Increasing evidence points to a critical role of microbial microevolution during chronic C. neoformans infection as a mechanism, which allows C. neoformans to escape host response and persist during chronic infection. We recently demonstrated that C. neoformans can switch from a smooth (SM) to a mucoid (MC) colony variant during chronic infection and showed that this switch is associated with lethal outcome. Simultaneously we showed that the newly generated MC switch variant produces a viscous capsular polysaccharide, which leads to dysfunctional phagocytosis by macrophages. The inflammatory response in the lung of MC infected mice is characterized by intense macrophage infiltration and lung destruction, whereas lungs of SM infected mice exhibit an effective lymphocyte dominated inflammatory response. Analysis of differentially expressed genes between the switch variants demonstrated that an immunogenic epitope is downregulated in the MC switch variant. Consistent with these findings we find a lack of effective T-cell response and evidence for inadequate phagocytosis and overstimulation of alveolar macrophages. Here we will examine the effects of phenotypic switching on the inflammatory immune response and survival. We propose three specific Aims to test our central hypothesis: 1.) To explore mechanisms by which phenotypic switching affects interactions of alveolar macrophages with C. neoformans.
Aim 2.) To determine if down regulation of an immunogenic epitope in the pathogen affects T-cell response and Aim 3.) To examine the effects of macrophage function in the host and epitope expression in the pathogen on outcome of C. neoformans infection in mice. If our hypothesis is correct, the work proposed here will have broad significance in the long-term, because it will establish insight into the dynamics of host-pathogen interaction in chronic cryptococcosis. This should in the long-term enable us to develop novel, selective lung-protective therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI059681-04
Application #
7272032
Study Section
Special Emphasis Panel (ZRG1-BM-2 (02))
Program Officer
Duncan, Rory A
Project Start
2004-06-01
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
4
Fiscal Year
2007
Total Cost
$412,547
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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