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Kirsten Nielsen, Ph.D
Assistant Professor
Department of Microbiology
North Carolina State University, 2001, Ph.D.
knielsen@umn.edu
office - 612-625-4979
lab - 612-625-4975
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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., 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.
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