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Diseases of Innate Immunity

Once unleashed, the innate immune response has the power to eliminate infections. However, because the ensuing response has the potential to damage the host, tight regulation is critical to prevent disease. Failure to curb the activity of innate immunity leads to Inflammatory diseases, Autoimmune diseases, Atherosclerosis, Neurodegenerative diseases and Cancer

Anti-bacterial immunity: Throughout history, millions of people have died of diseases such as bubonic plague or the Black Death, which is caused by Yersinia pestis bacteria. Researchers in the PII program are trying to understand how the immune system responds to pathogenic organisms such as Yersinia, Salmonella, Listeria and other bacterial pathogens. In addition, a number of groups study how the bacteria that cause gonorrhea and meningitis escape killing by the complement system. Knowledge of such immune evasion mechanisms are being translated to develop novel vaccines and therapies.

Anti-viral immunity: In recent times, viral infections have been responsible for two major pandemics: the 1918-1919 “Spanish flu” epidemic that killed 20-40 million people, and the ongoing HIV/AIDS epidemic. A major focus of research in the PII program is geared towards understanding the molecular basis of anti-viral immunity.

Anti-fungal immunity: About one million people die of fungal infections annually.  Most victims have compromised immune systems emphasizing the importance of host defenses for controlling fungal pathogens. Better understand of how the immune system innately recognizes and responds to encounters with fungi could lead to novel approaches to immunotherapies and preventive vaccines. Several groups in the Program in innate immunity are focused on understanding the molecular basis of anti-fungal immunity.

Immune responses during Malaria infection: Malaria is a parasitic disease that kills nearly 750,000 individuals annually. Much of the pathophysiology results from the overabundant production of cytokines, which cause painful paroxysms of fever and chills, severe anemia and often fatal cerebral disease in young children. The nature of the innate immune response to malaria is an important component of the pathophysiology. Researchers in the PII program believe that much of this innate immune response is activated via the recognition of parasite DNA by phogocytes. The Golenbock, Fitzgerald and Gazzinelli laboratories are all focused on understanding the role of innate immune pathways in responding to malaria and driving disease.

Inflammation and Neurodegenerative Disease: Alzheimer's Disease is the most important cause of dementia in the World, perhaps affecting 35 million individuals including 7% of all individuals over the age of 65. It has become increasingly clear that the neurodegeneration associated with Alzheimer's Disease results from inflammation in the brain, which causes neuronal cell death, especially in those tissues responsible for memory. We have hypothesized that central to this process is the NLRP3 inflammasome, a multiprotein complex that generates IL-1 beta in abundance in response the the phagocytosis of amyloid peptide by microglial cells. This hypothesis has been tested in transgenic mice, which are protected from adverse effects from amyloid deposition when inflammasome activation is inhibited. We continue to explore this hypothesis in mice in the hopes that a specific anti inflammatory therapy can be devised that will stop the progression of this devastating disease.

Autoimmune diseases: Several PII labs are involved in cutting edge research of autoimmune diseases. Work in the Rothstein laboratory is aimed at understanding the role of innate immune sensors in the activation of autoreactive B cells and T cells in models of systemic autoimmunity, autoinflammation, and fibrosi. Work in the Fitzgerald laboratory is focused on understanding how cytosolic sensors of nucleic acids regulate autoimmunity and autoinflammatory diseases. Work in the Harris lab is trying to understand the pathogenesis of Vitiligo.