IP3-4 kinase Arg1 regulates cell wall homeostasis and surface architecture to promote Cryptococcus neoformans infection in a mouse model

Virulence

Desmarini Desmarini¹  Keren Kaufman-Francis²  Cecilia Li³  Sophie Lev³  Julianne T. Djordjevic⁴  Tania C. Sorrell⁴  Adolfo Saiardi⁵  Philip E. Thompson⁶  Ana P.G Silva⁷  Joel P. Mackay⁷ 

[1] Centre for Infectious Diseases and Microbiology, The Westmead Institute for Medical Research, 176 Hawkesbury road, Westmead NSW 2145, Australi;Centre for Infectious Diseases and Microbiology, The Westmead Institute for Medical Research, 176 Hawkesbury road, Westmead NSW 2145, Australi;Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, NSW Australi;Centre for Infectious Diseases and Microbiology, The Westmead Institute for Medical Research, 176 Hawkesbury road, Westmead NSW 2145, Australi;Sydney Medical School-Westmead, The University of Sydney, Westmead NSW 2145, Australi;Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, NSW Australi;Centre for Infectious Diseases and Microbiology, The Westmead Institute for Medical Research, 176 Hawkesbury road, Westmead NSW 2145, Australi;Sydney Medical School-Westmead, The University of Sydney, Westmead NSW 2145, Australi;Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, NSW Australi;Westmead Hospital, Westmead, NSW 2145, Australi;Medical Research Council Laboratory for Molecular Cell Biology, University College London, Gower street, London WC1E 6BT, U;Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australi;School of Life and Environmental Sciences, The University of Sydney, Camperdown, NSW 2006, Australi;

关键词: Cryptococcus neoformans;    inositol pyrophosphate;    PP-IP;    IP;    inositol polyphosphate kinase;    virulence;    molecular fungal pathogenesis;    mouse model;    meningitis;    cell wall;   

DOI  :  10.1080/21505594.2017.1385692

来源: Taylor & Francis

【 摘 要 】

We previously identified a series of inositol polyphosphate kinases (IPKs), Arg1, Ipk1, Kcs1 and Asp1, in the opportunistic fungal pathogen Cryptococcus neoformans. Using gene deletion analysis, we characterized Arg1, Ipk1 and Kcs1 and showed that they act sequentially to convert IP3 to PP-IP5 (IP7), a key metabolite promoting stress tolerance, metabolic adaptation and fungal dissemination to the brain. We have now directly characterized the enzymatic activity of Arg1, demonstrating that it is a dual specificity (IP3/IP4) kinase producing IP5. We showed previously that IP5 is further phosphorylated by Ipk1 to produce IP6, which is a substrate for the synthesis of PP-IP5 by Kcs1. Phenotypic comparison of the arg1Δ and kcs1Δ deletion mutants (both PP-IP5-deficient) reveals that arg1Δ has the most deleterious phenotype: while PP-IP5 is essential for metabolic and stress adaptation in both mutant strains, PP-IP5 is dispensable for virulence-associated functions such as capsule production, cell wall organization, and normal N-linked mannosylation of the virulence factor, phospholipase B1, as these phenotypes were defective only in arg1Δ. The more deleterious arg1Δ phenotype correlated with a higher rate of arg1Δ phagocytosis by human peripheral blood monocytes and rapid arg1Δ clearance from lung in a mouse model. This observation is in contrast to kcs1Δ, which we previously reported establishes a chronic, confined lung infection. In summary, we show that Arg1 is the most crucial IPK for cryptococcal virulence, conveying PP-IP5–dependent and novel PP-IP5–independent functions.

【 授权许可】

Unknown