The main focus of the Scheld research laboratory is the pathogenesis and pathophysiology of serious bacterial infections. Early work focused on endocarditis and bacterial meningitis. The latter resulted in scores of publications and led eventually to the use of adjunctive corticoidsteroids in both adults and children with bacterial meningitis as well as publication of the “gold standard” textbook in the field, Infections of the Central Nervous System, currently in its 3rd edition and edited by Scheld, Whitley, and Marra.
Since 2000, the Scheld laboratory has focused on two distinct but inter-related processes, sepsis/septic shock, and anthrax. Adenosine, a pluripotent purine nucleotide, is released in times of stress as a result of the metabolism of ATP, including sepsis and septic shock. Adenosine produces its myriad of effects through binding to four distinct receptor subtypes, A1, A2A, A2B, and A3. Engagement of the A2A receptor results in an anti-inflammatory phenotype. We have shown that A2A receptors are present on multiple inflammatory cell types, and the inflammatory response is markedly down regulated in neutrophils, monocytes, macrophages, and T cells, by A2A agonists in vitro. Furthermore, administration of adenosine A2A receptor agonist’s in vivo leads to anti-inflammatory affects in experimental murine models of meningitis, peritonitis, septic arthritis, and sepsis/septic shock. Protective effects have been seen in mouse models of sepsis induced by LPS, E. coli, S. aureus, S. pneumoniae, Y. enterocolytica, and a mixed aerobic/anaerobic infection, among others. We have characterized the cytokine kind response and some of the mechanisms for this protective effect. Somewhat surprisingly, it appears that a major target for Adenosine A2A agonists in sepsis is T cells. Current work is focused on elaboration of the T cell subset responsible, and intracellular signaling pathways affected by the agonist.
When the Scheld laboratory first started investigating the pathogenesis and pathophysiology of anthrax, the dogma was that anthrax kills by a septic shock “cytokine storm” mechanism. We have since shown that this dogma is completely incorrect, in fact, anthrax lethal toxin itself is a markedly anti-inflammatory substance. The laboratory has since shown that agonists of Toll like receptors protect against anthrax lethal toxin induced death. Furthermore, the administration of sub lethal quantities of anthrax lethal toxin sensitizes animals to a TNF-alpha induced death. Inhibitors of TNF reverse this effect. This has been confirmed in mouse models of anthrax following challenge with live vegetative baccilli, as well as spores. Current work is investigating the mechanisms of this protective effect.
The Scheld laboratory is also investigating the use of innate stimulation as a protective mechanism in experimental sepsis. Agonists of TLR4, for example, as adjunctive treatment before and after challenge with live bacteria, improve outcome. Furthermore, this strategy also protects against death upon subsequent bacterial challenge even in the absence of antimicrobial agents. This startling result is under current investigation as to its mechanism.
Finally, the Scheld group conducts extensive studies on the pathogenesis and management of sepsis in a largely HIV-infected population in Uganda. These studies have led to an appreciation of the role of portable whole blood lactate as a triage tool, the role of artemisinins in the protection from death due to bacterial sepsis, and strengthening of various management protocols including early aggressive fluid resuscitation in this group of patients. Some of these results have informed WHO policy regarding management of critical illness due to bacterial infections worldwide.
Jacob ST, Moore CC, Banura P, Pinkerton R, Meya D, Opendi P, Reynolds SJ, Kenya-Mugisha N, Mayanja-Kizza H, Scheld WM. Severe sepsis in two Ugandan hospitals: a prospective observational study of management and outcomes in a predominantly HIV-1 infected population. PLoS ONE 2009; 4(11): e7782.
Moore CC, Martin EN, Lee G, Taylor C, Dondero R, Reznikov LL, Dinarello C, Thompson J, Scheld WM. Eukaryotic translation initiation factor 5A small inferference RNA- lipsome complexes reduce inflammation and increase survival in murine models of severe sepsis and acute lung injury. J Infect Dis 2008; 198:1407-14.
Moore CC, Martin EN, Lee G, Obrig T, Linden J, Scheld WM. An A2A adenosine receptor agonist ATL313, reduces inflammation and improves survival in murine sepsis models. BMC Infect Dis 2008; 8:141.
Sullivan GW, Fang G, Linden J, Scheld WM. A2A adenosine receptor activation improves survival in mouse models of endotoxemia and sepsis. J Infect Dis 2004;189:1897-904.
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