Spindle assembly checkpoint component CaMad2p is indispensable for Candida albicans survival and virulence in mice.
Here, we report an indispensable role for spindle assembly checkpoint (SAC) component CaMad2p in the survival and virulence of Candida albicans in mice. We hypothesized that cell cycle checkpoint functions, especially those monitoring the integrity of DNA and chromosome segregation, might be required for the pathogen to repair damage caused by host defence. To test this idea, we created SAC-defective mutants by deleting the CaMAD2 gene that encodes a key component of the SAC pathway. The CaMAD2 mutant appears normal in morphology, growth rate and growth mode switch in unperturbed conditions. However, it quickly loses viability when treated with nocodazole, which causes disassembly of mitotic spindles. The mutant also exhibits increased frequency of chromosome loss. The virulence of the mutant is greatly reduced in mice, presumably because of the inability of the mutant cells to stop the cell cycle when the host defence damages cellular components important for chromosome segregation. Supporting this hypothesis, unlike the wild-type cells that can proliferate within and eventually grow out of macrophages, most of the CaMAD2 null mutant cells are unable to survive. This study suggests that SAC is required for survival of C. albicans in the host and could thus be targeted for anti-C. albicans therapies.
Bai
Chen
C
Microbial Collection and Screening Laboratory, Institute of Molecular and Cell Biology, Singapore.
Ramanan
Narendrakumar
N
Wang
Yan Ming
YM
Wang
Yue
Y
D000595:Amino Acid Sequence; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002176:Candida albicans / Q000235:genetics / Q000254:growth & development* / Q000472:pathogenicity*; D002177:Candidiasis / Q000382:microbiology*; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D020090:Chromosome Segregation; D005260:Female; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005816:Genetic Complementation Test; D006861:Hydrogen Peroxide / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000382:microbiology; D064246:Mad2 Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D015739:Nocodazole / Q000494:pharmacology; D009687:Nuclear Proteins; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D016415:Sequence Alignment; D008941:Spindle Apparatus / Q000502:physiology*; D014774:Virulence
D000935:Antifungal Agents; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D005656:Fungal Proteins; C577695:MAD2 protein, S cerevisiae; D064246:Mad2 Proteins; C577698:Mad2l1 protein, mouse; C577699:Mad2l2 protein, mouse; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; D006861:Hydrogen Peroxide; D015739:Nocodazole