Calcineurin controls growth, morphology, and pathogenicity in Aspergillus fumigatus.
Calcineurin is implicated in a myriad of human diseases as well as homeostasis and virulence in several major human pathogenic microorganisms. The fungus Aspergillus fumigatus is a leading cause of infectious death in the rapidly expanding immunocompromised patient population. Current antifungal treatments for invasive aspergillosis are often ineffective, and novel therapeutic approaches are urgently needed. We demonstrate that a mutant of A. fumigatus lacking the calcineurin A (cnaA) catalytic subunit exhibited defective hyphal morphology related to apical extension and polarized growth, which resulted in drastically decreased filamentation. The delta cnaA mutant lacked the extensive lattice of invading hyphae seen with the wild-type and complemented strains. Sporulation was also affected in the delta cnaA mutant, including morphological conidial defects with the absence of surface rodlets and the added presence of disjunctors creating long conidial chains. Infection with the delta cnaA mutant in several distinct animal models with different types of immunosuppression and inoculum delivery led to a profound attenuation of pathogenicity compared to infection with the wild-type and complemented strains. Lung tissue from animals infected with the delta cnaA mutant showed a complete absence of hyphae, in contrast to tissue from animals infected with the wild-type and complemented strains. Quantitative fungal burden and pulmonary infarct scoring confirmed these findings. Our results support the clinical observation that substantially decreasing fungal growth can prevent disease establishment and decrease mortality. Our findings reveal that calcineurin appears to play a globally conserved role in the virulence of several pathogenic fungi and yet plays specialized roles in each and can be an excellent target for therapeutic intervention.
Steinbach
William J
WJ
Department of Pediatrics, Division of Pediatric Infectious Diseases, Box 3499, Duke University Medical Center, Durham, North Carolina 27710, USA. stein022@mc.duke.edu
Cramer
Robert A
RA
Perfect
B Zachary
BZ
Asfaw
Yohannes G
YG
Sauer
Theodor C
TC
Najvar
Laura K
LK
Kirkpatrick
William R
WR
Patterson
Thomas F
TF
Benjamin
Daniel K
DK
Heitman
Joseph
J
Perfect
John R
JR
D000818:Animals; D001232:Aspergillus fumigatus / Q000166:cytology* / Q000254:growth & development* / Q000472:pathogenicity*; D017848:Blood-Borne Pathogens / Q000302:isolation & purification; D019703:Calcineurin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015169:Colony Count, Microbial; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA / Q000382:microbiology; D008813:Mice, Inbred ICR / Q000382:microbiology; D009024:Morphogenesis; D009154:Mutation; D020953:Neuroaspergillosis / Q000188:drug therapy; D017384:Sequence Deletion
D019703:Calcineurin