Wednesday, June 10, 2009

Carlos Subauste, M.D.
Associate Professor of Medicine

Division of Infectious Diseases and HIV Medicine, Department of Medicine
Department of Pathology
Department of Ophthalmology and Visual Sciences

Case Western Reserve University School of Medicine


MD - Universidad Peruana Cayetano Heredia, 1983
Residency and Chief Resident - Southern Illinois University, 1988
Fellowship - Stanford University, 1992


CD40 is relevant because: 1) impaired CD40 signaling leads to susceptibility to various infections while 2) hyper-activation of CD40 promotes pro-inflammatory disorders such as atherosclerosis, ischemic injury, autoimmunity, graft rejection and neurodegenerative disorders. Dr. Subauste’s laboratory focuses on both aspects of CD40 signaling.

CD40 and host protection

Using Toxoplasma gondii as a model, studies are being done to determine how CD40 promotes host protection. The laboratory also explores how CD40 signaling is dysregulated by HIV-1.

CD40 and T gondii. Dr. Subauste’s laboratory demonstrated that CD40 has a dual role in protection against T. gondii: it drives production of IL-12 / IFN-g and activates pathogen killing via autophagy (Fig. 1). Autophagy is a process of lysosomal degradation recently recognized to result in killing of pathogens. Dr. Subauste’s laboratory is identifying the signaling pathways by which CD40 activates autophagy and how T. gondii blocks full activation of the process. These studies are conducted both in vitro and in vivo using models of toxoplasmic encephalitis and retinochoroiditis in mice with genetic defects in components of CD40 and autophagy signaling.

Dysregulation of CD40 signaling by HIV-1. The laboratory studies how HIV-1 diminishes the expression of CD154 (the ligand for CD40) on CD4+ T cells . In addition, studies are being done to determine how HIV-1 proteins trigger counter-regulatory cascades that inhibit autophagy. The relevance of blockade of autophagy to the biology of HIV-1 infection will be studied.

CD40 and pro-inflammatory disorders

The focus of this work is to identify novel approaches to block inflammation induced by CD40 while leaving host protective mechanisms largely intact (Fig. 2). We have identified signaling molecules downstream of CD40 that may enable selective blockade of inflammation. Three approaches are being pursued to examine the role of these molecules: expression of mutant molecules using retroviral/lentiviral vectors, use of novel pharmacologic agents that block selective signaling cascades and development of transgenic mice that express mutant molecules in a tissue-specific manner. These studies are being done using models of atherosclerosis, diabetic retinopathy and ischemia.

NIH Biosketch

Selected Publications

Portillo, J.A., G. Okenka, T.S. Kern and C.S. Subauste. Identification of primary retinal cells and ex vivo detection of pro-inflammatory molecules using flow cytometry. Mol. Vision. In press.

Portillo, J.A, J. Van Grol, L. Zheng, G. Okenka, A. Garland, K. Gentil, E. Carlson, T.S. Kern, and C.S. Subauste. 2008. CD40 mediates retinal inflammation and neuro-vascular degeneration. J. Immunol. 181: 8719-8726.

Subauste, C.S., A. Subauste and M. Wessendarp.2007. Role of CD40-dependent downregulation of CD154 in impaired induction of CD154 in CD4+ T cells from HIV-1-infected patients. J. Immunol. 178:1645-1653.

Subauste, C.S., R.M. Andrade, and M. Wessendarp. 2007. CD40-TRAF6 and autophagy-dependent macrophage anti-microbial activity. Autophagy. 3: 245-248.

Andrade, R.M., M. Wessendarp. M.J. Gubbels, B. Striepen and C.S. Subauste. 2006. CD40 induces macrophage anti-microbial activity by triggering autophagy-dependent fusion of pathogen-containing vacuoles and lysosomes. J. Clin. Invest. 116:2366-2377.

Subauste, C.S. and M. Wessendarp. 2006. CD40 restrains in vivo growth of Toxoplasma gondii independently of gamma interferon. Infect. Immun. 74: 1573-1579.

Andrade, R.M., J-A.C. Portillo, M. Wessendarp, J. Yang, and C.S. Subauste. 2005. TNF-receptor associated factor 6 dependent CD40 signaling CD40 primes macrophages to acquire antimicrobial activity in response to TNF-a. J. Immunol. 175: 6014-6021.

Andrade, R.M., J-A.C. Portillo, M. Wessendarp and C.S. Subauste. 2005. CD40
signaling in macrophages induces anti-microbial activity against an intracellular
pathogen independently of IFN-g and reactive nitrogen intermediates. Infect. Immun. 73: 3135-3123.