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.
Using Toxoplasma gondii as a model, studies are being done to determine how CD40 promotes host protection. T. gondii is an obligate intracellular protozoan that infects approximately 30% of the world population. While immunocompetent individuals typically control the infection, those with defects in cell-mediated immunity (patients with AIDS or transplanted organs as well as unborn babies and newborns) can develop diseases typically manifested as encephalitis and/or retino-choroiditis.
Dr. Subauste’s laboratory demonstrated that CD40 has a dual role in protection against T. gondii: it drives production of IL-12 / IFN-γ and activates pathogen killing via autophagy (Fig. 1). Autophagy is a process of lysosomal degradation recognized to result in killing of pathogens. Dr. Subauste’s laboratory is identifying the signaling pathways by which CD40 activates autophagy (Fig. 1) as well as mechanisms used by pathogens to inhibit this 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.
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 microvascular complications of diabetes, atherosclerosis and ischemia.