Severe sepsis leads to systemic inflammation, wherein activation of the complement and coagulation systems play critical roles. Evidence from patients and animal models suggest that sepsis is a multi-stage, multi- factorial disease in which the early fulminate inflammatory response to the invading bacteria leads to hypo- perfusion and ischemia reperfusion (IR) injury that evolves to multiple organ failure (MOF) and ultimately to death. The objectives of this proposal are to investigate if the crosstalk between the coagulation and complement activation pathways during sepsis caused by two most common pathogens, Escherichia coli and Staphylococcus aureus contribute to microthrombosis, vascular dysfunction, organ failure and death; and, whether inhibition of complement activation at the C5 level could prevent MOF and improve the outcome of sepsis. We will use clinically relevant models of sepsis to address the following objectives: (i) determine the role of complement activation during the bacteremic stage of E. coli sepsis and characterize the protective effects of early treatments with C5 inhibitors; (ii) determine the effect of complement activation on platelet clearance in sepsis; (iii) determine if delayed treatment with C5 inhibitors provides organ protection and survival benefit in a model of sepsis-induced progressive organ failure. Successful completion of these aims will determine: (i) whether timed complement inhibition at the C5 level could be used as an effective therapy for sepsis-induced MOF; (ii) if deposition of complement fragments on platelets contribute to their removal from circulation; (iii) which is the optimum therapeutic time window for complement inhibition to attenuate the disease progression without affecting bacteria clearance. Altogether, our project will combine basic and preclinical research to verify novel hypotheses on the pathophysiology of Gram-negative and Gram-positive sepsis and test innovative approaches, which, in the long-term may save lives from a deadly disease with no specific cure. !
Sepsis or blood poisoning is a life-threatening illness caused when the body is overcome by infection that has spread via the bloodstream. Sepsis is a major cause of death worldwide. Currently, there is a lack of effective treatments targeting the mechanisms of sepsis. This project aims to understand how the body respond to blood infections and to develop new therapies that protect the organs against the damaging effects of the body's own uncontrolled defense system.
|Popescu, Narcis I; Silasi, Robert; Keshari, Ravi S et al. (2018) Peptidoglycan induces disseminated intravascular coagulation in baboons through activation of both coagulation pathways. Blood 132:849-860|
|Keshari, Ravi S; Silasi, Robert; Lupu, Cristina et al. (2017) In vivo-generated thrombin and plasmin do not activate the complement system in baboons. Blood 130:2678-2681|
|Marsman, Gerben; von Richthofen, Helen; Bulder, Ingrid et al. (2017) DNA and factor VII-activating protease protect against the cytotoxicity of histones. Blood Adv 1:2491-2502|
|Keshari, Ravi Shankar; Silasi, Robert; Popescu, Narcis Ioan et al. (2017) Inhibition of complement C5 protects against organ failure and reduces mortality in a baboon model of Escherichia coli sepsis. Proc Natl Acad Sci U S A :|