key: cord-1039182-c6w7eucp authors: Zhang, Jinsong; Saad, Ramy; Taylor, Ethan Will; Rayman, Margaret P. title: Selenium and selenoproteins in viral infection with potential relevance to COVID-19 date: 2020-09-10 journal: Redox Biol DOI: 10.1016/j.redox.2020.101715 sha: 016e2ab5ece39f808bdbcdcc68488bb2a8f137e7 doc_id: 1039182 cord_uid: c6w7eucp Selenium is a trace element essential to human health largely because of its incorporation into selenoproteins that have a wide range of protective functions. Selenium has an ongoing history of reducing the incidence and severity of various viral infections; for example, a German study found selenium status to be significantly higher in serum samples from surviving than non-surviving COVID-19 patients. Furthermore, a significant, positive, linear association was found between the cure rate of Chinese patients with COVID-19 and regional selenium status. Moreover, the cure rate continued to rise beyond the selenium intake required to optimise selenoproteins, suggesting that selenoproteins are probably not the whole story. Nonetheless, the significantly reduced expression of a number of selenoproteins, including those involved in controlling ER stress, along with increased expression of IL-6 in SARS-CoV-2 infected cells in culture suggests a potential link between reduced selenoprotein expression and COVID-19-associated inflammation. In this comprehensive review, we describe the history of selenium in viral infections and then go on to assess the potential benefits of adequate and even supra-nutritional selenium status. We discuss the indispensable function of the selenoproteins in coordinating a successful immune response and follow by reviewing cytokine excess, a key mediator of morbidity and mortality in COVID-19, and its relationship to selenium status. We comment on the fact that the synthetic redox-active selenium compound, ebselen, has been found experimentally to be a strong inhibitor of the main SARS-CoV-2 protease that enables viral maturation within the host. That finding suggests that redox-active selenium species formed at high selenium intake might hypothetically inhibit SARS-CoV-2 proteases. We consider the tactics that SARS-CoV-2 could employ to evade an adequate host response by interfering with the human selenoprotein system. Recognition of the myriad mechanisms by which selenium might potentially benefit COVID-19 patients provides a rationale for randomised, controlled trials of selenium supplementation in SARS-CoV-2 infection. 28 Selenium (Se) is a unique trace element; it is the only one of the trace elements to be specified in the 29 genetic code. It is essential at a very low level of intake, from 55 to 75 µg/d [1, 2], yet toxic above 30 800 µg/d, with the Safe Upper Limit being defined as 400 µg/d [1] . The essentiality of selenium is 31 linked to the remarkable range of functions of the selenoproteins that are described below [3] . 32 33 Selenium gets into the food chain through plants which take it up from the soil. The amount taken 34 up is dependent not only on the selenium content of the soil which relates to the underlying 35 geology, but to soil pH, the presence of organic matter and climatic conditions [4] . The effect of 36 climate is nicely exemplified by the selenium-poor belt in China where the selenium status is 37 decisively affected by monsoonal precipitation [5] . 38 39 An unusual aspect of selenium is the extremely wide range of intake seen across the globe 40 (Supplemental Table 1 Figure 1 [6, 7] ). In the 1960s, Se toxicity (selenosis) was prevalent in Enshi County 45 and, as late as 1981, intake was reported to be as high as 4990 µg/d in some areas of Enshi [9] . 46 47 With this remarkable degree of variation in intake, it is not surprising that there have been 48 numerous examples of adverse health conditions linked to selenium deficiency including those 49 caused by viruses [3, 10] and also by selenium excess [11] . As with many nutrients, there is a U-50 shaped relationship between Se intake or status and its health effects; that relationship is 51 particularly noticeable for selenium [11] . 52 53 In this comprehensive review we will explore the evidence for the involvement of selenium, whether 54 as particular selenium species or selenoproteins, in viral infections. We will first cover the important 55 role of the selenoproteins in combatting viral infection. We will then describe the evidence for the 56 encode selenoproteins. These selenoproteins have a wide range of functions, from antioxidant and 72 anti-inflammatory roles to the production of active thyroid hormone [12, 13] -increase the production of 15d-PGJ2 decreasing activation of NF-κB and downregulating inflammatory-gene expression [14, 22] -activate PPAR-γ, repressing inflammatory gene expression [14, 22] . GPXs: metabolise ROS to prevent activation of NF-κB, its translocation to the nucleus and its binding to pro-inflammatory cytokine genes [23] . TXNRD1: induces haem oxidase-1 which has anti-inflammatory functions linked to its removal of the pro-oxidant, haem, its production of the antioxidant biliverdin and the vasodilatory, anti-inflammatory carbon monoxide [22, 24] . (Figure 1) . 141 J o u r n a l P r e -p r o o f We were interested to see what range of selenium intake was represented by the hair-selenium 142 concentrations in Figure 1 , so we searched the literature for data on selenium intake that had 143 corresponding values of hair-selenium concentration (see Supplemental Table 2 ). The regression of 144 selenium intake against hair selenium (Supplemental Figure 1 ) enabled us to determine the hair-145 selenium concentration corresponding to an intake of 55 µg/d, at which platelet GPX1 activity is 146 maximised [58], i.e. 0.43 mg/kg (see Supplemental Table 2 ). We similarly determined the hair 147 selenium concentration corresponding to an intake of 105 µg/d at which SELENOP concentration is 148 optimised, i.e. 64 mg/kg [58] . Interestingly, there is no sign of a plateau in Figure 1 at either of those 149 hair-selenium concentration values. Indeed, the cure rate continues to rise above those points, 150 reaching the high end of the regression line at a cure rate of 56% and hair-selenium concentration of 151 1.0 mg/kg, corresponding to an intake of 188 µg/d (see Supplemental Potential mechanisms by which selenium species could affect SARS-CoV-2 or COVID-19 188 We have presented above the evidence that shows an association between selenium species and 189 SARS-CoV-2 or COVID-19 disease. While there is as yet no evidence for causality, there are a number 190 of plausible mechanisms by which selenium, in one or other of its forms, could affect the virus and 191 indeed vice-versa. These will be explored below beginning with immune system effects. 192 Our understanding of the full role the immune system plays in COVID-19 is still developing; however, 194 there is mounting evidence that excessive innate responses and cytokine release contribute to 195 morbidity and mortality. It has been noted that severe disease correlates with tissue accumulation 196 of macrophages and the production of the inflammatory cytokines IL-1β, IL-6, and TNF-α The effect that selenium may have on Th1:Th2 ratios needs further investigation; while a Th1 231 phenotype can be beneficial in developing cellular immunity, it is also associated with many of the 232 cytokines that correlate with COVID-19 severity [78] . Whether selenium supplementation can 233 promote a Th1 response that results in a beneficial cellular response without contributing to further 234 inflammation, remains to be seen. 235 236 Within the innate immune system, selenium supplementation has been shown to affect macrophage 237 responses, shifting them away from a "pro-inflammatory" reaction with regard to cytokine release 238 [79]. In mice inoculated with Influenza A, selenium deficiency led to higher rates of macrophage 239 infiltration of the lungs than in selenium-replete mice [80] . In one recent murine study, selenium 240 deficiency was shown to inhibit macrophage phagocytosis directly and promote NF-κB-mediated 241 inflammation [81] . The above examples appear to demonstrate that higher selenium status, or selenium 298 supplementation, reduces the level of inflammatory cytokines; this observation requires an attempt 299 to explain the mechanism which we have attempted to do below. 300 301 The activation of inflammatory cytokines, including IL-6, is coordinated by the transcription factor 303 NF-κB, which has been shown to be specifically inhibited by selenite in cell culture studies [106] . TXNRD3 protein levels are as high or higher in the lung and GI tract, which are major sites of SARS-357 CoV-2 replication. Significantly, the ACE2 receptor used by SARS-CoV-2 is also expressed at high 358 levels in the testes. Testicular mumps infection is classic, and EBOV infection of the testes is now 359 understood to be a major cause of persistent infection [118] . Because of the high levels of ACE2 360 receptor there, SARS-CoV-2 could also target the testes. So all three of these TXNRD3-targeting 361 viruses appear to at least have the potential to infect the tissue in which TXNRD3 is most highly 362 expressed in human males [114] . 363 A similar viral mechanism that is at least theoretically possible is the targeting of host selenoproteins 364 for degradation by proteolysis, achieving a similar result as antisense knockdown, but by a different 365 mechanism. Targeting of host proteins by viral proteases is a well-documented phenomenon but has 366 until now never been observed vs. a host selenoprotein. However, the recent demonstration of a 367 high quality protein-protein interaction between an inactive C145A mutant of the SARS-CoV-2 main 368 cysteine protease, M pro , and human GPX1 [119], although rather paradoxical because of the failure 369 to observe any interaction between wild type M pro and GPX1, raises the possibility that GPX1 may be 370 a substrate for M pro , and that the products of proteolytic cleavage had disassociated from the active 371 enzyme prior to detection. This interpretation is strengthened by the identification of potential M pro 372 cleavage site sequences in GPX1 as well as in TXNRD1 and SELENOF, with the latter being essentially 373 identical to a known M pro cleavage site over a span of 8 residues [120] . Proteolytic targeting of 374 SELENOF would complement its 76% knockdown at the mRNA level by SARS-CoV-2, suggesting that 375 the viral agenda is significantly enhanced by interference in the function of this particular 376 selenoprotein. 377 The location of the predicted M pro cleavage site in TXNRD1, five residues from its C-terminal, would 378 remove its selenocysteine-containing redox centre, making it incapable of regenerating reduced 379 thioredoxin [120] . Along with the demonstrated knockdown of TXNRD3 at the mRNA level , this 380 outcome is consistent with the hypothesis that SARS-CoV-2 may be actively inhibiting DNA synthesis, 381 which would result in the increased availability of ribonucleotides for viral RNA synthesis [114, 120] . 382 Taken together, these proposed mechanisms, targeting selenoproteins at both the mRNA and 383 protein levels, would represent an unprecedented frontal assault on selenoprotein biosynthesis by a 384 pathogen, and suggest a potentially significant role of selenium status in the pathogenesis of COVID-385 The SARS-CoV-2 replicase gene encodes two overlapping polyproteins for viral replication and Based on all the evidence described above, both selenoproteins and redox-active selenium species 538 (that mimic selenium-containing ebselen [121]) in the selenium metabolic pool could employ their 539 separate mechanisms to attenuate virus-triggered oxidative stress, excessive inflammatory 540 responses and immune-system dysfunction, thus improving the outcome of SARS-CoV-2 infection, as 541 hypothesised in Figure 3 . A possible area for future study will be the strategies that viruses use to 542 interfere with selenium-based host-protective mechanisms. 543 544 Finally, it is well documented that there is a narrow dose range spanning the beneficial and adverse 545 effects of selenium [3, 11] . In general, the current literature discourages selenium-adequate 546 individuals from increasing their selenium intake to a level normally associated with toxicity that 547 would markedly increase the formation of redox-active selenium species [3, 11, 178] . However, for 548 COVID-19 disease, we have identified an association between more-than-adequate selenium 549 intake/status and higher cure rate [7] . The acute infection phase in COVID-19 is only a few weeks in 550 typical cases, which is comparable to the time frame over which daily doses of 1 mg selenium (as 551 selenite) have been used in sepsis and critical care applications [105, 179, 180] . Based on such 552 precedents, over a similar time-frame, a comparable supranutritional dose of selenium would be 553 very unlikely to result in toxicity in COVID-19 patients and might be beneficial in those with 554 moderate-to-severe symptoms. However, the potential benefit of such a strategy would need to be 555 tested clinically, preferably in a randomised, controlled trial. 556 557 All authors drafted sections of the manuscript. MPR prepared Table 1 606 2. 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Is this still the question? Nutrition