The Moskophidis Lab

Function of molecular chaperones and heat shock transcription factors in mouse models of human diseases (cancer)

This research area involves the study of cellular processes via which molecular chaperones and heat shock transcription factors (HSFs) mediate the host response to environmental stress and the role of these processes in human diseases such as cancer. Using genetically manipulated (knock-in and knock-out) mouse models and employing metabolic, proteomic and genomic methods we probe the basic mechanisms, by which the HSP70 and HSP90 chaperone machineries, in the endoplasmic reticulum (GRP78, GRP170, SIL1, GRP94), cytoplasm (HSP70, HSC70, HSP25), and mitochondria (GRP75), impact the progression of human metabolic diseases, cancer and neurodegeneration. Our work provided proof-of-concept information to demonstrate that the ability of the evolutionary conserved Heat Shock Transcription factors (HSFs) and particularly HSF1 to promote malignant cell transformation resides in its ability to stimulate transcription of mRNAs that encode proteins regulating adaptive energetic and metabolic pathways. Targeting inactivation of HSF1 interferes with the anabolic malignant state and is an effective strategy for prevention and therapy of several cancer types. Notably, this important research is the result of a long-term collaboration with Dr. N. Mivechi at the Georgia Cancer Center.

Deciphering the fundamental mechanisms coordinating the immune response to acute versus persistent viral infections and the implications in cancer immune evasion

Persistent viral infections create conditions for long-term pathologic consequences in human populations. A specific focus of my laboratory has been to elucidate the mechanisms by which viruses persist and escape immune surveillance. This research is important for our understanding of viral pathogenesis and for the development of measures to control and eliminate such infections and the diseases they cause. Our  have provided proof-of-concept that:

• The evolution of the immune system has developed regulatory mechanisms to ensure efficient clearance of an infection with minimal damage to host tissues. Specifically, we discovered that during a rapidly spreading viral infection, the initially induced virus-specific CD8+ T cells fail to contain the infection as a result of progressive functional loss and physical elimination. This phenomenon, called “T cell exhaustion,” represents an important aspect in the regulation of protective immune responses. This observation has not only provided an avenue for studying interactions between viruses and the immune system in the context of acute or persistent infections, but also has stimulated innovative research on mechanisms facilitating malignant cell evasion from immune-mediated surveillance.
• Viruses persist in an immune population, as in the case of influenza, or in an individual, as postulated for HIV, when they are able to escape neutralizing antibodies by changing their antigens. This has been known since the original discovery in the 1980s that revealed that the evolution of influenza viruses is associated with the generation of antibody-resistant viral strains. We made the original discovery that viruses can escape surveillance by virus-specific T cells through introducing mutations in their genomes that alter the presentation of antigen-specific T cell epitopes. Since T cell-mediated immunity represents a critical defense mechanism of the host against microbial infections, this discovery has profoundly influenced our understanding about the evolution of microbial pathogens. Notably, antigenic variation, the rapid acquisition of latency in the infected host, and acute immune suppression, are features of many persistent viral infections.