Affiliation:
1. Department of Pharmacology, School of Medicine, University of California, Genome and Biomedical Sciences Facility, Davis, California, USA
2. Veterinary Genetic Laboratory, School of Veterinary Medicine, University of California, Davis, California, USA
Abstract
ABSTRACT
Pathogenic fungi have developed mechanisms to cope with stresses imposed by hosts. For
Cryptococcus
spp., this implies active defense mechanisms that attenuate and ultimately overcome the onslaught of oxidative stresses in macrophages. Among cellular pathways within
Cryptococcus neoformans
' arsenal is the plasma membrane high-affinity Cch1-Mid1 calcium (Ca
2+
) channel (CMC). Here we show that CMC has an unexpectedly complex and disparate role in mitigating oxidative stress. Upon inhibiting the Ccp1-mediated oxidative response pathway with antimycin, strains of
C. neoformans
expressing only Mid1 displayed enhanced growth, but this was significantly attenuated upon H
2
O
2
exposure in the absence of Mid1, suggesting a regulatory role for Mid1 acting through the Ccp1-mediated oxidative stress response. This notion is further supported by the interaction detected between Mid1 and Ccp1 (cytochrome
c
peroxidase). In contrast, Cch1 appears to have a more general role in promoting cryptococci survival during oxidative stress. A strain lacking Cch1 displayed a growth defect in the presence of H
2
O
2
without BAPTA [(1,2-bis(2-aminophenoxy)ethane-
N
,
N
,
N
′,
N
′-tetraacetic acid, cesium salt] or additional stressors such as antimycin. Consistent with a greater contribution of Cch1 to oxidative stress tolerance, an intracellular growth defect was observed for the
cch1
Δ strain in the macrophage cell line J774A.1. Interestingly, while the absence of either Mid1 or Cch1 significantly compromises the ability of
C. neoformans
to tolerate oxidative stress, the absence of both Mid1 and Cch1 has a negligible effect on
C. neoformans
growth during H
2
O
2
stress, suggesting the existence of a compensatory mechanism that becomes active in the absence of CMC.
Publisher
American Society for Microbiology
Subject
Molecular Biology,General Medicine,Microbiology
Cited by
13 articles.
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