If a bacterial infection is resistant to antibiotics, it can proceed to sepsis or blood poisoning. Sepsis happens to hundreds of thousands of Americans every year and will be fatal in one in four of these victims. In severe sepsis, the blood pressure drops, the blood coagulates, and the heart rate slows. The patient progresses towards septic shock where organs become deprived of oxygen and fail.
Our lab studies Gram-positive bacteria like Staphylococcus aureus and Bacillus anthracis that cause sepsis. We focus on identifying the parts of bacteria that can induce sepsis-associated pathologies in the human body and the mechanism by which the bacterial products cause damage.
The outer layer of the bacterial cell wall contains peptidoglycan. It is a common component of all bacteria but present in especially large amounts in Gram-positive bacteria. Our test tube results showed that peptidoglycan stimulates the human immune system to make proinflammatory cytokines, activate the complement system of blood proteins and stimulate platelets to aggregate. We found that these events are driven by blood proteins like immunoglobulin binding to peptidoglycan and the resulting immune complex stimulating cells that express immunoglobulin (Fc-gamma) receptors like monocytes, neutrophils, and platelets, among others.
In animal challenges, peptidoglycan caused the same pathologies we saw in the test tube: inflammation, complement activation and platelet loss. Unexpectedly, we also saw loss of blood pressure, vascular leakage and blood coagulation. Our current work is directed at how peptidoglycan causes blood coagulation and vascular leakage. We are also testing new blocking antibodies that can halt blood coagulation to see if the antibodies can rescue animals challenged with peptidoglycan and with live bacteria.
In 2001, 11 individuals contracted inhalation anthrax from letters laced with Bacillus anthracis spores. These patients showed extreme bacteremia, systemic inflammation, disseminated intravascular coagulation (DIC) and organ failure, all features suggestive of sepsis. Other Gram-positive pathogens also cause sepsis, but a Gram-positive pathogen associated molecular pattern (PAMP) that can account for the sepsis pathology had not been identified at that time. Our work established that human plasma, platelets, monocytes and neutrophils respond vigorously to B. anthracis-derived peptidoglycan (PGN) by complement activation, platelet aggregation and inflammatory cytokine production. In addition, the DIC and organ failure seen in animals challenged in vivo with PGN closely resembles the pathology in primates challenged with live B. anthracis and humans with inhalation anthrax. Therefore, PGN is likely a PAMP capable of inducing the pathology associated with sepsis and contributing to the lethality of Gram-positive infections like inhalation anthrax.
In spite of our discovery that PGN acts as a PAMP in B. anthracis infections, there is still much that we don’t understand about the pathology of B. anthracis sepsis. This lack of information impacts the development of more effective therapies. First, all of our in vivo and in vitro studies to date on PGN have been done in the absence of anthrax toxins, edema and lethal toxin. Both of these toxins are capable of suppressing the immune response and could alter the consequences of PGN challenge. We are now performing PGN challenges in the presence of toxin to more accurately model the host response in the face of an actual anthrax infection. Second, although we see evidence of activation of the contact coagulation pathway in the in vivo PGN challenges, we have no mechanism to account for its activation. Factor XII and prekallikrein, activators of the contact pathway, bind directly to PGN. However, the purified enzymes and zymogens fail to become activated in vitro in the presence of PGN, indicating that the activation of the pathway is indirect. We are now evaluating other potential mechanisms of contact pathway activation, including platelet polyphosphate release and neutrophil NET contents. Last, PGN and the B. anthracis pathogen activate the complement and coagulation cascades, but we do not know if one or the other or both of these pathophysiological changes are causally related to the subsequent organ failure. We will apply biologic agents to separately and together block complement at the C5 level and/or the contact and/or extrinsic coagulation cascades in a lethal PGN and live B. anthracis challenge to see if the animal is protected from the challenge. The results will greatly inform treatment options for patients with Gram-positive bacteremia.
B.S., Southern Illinois University, 1979
M.S., Southern Illinois University, 1981
Ph.D., Duke University, 1985
Honors and Awards
NIH Predoctoral Fellowship, Duke University Medical Center
1989-1991 Cancer Research Institute Fellowship
Recipient, Scholar of the Leukemia and Lymphoma Society
Panel member, NSF Signal Transduction & Regulation Panel Group
Panel member, NIH Immunobiology Study Section (T32s)
Ad Hoc Panel Member, NIH Allergy & Immunology (2/00): Experimental Immunology (6/00) Study Sections
Session Chair, B cell activation and development; Autumn Immunology Conference, Chicago, IL
Council Member, Autumn Immunology Conference (02-05)
Special Emphasis Panel: Biology of Dendriitic Cells; 2001
Special Emphasis Panel: Technology Centers for Networks and Pathways: 2005
Session Chair, Molecular events in B cell activation; AAI Conference, Seattle, WA
2014 Fred Jones Award for Scientific Achievement
Panel Member, AHA Immunology & Microbiology II.
Associate editor, Journal of Biological Chemistry
Associate editor, Journal of Immunology
American Society of Biochemists and Molecular Biologists
Joined OMRF Scientific Staff in 1999
Keshari RS, Popescu NI, Silasi R, Regmi G, Lupu C, Simmons JH, Ricardo A, Coggeshall KM, Lupu F. Complement C5 inhibition protects against hemolytic anemia and acute kidney injury in anthrax peptidoglycan-induced sepsis in baboons. Proc Natl Acad Sci U S A 118, 2021 September, PMID: 34507997, PMCID: PMC8449412
Popescu NI, Keshari RS, Cochran J, Coggeshall KM, Lupu F. C3 Opsonization of Anthrax Bacterium and Peptidoglycan Supports Recognition and Activation of Neutrophils. Microorganisms 8, 2020 July, PMID: 32668703, PMCID: PMC7409185
Popescu NI, Girton A, Burgett T, Lovelady K, Coggeshall KM. Monocyte procoagulant responses to anthrax peptidoglycan are reinforced by proinflammatory cytokine signaling. Blood Adv 3:2436-2447, 2019 August, PMID: 31416821, PMCID: PMC6712522
Popescu NI, Silasi R, Keshari RS, Girton A, Burgett T, Zeerleder SS, Gruber A, Lupu F, Coggeshall KM. Peptidoglycan induces disseminated intravascular coagulopathy through activation of both coagulation pathways. Blood. 2018 132(8):849-860. PMID: 29921614 PMCID: PMC6107880
Sun D, Popescu NI, Raisley B, Keshari RS, Dale GL, Lupu F, Coggeshall KM. B. anthracis peptidoglycan activates human platelets through FcγRII and complement. Blood. 2013 Jul 25;122(4):571-9. PMID: 23733338 PMCID: PMC3724192
Coggeshall KM, Lupu F, Ballard J, Metcalf JP, James JA, Farris AD, Kurosawa S. The sepsis model: an emerging hypothesis for the lethality of inhalation anthrax. J Cell Mol Med. 2013 Jul;17(7):914-20. PMID: 23742651 PMCID: PMC3729634
Sun D, Raisley B, Langer M, Iyer JK, Vedham V, Ballard JL, James JA, Metcalf JP, Coggeshall KM. 2012. Anti-peptidoglycan antibodies and Fcγ receptors are the key mediators of inflammation in gram-positive sepsis. J Immunol. 2012 Sep 1;189(5):2423-31. PMID: 22815288 PMCID: PMC3424298
Iyer JK, Coggeshall KM. Cutting edge: primary innate immune cells respond efficiently to polymeric peptidoglycan, but not to peptidoglycan monomers. J Immunol. 2011 Apr 1;186(7):3841-5. PMID: 21357534 PMCID: PMC3071148
Iyer JK, Khurana T, Langer M, West CM, Ballard JD, Metcalf JP, Merkel TJ, Coggeshall KM. Inflammatory cytokine response to Bacillus anthracis peptidoglycan requires phagocytosis and lysosomal trafficking. Infect. Immun., 78:2418-2428, 2010. PMID: 20308305 PMCID: PMC2876538
Arthritis & Clinical Immunology Research Program, MS 53
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, OK 73104
Phone: (405) 271-7905
Lab: (405) 271-7883
Fax: (405) 271-8568
News from the Coggeshall lab
As a resurgent H1N1 flu virus worries medical professionals and families, more people are looking to vaccines to keep them safe. Now a new discovery by scientists at OMRF could shed light on why vaccines are ineffective in some patients. In a paper published in the current issue of the Journal of Biological Chemistry, OMRF researchers Shikha […]
The National Institutes of Health has awarded two grants worth a total of $26.3 million to OMRF for research into anthrax and to help train new scientists. Each grant will allow scientists to continue research started in 2004 and 2005 and keep them working through 2014 on several interconnected projects. In the first project, a $14.5 […]
The National Institutes of Health has awarded the Oklahoma Medical Research Foundation a $9.16 million grant to train junior scientists and build research infrastructure at OMRF. The five-year award will fund the work of five junior scientists and provide operating support for core facilities at the foundation. “This is yet another important step in the […]
The National Institutes of Health has awarded the Oklahoma Medical Research Foundation $8.132 million to study the influenza vaccine. The five-year project will examine why the vaccine does not protect certain individuals with compromised immune systems.”Influenza research is one of the most competitive and difficult arenas in which to secure funding,” said J. Donald Capra, […]
The Oklahoma Medical Research Foundation has received a $13.8 million grant from the National Institutes of Health to study the toxin that causes anthrax. The grant will pay $2.76 million a year through 2009 and is the largest ever awarded to an Oklahoma institution to fund bioterrorism research.With this grant, nine scientists will explore natural […]
Oklahoma City, April 23, 2003 – At its semiannual board meeting last night, the Oklahoma Medical Research Foundation presented the Edward L. and Thelma Gaylord Prize for Scientific Achievement to OMRF scientist Paul W. Kincade, Ph.D. Also Tuesday, OMRF honored longtime director H.E. “Gene” Rainbolt, named K. Mark Coggeshall, Ph.D., as the first holder of […]
For the second time in 13 months, a substantial gift from the Kerr Foundation has created a new endowed chair at the Oklahoma Medical Research Foundation. The most recent donation will establish the Lou C. Kerr Endowed Chair in Biomedical Research. Robert S. Kerr Jr. made the gift on behalf of the Kerr Foundation in […]