W. Michael Scheld, MD
Graduate School: Cornell University, Medical College
Primary Appointment: Professor, Medicine, Infectious Diseases and International Health
Molecular mechanisms of bacterial pathogenesis, sepsis/septic shock, adenosine receptors, inflammation, innate immunity, anthrax, vaccines
Email Address: firstname.lastname@example.org
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 preparation of the 4th 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 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.
Doka NI, Jacob ST, Banura P, Moore CC, Meya D, Mayanja-Kizza H, Reynolds SJ, Scheld WM, Yuan W. Enrichment of HIV-1 Subtype AD Recombinants in a Ugandan Cohort of Severely Septic Patients. PLoS One. 2012;7(10):e48356. doi: 10.1371/journal.pone.0048356. Epub 2012 Oct 29.
Mathers AJ, Cox HL, Kitchel B, Bonatti H, Brassinga AK, Carroll J, Scheld WM, Hazen KC, Sifri CD. Molecular dissection of an outbreak of carbapenem-resistant enterobacteriaceae reveals Intergenus KPC carbapenemase transmission through a promiscuous plasmid. MBio. 2011 Nov 1;2(6):e00204-11. doi: 10.1128/mBio.00204-11. Print 2011.
Tessier JM, Scheld WM. Principles of antimicrobial therapy. Handb Clin Neurol. 2010;96:17-29. doi: 10.1016/S0072-9752(09)96002-X. Epub 2010 Jan 19. Review.
Devasahayam G, Scheld WM, Hoffman PS. Newer antibacterial drugs for a new century.Expert Opin Investig Drugs. 2010 Feb;19(2):215-34. Review.
Moore CC, Jacob ST, Pinkerton R, Banura P, Meya DB, Reynolds SJ, Kenya-Mugisha N, Mayanja-Kizza H, Scheld WM; Promoting Resource-Limited Interventions for Sepsis Management in Uganda (PRISM-U) Study Group.Treatment of severe sepsis with artemether-lumefantrine is associated with decreased mortality in Ugandan patients without malaria. Am J Trop Med Hyg. 2009 May;80(5):723-8.
Aregawi D, Lopez D, Wick M, Scheld WM, Schiff D. Disseminated strongyloidiasis complicating glioblastoma therapy: a case report. J Neurooncol. 2009 Sep;94(3):439-43.