No abstract

Previous work from our laboratory demonstrated that selenium deficiency in the mouse allows a normally benign (amyocarditic) cloned and sequenced Coxackievirus to cause significant heart damage. Furthermore, Coxsackievirus recovered from the hearts of selenium-deficient mice inoculated into selenium-adequate mice still induced significant heart damage, suggesting that the amyocarditic Coxsackievirus had mutated to a virulent phenotype. Here we report that sequence analysis revealed six nucleotide changes between the virulent virus recovered from the selenium-deficient host and the avirulent input virus. These nucleotide changes are consistent with known differences in base composition between virulent and avirulent strains of Coxsackievirus. To the best of our knowledge, this is the first report of a specific nutritional deficiency driving changes in a viral genome, permitting an avirulent virus to acquire virulence due to genetic mutation.

Selenium (Se) deficiency has previously been shown to induce myocarditis in mice infected with a benign strain of coxsackievirus. To determine if Se deficiency would also intensify an infection with influenza virus, Se‐deficient and Se‐adequate mice were infected with a mild strain of influenza, influenza A/Bangkok/1/79 (H3N2). Infected Se‐deficient mice developed much more severe interstitial pneumonitis than did Se‐adequate mice. This increase in pathology was associated with significant alterations in mRNA levels for cytokines and chemokines involved in pro‐inflammatory responses. These results demonstrate that adequate nutrition is required for protection against viral infection and suggest that nutritional deprivation may be one of many factors that increase the susceptibility of individuals to influenza infection.

S-Adenosyl-L-methionine (AdoMet):arsenic(III) methyltransferase, purified from liver cytosol of adult male Fischer 344 rats, catalyzes transfer of a methyl group from AdoMet to trivalent arsenicals producing methylated and dimethylated arsenicals. The kinetics of production of methylated arsenicals in reaction mixtures containing enzyme, AdoMet, dithiothreitol, glutathione (GSH), and arsenite are consistent with a scheme in which monomethylated arsenical produced from arsenite is the substrate for a second methylation reaction that yields dimethylated arsenical. The mRNA for this protein predicts a 369-amino acid residue protein (molecular mass 41056) that contains common methyltransferase sequence motifs. Its sequence is similar to Cyt19, a putative methyltransferase, expressed in human and mouse tissues. Reverse transcription-polymerase chain reaction detects S-adenosyl-L-methionine:arsenic(III) methyltransferase mRNA in rat tissues and in HepG2 cells, a human cell line that methylates arsenite and methylarsonous acid. S-Adenosyl-L-methionine:arsenic-(III) methyltransferase mRNA is not detected in UROtsa cells, an immortalized human urothelial cell line that does not methylate arsenite. Because methylation of arsenic is a critical feature of its metabolism, characterization of this enzyme will improve our understanding of this metalloid's metabolism and its actions as a toxin and a carcinogen.In many species, including humans, exposure to inorganic arsenic results in urinary excretion of methylated and dimethylated arsenicals (1-3). Cullen and co-workers (4) summarized the conversion of inorganic arsenic into these methylated products in a reaction scheme which incorporates oxidative methylation and the cycling of arsenic between the pentavalent (As V ) 1 and trivalent (As III ) oxidation states,Because reduction of arsenic to trivalency is a prerequisite for its oxidative methylation, pentavalent arsenicals are reduced by endogenous thiols such as glutathione (GSH) (5, 6) or by As V reductases (7-9). A protein has been purified from rabbit liver cytosol that catalyzes the methylation of both arsenite and methylarsonous acid (10, 11); however, this protein has not been sequenced. These activities are designated arsenite methyltransferase (EC 2.1.1.137) and methylarsonite methyltransferase (EC 2.1.1.138), respectively. This protein (estimated molecular mass 60 kDa) uses S-adenosyl-L-methionine (AdoMet) as the methyl group donor. The methylation of arsenite by this protein is stimulated by a monothiol (GSH) and the methylation of methylarsonous acid is highly stimulated by a dithiol, dithiothreitol (DTT). The methylation of arsenic has been commonly regarded as a mechanism for its detoxification (12). However, recent research has shown that methylated arsenicals that contain As III are important intermediates in the metabolism of inorganic arsenic. Methylated arsenicals that contain As III are found in the urine of individuals who chronically consume drinking water that contains inorganic arsenic and in cells cu...

During the 2009 pandemic H1N1 (pH1N1) influenza outbreak, obese individuals were at greater risk for morbidity and mortality to pandemic infection. However, the mechanisms contributing to greater infection severity in obese individuals remain unclear. Although most individuals lacked pre-existing, neutralizing antibody protection to the novel pH1N1 virus, heterologous defenses conferred from exposure to circulating strains or vaccination have been shown to impart protection against pH1N1 infection in humans and mice. Because obese humans and mice have impaired memory T-cell and antibody responses following influenza vaccination or infection, we investigated the impact of obesity on heterologous protection to pH1N1 infection using a mouse model of diet-induced obesity. Lean and obese mice were infected with influenza A/PR/8/34 and five weeks later challenged with a lethal dose of heterologous pH1N1 (A/Cal/04/09). Cross-neutralizing antibody protection was absent in this model, but obese mice exhibited a significantly lower level of non-neutralizing, cross-reactive pH1N1 nucleoprotein antibodies following the primary PR/8 infection. Further, obese mice had elevated viral titers, greater lung inflammation, lung damage, and an increased number of cytotoxic memory CD8+ T cells in the lung airways. Although obese mice had more regulatory T cells (Tregs) in the lung airways compared with lean controls during the pH1N1 challenge, Tregs isolated from obese mice were 40% less suppressive than Tregs isolated from lean mice. Taken together, excessive inflammatory responses to pH1N1 infection, potentially due to greater viral burden and impaired Treg function, may be a novel mechanism by which obesity contributes to greater pH1N1 severity.