Only a handful of fungal species commonly cause disease in humans, making it easy to overlook their threat to public health, yet invasive fungal infections account for 22 of every 100,000 hospitalizations. Thus, fungi are robust pathogens that often establish lifelong infections in humans and can cause life-threatening disease, particularly in immune-compromised individuals. The fungus Cryptococcus neoformans commonly causes life- threatening meningitis in immune-compromised individuals, resulting in more than 650,000 deaths annually. Exposure to C. neoformans in early childhood results in an initial pulmonary infection that is controlled (latent), indicating that our immune system has effective mechanisms for coping with the infection and preventing disease. When the immune system fails, due to HIV infection or medical interventions that suppress immunity, this immune control is lost and the latent C. neoformans infection disseminates to the central nervous system to cause meningitis. Thus, a primary focus of this research application is to investigate the cellular and molecular basis for host control of C. neoformans in order to identify the holes in immune-mediated host defenses that are critical for the development of disease in immune-compromised individuals and that must be filled to prevent disease in at-risk patient populations. Most fungal infections, including cryptococcosis, are associated with diseases or medical interventions that affect cell mediated immunity - particularly CD4 T-cell mediated immunity. Given the vast immunological tools currently available in mice to study the priming and function of CD4 T-cell subsets, we developed a mouse inhalation model of latent cryptococcal infection. Using this model, we find infection is controlled by CD4 T-cell mediated immunity - mice only develop disease upon T-cell depletion. Therefore, our first aim is to identify the T-cell subsets, and their intrinsic properties, that control the cryptococcal infection. In our second aim, we will define the host and pathogen mediators of the T-cell response by testing the working hypothesis that differential activity of dendritic cell subsets primes beneficial T-cell responses that contro infection, in contrast to detrimental responses that promote disease. These studies will lay the foundation for future research to define the critical T-cell actions that prevent disease, determin why the immune response is unable to eradicate many fungal infections (resulting in latency), and identify novel strategies for immune modulatory or preferential replacement/reconstitution of essential T-cell populations in at-risk patient populations.
Only a handful of fungal species commonly cause disease in humans, making it easy to overlook their threat to public health, yet fungal infections account for 22 of every 100,000 hospitalizations. Thus, the medically- relevant fungi are robust pathogens that can cause acute disease. In addition, many fungi establish lifelong infections that can reactive when the immune system fails. The fungus Cryptococcus neoformans commonly causes life-threatening brain infections (meningitis) in immune-compromised individuals, resulting in more than 600,000 deaths annually. Most people are exposed to Cryptococcus in childhood and have a controlled (latent) infection in their lungs, indicating that our immune system has effective mechanisms for coping with the infection and preventing disease. When the immune system fails, due to HIV infection or medical interventions that suppress immunity, this control is lost and the latent Cryptococcus infection disseminates to the brain where it causes meningitis. Our research goal is to understand how the healthy immune system prevents fungal infections in order to identify the 'holes' that must be filled to prevent fungal infections when the immune system fails.
| 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 |
| Li, Zhongming; Nielsen, Kirsten (2017) Morphology Changes in Human Fungal Pathogens upon Interaction with the Host. J Fungi (Basel) 3: |
| 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 |
| 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 |
