Deciphering The C-Type Lectin Receptor Signaling Pathway In Macrophages In Response to Candida Albicans

<p><em>Candida albicans </em>causes opportunistic fungal infections in humans and is a significant cause of mortality and morbidity in immune-compromised individuals. Dectin-2, a C-type lectin receptor, is required for recognition of <em>C. albicans </em>by innate immune cells and is required for initiation of the anti-fungal immune response. We set out to identify components of the intracellular signaling cascade downstream of Dectin-2 activation in macrophages and to understand their importance in mediating the immune response to <em>C.</em> <em>albicans in vivo</em>. Using macrophages derived from Phospholipase-C-gamma 1 and 2 (PLCγ1and PLCγ2) knockout mice, we demonstrate that PLCγ2, but not PLCγ1, is required for activation of NF-κB and MAPK signaling pathways after <em>C. albicans </em>stimulation, resulting in impaired production of pro-inflammatory cytokines and reactive oxygen species. PLCγ2-deficient mice are highly susceptible to infections with <em>C. albicans, </em>indicating the importance of this pathway to the anti-fungal immune response<em>. </em>TAK1 and TRAF6 are critical nodes in NF-κB and MAPK activation downstream of immune surveillance and may be critical to the signaling cascade initiated by C-type lectin receptors in response to <em>C.</em> <em>albicans</em>. Macrophages derived from both TAK1 and TRAF6-deficient mice were unable to activate NF-κB and MAPK and consequently failed to produce inflammatory cytokines characteristic of the response to <em>C. albicans</em>. In this work we have identified PLCγ2, TAK1 and TRAF6 as components of a signaling cascade downstream of <em>C. albicans </em>recognition by C-type lectin receptors and as critical mediators of the anti-fungal immune response. A mechanistic understanding of the host immune response to <em>C. albicans </em>is important for the development of anti-fungal therapeutics and in understanding risk-factors determining susceptibility to <em>C. albicans </em>infection.</p> <p><em><br /></em></p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2012

Author dc:creator

• Gorjestani, Sara

Contributors dc:contributor

• Xin Lin, Ph.D.
• Shao-Cong Sun, Ph.D.
• Bryant G. Darnay, Ph.D.

• Immunology and Infectious Disease
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/258

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1310