Ellen Upton

Function of ISG15 in immune response and protection during Francisella infection

Although, interferon is known to be a vital cytokine for initiating protective immune responses in many viral and bacterial diseases, the specific function of many of its downstream effector molecules remains unclear. ISG15, a ubiquitin-like protein (UBL), is one of these understudied effectors, and has been implicated in antiviral and antibacterial immunity. When ISG15 deficiency is observed in humans, they seem to have no change in viral susceptibility and instead have trouble clearing mild bacterial infections, such as the BCG vaccine1,4. This human deficiency has also been linked to interferon-driven autoinflammatory diseases such as Aicardi–Goutières syndrome and other interferonopathies4. ISG15 is also upregulated following bacterial infections such as Listeria monocytogenes<\i> and Mycobacterium tuberculosis both in vivo and in 2,3. The mechanism of this bacterial driven response is still unclear, as well as the function of the increased ISG15. Addressing this knowledge gap will allow us to link the mechanistic function of ISG15 intracellularly to the greater role it plays in regulation of inflammation responses, which could then be further studied and potentially therapeutically targeted in the context of cancers and autoimmune disorders.

In our lab we aim to learn how ISG15 functions both in vivo and in vitro following bacterial infections using cell biology, immunology, and cutting-edge proteomic methods. We have observed that cells and mice lacking ISG15 have increased bacterial burden when infected with Listeria monocytogenes. Some preliminary studies have shown that Francisella novicida also has a similar phenotype in ISG15 knock out cells. Previous work in the laboratory also suggests that increased ISG15 alters canonical cytokine secretion as well as the endoplasmic reticulum and autophagy pathways 3,5. The goal of my project is to determine ISG15’s role in response to Francisella novicida infection. This information will be valuable in expanding our knowledge of the mechanistic cause of both interferon driven protection from bacterial infections and potential causes of autoinflammatory diseases.

Ellen Upton
Hillsboro, OR
BS, Biochemistry and Microbiology, Grove City College
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