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Abstract
Inflammation is a rapid, protective response that the cells of the innate immune system induce upon microbial infection. However, sustained or excessive inflammation can be deleterious to the host and occasionally this response can benefit the pathogen or cause serious sequelae after the resolution of infection. In this work, we sought to better understand two separate cases where dampening of the inflammatory response may be protective for host cells. Macrophages are professional phagocytes and important mediators of many biological processes in the body. We characterized the macrophage role in immune modulation in response to two common bacterial pathogens: Mycobacterium tuberculosis and Campylobacter jejuni. These bacteria exert a significant burden on our health systems worldwide, as M. tuberculosis latently infects a quarter of the world population and C. jejuni is the leading cause of bacterial diarrheal. In our first investigation we explore the relationship of iron and inflammation. Iron is an essential micronutrient for almost all forms of life and is carefully regulated due in part to the peptide hepcidin. Hepcidin secretion leads to intracellular iron arrest, while hepcidin inhibition lowers intracellular iron levels, decreasing the availability of this critical nutrient to pathogens such as M. tuberculosis and additionally modulating the production of proinflammatory cytokines. Through our research, we show that chemical inhibitors of hepcidin dampen the proinflammatory cytokine response and inhibit the intracellular replication of M. tuberculosis.
Our second investigation examines immune tolerance to C. jejuni glycolipids. Infection with C. jejuni is the most common event that triggers the rare autoimmune disease Guillain-Barré Syndrome, which occurs when autoreactive antibodies damage host neurons. The ability of C. jejuni glycolipids to mimic structures on human neurons causes this aberrant immune response. Using a macrophage model, we demonstrate that low doses of C. jejuni antigens tolerize cells to subsequent challenge with a strain of C. jejuni known to cause Guillain-Barré Syndrome.