Research Interests:

Central Nervous System Penetration by Cryptococcus neoformans

Over the past decade fungal infectious diseases have increased as the population of immunocompromised individuals has expanded due to aggressive cancer therapy and AIDS. Cryptococcus neoformans is an opportunistic human pathogenic fungus that causes cryptococcosis, which commonly presents as a disseminated meningoencephalitis that is universally fatal if untreated. An integral and defining feature of cryptococcosis is the ability of C. neoformans to cross the blood-brain barrier. In recent years the process of C. neoformans entry into the central nervous system (CNS) has begun to be elucidated, but the methods by which C. neoformans induces these processes remains unknown. If the mechanisms by which C. neoformans crosses the blood-brain barrier can be identified and characterized, treatment strategies can be designed to reduce C. neoformans entry into the CNS to alleviate disease symptoms and permit increased exposure to antifungal drugs.

C. neoformans has two mating types alpha and a. However, the vast majority of clinical isolates are alpha mating type. Interestingly, no differences in virulence are observed in individual infections with congenic alpha and a strains in the most commonly pathogenic variety of Cryptococcus. However, during coinfection, both strains are present in equal proportions in the lung and spleen yet alpha strains predominate in the CNS. This alpha cell predominance in the CNS during coinfections is due to the strains ability to penetrate the brain and could contribute to the predominance of alpha strains in clinical isolates, which are often derived from the cerebrospinal fluid when diagnosis is made from lumbar puncture. C. neoformans cells sense and respond to cells of the opposite mating partner by using pheromones. Since pheromones are known to be produced by C. neoformans during CNS infection and have been shown to play a role in virulence of alpha strains, we disrupted pheromone sensing in the two cell types to determine the mechanism by which alpha cells predominate in the brain. As a result of these studies, we discovered that a cells, when coinfected with alpha cells, are inhibited from entering the brain by pheromone signaling.

We hypothesize that pheromone signaling plays a central role not only during mating of C. neoformans but also during entry into the CNS. By perturbing pheromone signaling during individual and coinfections with congenic alpha and a strains we can identify key components required for CNS penetration in this pathogen and provide a foundation for further treatment strategies to reduce cryptococcal meningitis.

Selected Recent Publications:

• Charlier, C., Nielsen, K., Daou, S., Brigitte, M., Chretien, F., and Dromer, F. 2008. Evidence for a role of monocytes in dissemination and brain invasion by /Cryptococcus neoformans. Infection and Immunity, 77:120-127.

• Nielsen, K., and Heitman, J. 2007. Sex and virulence of human fungal pathogens. Advances in Genetics, 57:143-173.

• Nielsen, K., De Obaldia, A.L., and Heitman, J. 2007. Differences in mating of Cryptococcus species on pigeon guano defines their ecological niche. Eukarotic Cell, 6:949-959.

• Nielsen, K., Cox, G.M., Litvintseva, A.P., Mylonakis, E., Malliaris, S.D., Benjamin, D.K., Giles, S.S., Mitchell, T.G., Casadevall, A., Perfect, J.R. and Heitman, J. 2005. Cryptococcus neoformans alpha strains preferentially disseminate to the central nervous system during coinfection. Infection and Immunity, 73:4922-4933.

• Nielsen, K., Marra, R.E., Hagen, F., Boekhout, T., Mitchell, T.G., Cox, G.M., and Heitman, J. 2005. Interaction between genetic background and the mating type locus in Cryptococcus neoformans virulence potential. Genetics, 171:975-983.

• Nielsen, K., Cox, G.M., Wang, P., Toffaletti, D.L., Perfect, J.R., and Heitman, J. 2003. Sexual cycle of Cryptococcus neoformans variety grubii and virulence of congenic a and alpha isolates. Infection and Immunity, 71:4831-4841.

   

Last modified on: August 10, 2009