Pheromones and pheromone receptors have long been known to affect virulence of the opportunistic pathogen Cryptococcus neoformans, yet it is still entirely unclear how the biological ramifications of pheromone signaling affect pathogenesis. The Nielsen laboratory has shown that production of a newly characterized cell type - referred to as """"""""titan cells"""""""" - is altered by pheromone sensing. Over-production of titan cells is correlated with reduced CNS penetration. The objective of this application is to define the role of titan cells in pathogenesis and how pheromone signaling alters titan cell production. The central hypothesis of our application is that the pheromone signaling cascade, in conjunction with other signaling components, regulates titan cell formation, which affects subsequent dissemination to the CNS. The rationale for the proposed research is that, once the role of titan cells in pathogenesis and how they are regulated is known, titan cell production can be targeted in new and innovative approaches for the prevention and treatment of cryptococcosis. We plan to test our central hypothesis and accomplish the objective of this application by pursuing the following specific aims: 1) Establish the role of titan cells in pathogenesis, and 2) Identify signaling pathways involved in titan cell formation. The expected outcomes of this research are to answer the long-standing question of why pheromone signaling affects pathogenesis in C. neoformans, to define the effect of titan cell production on pathogenesis, to identify signals that lead to titan cell production, and to understand titan cell formation and replication. Such results will have an important positive impact, because identified signaling components and/or downstream targets important for titan cell formation are expected to provide new targets for preventative and therapeutic interventions that will aid HIV/AIDS patients. We expect our contribution to be a detailed understanding of how signal transduction cascades regulate titan cell formation and how titan cell formation affects subsequent cell dissemination to the CNS. The proposed research is significant because it is expected to provide knowledge about titan cell formation, regulation, and pathogenesis that will enhance our understanding of the fundamental requirements for cryptococcal disease and allow titan cells to be targeted by antifungal therapy.

Public Health Relevance

A leading cause of death in AIDS patients is meningitis caused by the opportunistic fungus Cryptococcus neoformans. In order to reduce disease prevalence we need to understand how this organism causes disease. This proposal studies morphological changes in response to the host environment. Once we know how C. neoformans is able to grow and survive in the host, we can develop treatment strategies that block this process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI080275-04
Application #
8602794
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Duncan, Rory A
Project Start
2011-02-15
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Li, Zhongming; Nielsen, Kirsten (2017) Morphology Changes in Human Fungal Pathogens upon Interaction with the Host. J Fungi (Basel) 3:
Wiesner, Darin L; Smith, Kyle D; Kashem, Sakeen W et al. (2017) Different Lymphocyte Populations Direct Dichotomous Eosinophil or Neutrophil Responses to Pulmonary Cryptococcus Infection. J Immunol 198:1627-1637
Mukaremera, Liliane; Nielsen, Kirsten (2017) Adaptive Immunity to Cryptococcus neoformans Infections. J Fungi (Basel) 3:
May, Robin C; Stone, Neil R H; Wiesner, Darin L et al. (2016) Cryptococcus: from environmental saprophyte to global pathogen. Nat Rev Microbiol 14:106-17
Wiesner, Darin L; Smith, Kyle D; Kotov, Dmitri I et al. (2016) Regulatory T Cell Induction and Retention in the Lungs Drives Suppression of Detrimental Type 2 Th Cells During Pulmonary Cryptococcal Infection. J Immunol 196:365-74
Homer, Christina M; Summers, Diana K; Goranov, Alexi I et al. (2016) Intracellular Action of a Secreted Peptide Required for Fungal Virulence. Cell Host Microbe 19:849-64
Katchanov, Juri; Blechschmidt, Cristiane; Nielsen, Kirsten et al. (2015) Cryptococcal meningoencephalitis relapse after an eight-year delay: an interplay of infection and immune reconstitution. Int J STD AIDS 26:912-4
Wiesner, Darin L; Specht, Charles A; Lee, Chrono K et al. (2015) Chitin recognition via chitotriosidase promotes pathologic type-2 helper T cell responses to cryptococcal infection. PLoS Pathog 11:e1004701
Evans, Robert J; Li, Zhongming; Hughes, William S et al. (2015) Cryptococcal phospholipase B1 is required for intracellular proliferation and control of titan cell morphology during macrophage infection. Infect Immun 83:1296-304
Gerstein, Aleeza C; Fu, Man Shun; Mukaremera, Liliane et al. (2015) Polyploid titan cells produce haploid and aneuploid progeny to promote stress adaptation. MBio 6:e01340-15

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