COMPUTATIONAL GENOMIC ANALYSIS OF HEMORRHAGIC-FEVER VIRUSES - VIRAL SELENOPROTEINS AS A POTENTIAL FACTOR IN PATHOGENESIS

A number of distinct viruses are known as hemorrhagic fever viruses ba sed on a shared ability to induce hemorrhage by poorly understood mech anisms, typically involving the formation of blood clots (''disseminat ed intravascular coagulation''). It is well documented that selenium p lays a significant role in the regulation of blood clotting via its ef fects on the thromboxane/prostacyclin ratio, and effects on the comple ment system. Selenium has an anticlotting effect, whereas selenium def iciency has a proclotting or thrombotic effect. It is also well docume nted that extreme dietary selenium deficiency, which is almost never s een in humans, has been associated with hemorrhagic effects in animals . Thus, the possibility that viral selenoprotein synthesis might contr ibute to hemorrhagic symptoms merits further consideration. Computatio nal genomic analysis of certain hemorrhagic fever viruses reveals the presence of potential protein coding regions (PPCRs) containing large numbers of in-frame UGA codons, particularly in the -1 reading frame. Ln some cases, these clusterings of UGA codons are very unlikely to ha ve arisen by chance, suggesting that these UGAs may have some function other than being a stop codon, such as encoding selenocysteine. For t his to be possible, a downstream selenocysteine insertion element (SEC IS) is required. Ebola Zaire, the most notorious hemorrhagic fever vir us, has a PPCR with 17 UGA codons, and several potential SECIS element s can be identified in the viral genome. One potential viral selenopro tein may contain up to 16 selenium atoms per molecule. Biosynthesis of this protein could impose an unprecedented selenium demand on the hos t, potentially leading to severe lipid peroxidation and cell membrane destruction, and contributing to hemorrhagic symptoms. Alternatively, even in the absence of programmed selenoprotein synthesis, it is possi ble that random slippage errors would lead to increased encounters wit h UGA codons in overlapping reading frames, and thus potentially to no nspecific depletion of SeC in the host.