cell, thereby causing its accelerated destruction. One of the biochemical mechanisms of lead poisoning may be the disruption of normal membrane architecture, thereby leading to peroxidative damage. Epidemiological surveys have suggested a negative correlation between the poor nutritional status of children with regard to calcium and the concentration of lead in blood. Other examples of potential interactions of mineral status and lead poisoning in humans include the hypothesized hazards of soft water to public health in areas with lead plumbing and the possible role of mineral deficiencies in the etiology of pica. Experimental studies have shown that in some situations combined nutritional deficiencies can have an additive effect in potentiating lead toxicity.

In 1979, Chinese scientists reported that selenium had been linked to Keshan disease, an endemic juvenile cardiomyopathy found in China. However, certain epidemiological features of the disease could not be explained solely on the basis of inadequate selenium nutrition. Fluctuations in the seasonal incidence of the disease suggested involvement of an infectious agent. Indeed, a coxsackievirus B4 isolated from a Keshan disease victim caused more heart muscle damage when inoculated into selenium-deficient mice than when given to selenium-adequate mice. Those results led us to study the relationship of nutritional status to viral virulence. Coxsackievirus B3/0 (CVB3/0), did not cause disease when inoculated into mice fed adequate levels of Se and vitamin E. However, mice fed diets deficient in either Se or vitamin E developed heart lesions when infected with CVB3/0. To determine if the change in viral phenotype was maintained, we passaged virus isolated from Se-deficient hosts, designated as CVB3/0 Se-, back into Se-adequate hosts. The CVB3/0 Se- virus caused disease in Se-adequate mice. To determine if the phenotype change was due to changes in the viral genome, we sequenced viruses isolated from Se-deficient mice and compared them with the input CVB3/0 virus. Six point mutations differed between the parent strain and the recovered CVB3/0 Se- isolates. When the experiment was repeated using vitamin E-deficient mice, the same 6 point mutations were found. This is the first report of a specific host nutritional deficiency altering viral genotype. Keshan disease may be the result of several interacting causes including a dominant nutritional deficiency (selenium), other nutritional factors (vitamin E, polyunsaturated fatty acids), and an infectious agent (virus).

Levander discusses some of the basic biological features of the coxsackievirus and considers the notion that the diet of the host could change virulence through an effect on the pathogen itself rather than through an effect on the host.

Excess iron (Fe) intake has been associated with an increased risk of cardiovascular disease in humans, presumably the result of increased oxidative stress. Previous work by us has shown that feeding a high-Fe diet to selenium (Se)-deficient weanling mice for 4 wk resulted in elevated plasma cholesterol and triglycerides and increased hepatic thiobarbituric acid reactive substances (TBARS). Here, we report the effect of Fe overload in mice lacking cellular glutathione peroxidase (GPX1 knockout [KO] mice), the selenoenzyme thought to account for much of the antioxidant action of Se. Four groups of 9-13 weanling wild-type (WT) or GPX1 KO mice were randomly assigned, then fed either an Fe-adequate (35 ppm Fe) or high-Fe (1100 ppm Fe) casein-based diet for 4 wk. Iron was added as ferric citrate. Both diets also contained 0.2 ppm Se added as sodium selenite. As expected, liver GPX1 activity was essentially absent in the KO mice. Another Se parameter measured (hepatic thioredoxin reductase activity) did not vary across groups. Although liver Fe was elevated in mice fed the high-Fe diet, liver TBARS was largely unaffected either by mouse genotype or diet fed. Moreover, plasma lipids were not elevated in the Fe-overloaded GPX1 KO mice. Thus, decreased GPX1 activity cannot account for the pro-oxidant hyperlipidemic effects observed earlier in mice fed the high-Fe Se-deficient diet. This suggests that impairment of Se functions other than GPX1 activity may be responsible for the elevated plasma lipids and hepatic TBARS seen in the Fe-overloaded Se-deficient mice.

Feeding 20% (w/w) menhaden-fish oil in a standard laboratory chow diet for 4 wk partially protected CBA/CaJ mice from the central nervous system consequences of infection with Plasmodium berghei (ANKA). Full protection (complete survival for 14 days postinfection) could be obtained by feeding a purified pro-oxidant vitamin E-deficient diet containing 4% (w/w) menhaden oil (MO - VE diet). The purified pro-oxidant MO - VE diet also exerted a pronounced suppressive effect against the parasite (depressed 6-day parasitemias). The anitmalarial effect of the MO - VE diet could be prevented by supplementing the diet with vitamin E or with either of 2 synthetic antioxidants, N,N′ -diphenyl-p-phenylenediamine or probucol. These results suggest that the fish oil exerts its antimalarial effect by imposing a dietary-induced oxidative stress on the infected host erythrocyte, the parasite, or both. Nutritional manipulation of host oxidative stress status may be a useful adjunct therapy in patients undergoing treatment with pro-oxidant antimalarials such as drugs of the qinghaosu family.

The experimental evidence obtained with laboratory animals which shows that the toxicities of lead, cadmium, and mercury can be increased by deficiencies of certain essential nutrients such as calcium, iron, zinc, and selenium is briefly reviewed. An idealized theoretical model which indicates the possible influence of multiple nutritional deficiencies on the toxicity of a heavy metal is presented. It is suggested that multiple marginal nutritional deficiencies may be of importance in determining the response of humans to the toxic effects of various heavy metal pollutants.

A trial was conducted to determine the effects of dietary level of selenium on the pathogenesis of Fusarium-induced tibial dyschondroplasia (FITD) in broiler chicks, and to assess the applicability of FITD as an animal model of Kashin-Beck disease of humans. Day-old female broilers were fed diets that were deficient in selenium (0.02 ppm Se), adequate in selenium (0.15 ppm Se), or generous in selenium (0.50 ppm Se). TDP-1, the toxic component of the fungus, was administered to 15 of 26 chicks in each dietary group starting at 1 week of age and continuing until the chicks were killed at 24-30 days of age. Plasma selenium levels and hepatic glutathione peroxidase activity were significantly lower in the selenium-deficient group than in other dietary groups; these parameters were not affected by treatment with TDP-1. The mortality rate of the TDP-1-treated selenium-generous group was significantly less than that in the other TDP-1-treated groups, but there were no differences in the incidence, severity, or character of the FITD lesions among the groups. Thus, the interaction of selenium and TDP-1 did not include an effect on FITD. /// Se realizó un experimento con el objeto de determinar los efectos de niveles de selenio en la dieta sobre la patogenesis de la discondroplasia tibial inducida por Fusarium en pollos de engorde. Así mismo, se analizó la aplicabilidad de estos resultados para desarrollar un modelo animal de estudio de la enfermedad de Kashin-Beck en humanos. Pollas de engorde de un día de edad fueron alimentadas con dietas deficientas en selenio (0.02 ppm), adecuadas (0.15 ppm) o en exceso (0.50 ppm). El selenio fue adicionado como selenita de sodio. El componente tóxico del hongo, identificado como TDP-1, fue administrado a 15 de las 26 pollas desde la primera semana hasta los 24-30 días cuando fueron sacrificadas. Los niveles de selenio en el plasma y la actividad de la glutationa peroxidasa hepática fueron significantemente menores en el grupo que recibió la dieta deficiente en selenio que en los otros grupos. Estos parámetros no se vieron afectados con el tratamiento con TDP-1. La mortalidad en el grupo con exceso de selenio en la dieta y tratado con TDP-1 fue significantemente menor que en los otros grupos tratados con TDP-1, pero no se encontraron diferencias en la incidencia, severidad o carácter de las lesiones de discondroplasia tibial inducida por Fusarium. Por lo tanto, la interacción del selenio y TDP-1 no aumentó el efecto sobre la discondroplasia tibial inducida por Fusarium.