Variation in chromosome copy number influences the virulence of Cryptococcus neoformans and occurs in isolates from AIDS patients.
BACKGROUND
The adaptation of pathogenic fungi to the host environment via large-scale genomic changes is a poorly characterized phenomenon. Cryptococcus neoformans is the leading cause of fungal meningoencephalitis in HIV/AIDS patients, and we recently discovered clinical strains of the fungus that are disomic for chromosome 13. Here, we examined the genome plasticity and phenotypes of monosomic and disomic strains, and compared their virulence in a mouse model of cryptococcosis


RESULTS
In an initial set of strains, melanin production was correlated with monosomy at chromosome 13, and disomic variants were less melanized and attenuated for virulence in mice. After growth in culture or passage through mice, subsequent strains were identified that varied in melanin formation and exhibited copy number changes for other chromosomes. The correlation between melanin and disomy at chromosome 13 was observed for some but not all strains. A survey of environmental and clinical isolates maintained in culture revealed few occurrences of disomic chromosomes. However, an examination of isolates that were freshly collected from the cerebrospinal fluid of AIDS patients and minimally cultured provided evidence for infections with multiple strains and copy number variation.


CONCLUSIONS
Overall, these results suggest that the genome of C. neoformans exhibits a greater degree of plasticity than previously appreciated. Furthermore, the expression of an essential virulence factor and the severity of disease are associated with genome variation. The occurrence of chromosomal variation in isolates from AIDS patients, combined with the observed influence of disomy on virulence, indicates that genome plasticity may have clinical relevance.
The Michael Smith Laboratories, Department of Microbiology and Immunology, and Faculty of Land and Food Systems, University of British Columbia, Vancouver, B.C. V6T 1Z4, Canada.
Guanggan
G
Hu
Joyce
J
Wang
Jaehyuk
J
Choi
Won Hee
WH
Jung
Iris
I
Liu
Anastasia P
AP
Litvintseva
Tihana
T
Bicanic
Rajeev
R
Aurora
Thomas G
TG
Mitchell
John R
JR
Perfect
James W
JW
Kronstad
D017088:AIDS-Related Opportunistic Infections / Q000134:cerebrospinal fluid / Q000382:microbiology*; D000818:Animals; D015825:Chromosomes, Fungal / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D003453:Cryptococcosis / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000235:genetics* / Q000302:isolation & purification / Q000472:pathogenicity; D056915:DNA Copy Number Variations; D005260:Female; D006801:Humans; D008543:Melanins / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics
D008543:Melanins; D037521:Virulence Factors