Everything that happens to a cell occurs as a result of “signals” that start or stop specific processes inside the cell. The signals tell the cell to grow, to make a new protein, or to become a different kind of cell. Whether it’s a brain, nerve, skin or bone cell, every process necessary to life only happens when signals are sent or received in the right way and at the right time. All the projects in my lab center on the study of those signals, an area we refer to as “signal transduction."
Signal transduction can be compared to an electric circuit, where wires from an on/off switch send power from its source to a device. The wiring diagram in a cell is very complicated and more like a stereo system. It will play tapes, CDs or radio; it will connect to your television or speakers, it will have volume, balance and tuning properties, and there are amplifiers and current regulators. We study what happens between the power source and the desired output—in this case, music. What specific thing is turned on with what switch, and how does it control the quality and quantity of the cellular music? That’s what we want to know.
One of our projects focuses on anthrax and why it kills people. Once anthrax is contracted, the on/off switch in blood cells should stimulate the circuit and activate the body’s bacteria fighters. But in anthrax, the on/off switch doesn’t work properly, so the bacteria continue to grow unchecked. This results in a sepsis-like condition, where the bacteria grow uncontrolled in the bloodstream. We are looking at how the cells respond to the bacteria and how to develop ways for them to fight it more effectively.
In a new project, we look at the reasons some vaccines work and some don’t. Vaccines introduce a small particle of a foreign substance into the body. Ideally, the body produces antibodies against the substance, which, in turn, provide immunity. But some people don’t respond to vaccines or are poorly protected, as often happens with the anthrax vaccine. In animals, we found many signaling proteins that control the music of vaccines. We think similar problems happen in people, too. By learning more about how vaccines signal the immune system, we may be able to predict which vaccines will work best and develop better, more targeted vaccines for anthrax and other diseases.
Our laboratory has three main projects, all of which study the signal transduction processes in hematopoietic cells. In the area of inflammation, we are studying the signal transduction process by receptors for gamma-type immunoglobulins on human macrophages and neutrophils. These IgG receptors stimulate many biological functions in these cells, including phagocytosis, release of inflammatory cytokines and the elimination of pathogenic organisms. We found that inflammatory cytokines, especially Interleukin-6 (IL-6), suppress development of B lymphocytes at a very early stage. Patients with elevated IL-6 have chronic inflammation, like that present in autoimmune diseases like rheumatoid arthritis. Likewise, elevated IL-6 is found in patients with lymphomas such as multiple myelomas and other plasmacytomas. We are identifying the individual proteins that signal cells to make IL-6.
We also study how B lymphocytes are activated by their antigen receptors. B lymphocytes respond to pathogenic proteins through surface immunoglobulin (sIg). Our work in signal transduction by sIg has shown recruitment of several proteins to the sIg receptor when it is stimulated by antigens. The enzyme phosphatidylinositol 3-kinase (PI3K) is central to protein recruitment since inhibiting PI3K blocks all aspects of B-cell activation. We use mice deficient in the enzymes that regulate PI3K to study the role of PI3K in B cells. Our current work focuses on how sIg-recruited proteins contribute to antigen internalization and B lymphocyte activation, with emphasis on the key role of PI3K.
The third project involves signal transduction by a receptor tyrosine kinase (c-fms) that triggers macrophage migration. We are studying how PI3K regulates small GTPases Rho, Rac and CDC42. Primary macrophages from the bone marrow of mice that have altered metabolism of PI3K products show elevated chemotactic responses. We have traced the elevation to constitutively-active Rac and Vav in these same macrophages. By retroviral transduction and fluorescence microscopy, we determined how Vav is regulated by PI3K products. Our future studies will examine how these proteins involved in the signal transduction process are able to regulate assembly of the actin cytoskeleton and movement of the cell.
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
Booth JL, Duggan ES, Patel VI, Wu W, Burian DM, Hutchings DC, White VL, Coggeshall KM, Dozmorov MG, Metcalf JP. Gene expression profiling of primary human type I alveolar epithelial cells exposed to Bacillus anthracis spores reveals induction of neutrophil and monocyte chemokines. Microb Pathog. 2018 Aug;121:9-21. doi: 10.1016/j.micpath.2018.04.039. Epub 2018 Apr 25. PMID: 29704667
Girton AW, Popescu NI, Keshari RS, Burgett T, Lupu F, Coggeshall KM. Serum Amyloid P and IgG Exhibit Differential Capabilities in the Activation of the Innate Immune System in Response to Bacillus anthracis Peptidoglycan. Infect Immun. 2018 Apr 23;86(5). pii: e00076-18. doi: 10.1128/IAI.00076-18. Print 2018 May. PMID: 29531132
Popescu NI, Silasi R, Keshari RS, Girton A, Burgett T, Zeerleder SS, Gailani D, Gruber A, Lupu F, Coggeshall KM. Peptidoglycan induces disseminated intravascular coagulation in baboons through activation of both coagulation pathways. Blood. 2018 Jun 19. [Epub ahead of print] PMID: 29921614
* Maier-Moore JS, Horton CG, Mathews SA, Confer AW, Lawrence C, Pan Z, Coggeshall KM, Farris AD. IL-6 Deficiency Corrects Nephritis, Lymphocyte Abnormalities and Secondary Sjogren's Features in Sle1.Yaa Lupus-Prone Mice. Arthritis Rheumatol 66:2521-2531, 2014. [Abstract]
*Lupu F, Keshari RS, Lambris JD, Coggeshall KM. Crosstalk between the coagulation and complement systems in sepsis. Thromb Res 133 Suppl 1:S28-S31, 2014. [Abstract]
An JH, Kurokawa K, Jung DJ, Kim MJ, Kim CH, Fujimoto Y, Fukase K, Coggeshall KM, Lee BL. Human SAP Is a Novel Peptidoglycan Recognition Protein That Induces Complement-Independent Phagocytosis of Staphylococcus aureus. J Immunol 191:3319-3327, 2013. [Abstract]
* Sun D, Popescu NI, Raisley B, Keshari RS, Dale GL, Lupu F, Coggeshall KM. B. anthracis peptidoglycan activates human platelets through FcgammaRII and complement. Blood 122:571-579,2013. [Abstract]
Iyer JK, Coggeshall KM. Cutting edge: primary innate immune cells respond efficiently to polymeric peptidoglycan, but not to peptidoglycan monomers. J Immunol 186:3841-3845, 2011. [Abstract]
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. [Abstract]
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