Cryptococcus neoformans Genotypic Diversity and Disease Outcome among HIV Patients in Africa

Kassaza, Kennedy; Wasswa, Fredrickson B.; Nielsen, Kirsten; Bazira, Joel

doi:10.3390/jof8070734

Cited by 5 publications

(2 citation statements)

References 137 publications

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“…Cryptococcus neoformans is an opportunistic human fungal pathogen responsible for more than 180,000 deaths annually worldwide ( 27 , 28 ). We previously characterized the catalytic subunit of the cryptococcal CK2 complex, Cka1, as a part of a systematic functional analysis of kinases in C. neoformans ( 29 ).…”

Section: Introductionmentioning

confidence: 99%

Casein kinase 2 complex: a central regulator of multiple pathobiological signaling pathways in Cryptococcus neoformans

Choi,

Yu,

Lee

et al. 2024

mBio

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The casein kinase 2 (CK2) complex has garnered extensive attention over the past decades as a potential therapeutic target for diverse human diseases, including cancer, diabetes, and obesity, due to its pivotal roles in eukaryotic growth, differentiation, and metabolic homeostasis. While CK2 is also considered a promising antifungal target, its role in fungal pathogens remains unexplored. In this study, we investigated the functions and regulatory mechanisms of the CK2 complex in Cryptococcus neoformans , a major cause of fungal meningitis. The cryptococcal CK2 complex consists of a single catalytic subunit, Cka1, and two regulatory subunits, Ckb1 and Ckb2. Our findings show that Cka1 plays a primary role as a protein kinase, while Ckb1 and Ckb2 have major and minor regulatory functions, respectively, in growth, cell cycle control, morphogenesis, stress response, antifungal drug resistance, and virulence factor production. Interestingly, triple mutants lacking all three subunits ( cka1 Δ ckb1 Δ ckb2 Δ) exhibited more severe phenotypic defects than the cka1 Δ mutant alone, suggesting that Ckb1/2 may have Cka1-independent functions. In a murine model of systemic cryptococcosis, cka1 Δ and cka1 Δ ckb1 Δ ckb2 Δ mutants showed severely reduced virulence. Transcriptomic, proteomic, and phosphoproteomic analyses further revealed that the CK2 complex controls a wide array of effector proteins involved in transcriptional regulation, cell cycle control, nutrient metabolisms, and stress responses. Most notably, CK2 disruption led to dysregulation of key signaling cascades central to C. neoformans pathogenicity, including the Hog1, Mpk1 MAPKs, cAMP/PKA, and calcium/calcineurin signaling pathways. In summary, our study provides novel insights into the multifaceted roles of the fungal CK2 complex and presents a compelling case for targeting it in the development of new antifungal drugs. IMPORTANCE The casein kinase 2 (CK2) complex, crucial for eukaryotic growth, differentiation, and metabolic regulation, presents a promising therapeutic target for various human diseases, including cancer, diabetes, and obesity. Its potential as an antifungal target is further highlighted in this study, which explores CK2’s functions in C. neoformans , a key fungal meningitis pathogen. The CK2 complex in C. neoformans , comprising the Cka1 catalytic subunit and Ckb1/2 regulatory subunits, is integral to processes like growth, cell cycle, morphogenesis, stress response, drug resistance, and virulence. Our findings of CK2’s role in regulating critical signaling pathways, including Hog1, Mpk1 MAPKs, cAMP/PKA, and calcium/calcineurin, underscore its importance in C. neoformans pathogenicity. This study provides valuable insights into the fungal CK2 complex, reinforcing its potential as a target for novel antifungal drug development and pointing out a promising direction for creating new antifungal agents.

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Section: Introductionmentioning

confidence: 99%

Casein kinase 2 complex: a central regulator of multiple pathobiological signaling pathways in Cryptococcus neoformans

Choi,

Yu,

Lee

et al. 2024

mBio

View full text Add to dashboard Cite

show abstract

“…These cells were first noted as a distinct population in lungs of infected mice often adjacent to giant (titan) forms [ 1 ]. It has been hypothesized that the formation of microcells may be important for the dissemination of fungal cells to the brain and the propagation of immune reconstitution inflammatory syndrome (IRIS) [ 28 ]. Analysis of clinical strains of C .…”

Section: Introductionmentioning

confidence: 99%