A broad range of molecules and cell types have been implicated in the development of burn complications. However, it is still not clearly understood how the complex network of post-burn pathologic events is coordinated. Endogenous retroviruses (ERVs) are permanently incorporated into the germline and they constitute -8 % and -10 % of the human and mouse genomes, respectively. Our recent data provide evidence that a selective group of murine ERVs (MuERVs) are activated in various organs of mice after burn or sepsis. Some of them are able to assemble virus particles and the envelope (env) glycoproteins differentially modulate various inflammatory mediators and/or exert cytotoxic effects. We hypothesize that burn-elicited stress signals activate certain ERVs, followed by virion assembly, infection, and random reintegration into the genome resulting in immune disorder and damage to distant organs.
Specific Aim. We will evaluate the effects of anti-retroviral treatment on the amelioration of pathologic changes in the immune system and other distant organs of mice after burn injury. In this study, we will test the hypothesis that inhibition of burn-activated MuERVs by treatment with anti-retroviral agents alters the course of post-burn pathogenesis in the immune system and distant organs. The siRNAs targeting gag (group specific antigen), pol (reverse transcriptase), or env RNA of the MuERVs as well as anti-retroviral agents prescribed for the control of replication of human immunodeficiency virus will be administered immediately after burn and a set of burn-associated pathophysiologic markers will be examined to determine their efficacy. The data from this study will provide direct insights into the pathologic roles of burn-activated MuERVs in immune disorder and damage to distant organs. Furthermore, the findings from this study may lead to a further investigation into the development of a novel therapeutic protocol for burn patients in combination with current regimens.
/Relevance Understanding the effects and underlying mechanisms of post-burn activation of endogenous retroviruses (ERVs) will broaden insights into the complex network of the burn-associated disease processes. It may ultimately lead to the development of a novel therapeutic protocol, such as anti-retroviral treatment including anti-human ERV siRNAs and anti-retroviral agents currently prescribed for the control of human immunodeficiency virus, in combination with current regimens for burn patients.
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