The Aspergillus fumigatus pkcA(G579R) Mutant Is Defective in the Activation of the Cell Wall Integrity Pathway but Is Dispensable for Virulence in a Neutropenic Mouse Infection Model

Autor(es)

Rocha, Marina Campos ^[1] ; de Godoy, Krissia Franco ^[1] ; de Castro, Patrcia Alves ^[2] ; Hori, Juliana Issa ^[3] ; Pedro Bom, Vinicius Leite ^[2] ; Brown, Neil Andrew ^[4] ; da Cunha, Anderson Ferreira ^[1] ; Goldman, Gustavo Henrique ^{[2, 5]} ; Malavazi, Iran ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Carlos, Ctr Ciencias Biol & Saude, Dept Genet Evolucao, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Ciencias Farmaceut, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Farmacol, Sao Paulo - Brazil

^[4] Rothamsted Res, Dept Plant Biol & Crop Sci, Harpenden, Herts - England

^[5] Lab Nacl Ciencia & Tecnol Bioetanol, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 10, n. 8 AUG 21 2015.
• Citações Web of Science: 18

Resumo

Aspergillus fumigatus is an opportunistic human pathogen, which causes the life-threatening disease, invasive pulmonary aspergillosis. In fungi, cell wall homeostasis is controlled by the conserved Cell Wall Integrity (CWI) pathway. In A. fumigatus this signaling cascade is partially characterized, but the mechanisms by which it is activated are not fully elucidated. In this study we investigated the role of protein kinase C (PkcA) in this signaling cascade. Our results suggest that pkcA is an essential gene and is activated in response to cell wall stress. Subsequently, we constructed and analyzed a non-essential A. fumigatus pkcA(G579R) mutant, carrying a Gly579Arg substitution in the PkcA C1B regulatory domain. The pkcAG579R mutation has a reduced activation of the downstream Mitogen-Activated Protein Kinase, MpkA, resulting in the altered expression of genes encoding cell wall-related proteins, markers of endoplasmic reticulum stress and the unfolded protein response. Furthermore, PkcA(G579R) is involved in the formation of proper conidial architecture and protection to oxidative damage. The pkcA(G579R) mutant elicits increased production of TNF-alpha and phagocytosis but it has no impact on virulence in a murine model of invasive pulmonary aspergillosis. These results highlight the importance of PkcA to the CWI pathway but also indicated that additional regulatory circuits may be involved in the biosynthesis and/or reinforcement of the A. fumigatus cell wall during infection. (AU)

• Processo FAPESP: 09/53546-5 - Caracterização molecular da via de sinalização celular mediada pela proteína Quinase C no fungo patogênico humano Aspergillus fumigatus
• Beneficiário: Iran Malavazi
• Linha de fomento: Auxílio à Pesquisa - Apoio a Jovens Pesquisadores