Role of Inter-alpha Inhibitors in Anthrax Intoxication

DESCRIPTION (provided by applicant): The primary goal of this proposal is to demonstrate the feasibility of utilizing Inter-alpha Inhibitor proteins (lalp) as an effective protective agent against exposure to anthrax, a lethal biological warfare agent. Inter-alpha inhibitor proteins are natural serine protease inhibitors found in relatively high concentration in human plasma. The protein complex has been shown to be important in the inhibition of serine proteases such as trypsin, elastase, plasmin and cathepsin G and has been demonstrated to play a role in immunomodulation of systemic inflammation and sepsis. In our preliminary experiments, lalp enhanced the survival of cells exposed to the lethal toxin and inhibited lethality in the experimental animals challenged with anthrax toxin in the form of protective antigen (PA) and lethal factor (LF). We have obtained evidence that lalp inhibit furin, a key enzyme that activates PA by removing a small 20 kDa fragment at the N-terminal yielding the active subunit PA63. This furin-mediated cleavage of PA is necessary for the assembly of the heptamer which mediates LF entry into the cell. We hypothesize that lalp administration will be beneficial in providing combined protection against anthrax exotoxins and in fighting sepsis which occurs in the late stage of anthrax infection. In this proposed study, we will confirm and expand our initial observations and further explore the feasibility of using the active bikunin subunit to prevent anthrax toxin induced lethality. We anticipate that these studies will ultimately lead to the development of novel strategies for management of systemic anthrax infection. Relevance: Anthrax is a lethal weapon of today's bioterrorism. Inter-alpha inhibitor proteins are natural proteins in human blood that inhibit furin, a key factor in blood cells that allows anthrax toxin to attack and destroy cells and cause septic shock, a critical condition with a high rate of death. Our research is focused on the development of a new and safe treatment based on the ability of inter-alpha proteins to prevent the fatal consequences of anthrax infection.