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Human cutaneous leishmaniasis: interferon‐dependent expression of double‐stranded RNA‐dependent protein kinase (PKR) via TLR2
Author(s) -
Carvalho Vivarini Áislan,
Meirelles Santos Pereira Renata,
Teixeira Karina Luiza Dias,
CalegariSilva Teresa Cristina,
Bellio Maria,
Laurenti Marcia Dalastra,
Corbett Carlos Eduardo Pereira,
Castro Gomes Cláudia Maria,
Soares Rodrigo Pedro,
Silva Aristóbolo Mendes,
Silveira Fernando Tobias,
Lopes Ulisses Gazos
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-185165
Subject(s) - protein kinase r , tlr2 , interferon , leishmania , biology , cutaneous leishmaniasis , leishmaniasis , eif 2 kinase , leishmania major , microbiology and biotechnology , immune system , kinase , virology , immunology , protein kinase a , innate immune system , parasite hosting , mitogen activated protein kinase kinase , world wide web , computer science , cyclin dependent kinase 2
We investigated the type I interferon (IFN‐1)/PKR axis in the outcome of the Leishmania (Leishmania) amazonensis infection, along with the underlying mechanisms that trigger and sustain this signaling pathway. Reporter assays of cell extracts from RAW‐264.7 macrophages infected with L. (L.) amazonensis or HEK‐293T cells cotransfected with TLR2 and PKR promoter constructions were employed. Primary macrophages of TLR2‐knockout (KO) or IFNR‐KO mice were infected, and the levels of PKR, IFN‐1, and superoxide dismutase 1 (SOD1) transcript levels were investigated and compared. Immunohistochemical analysis of human biopsy lesions was evaluated for IFN‐1 and PKR‐positive cells. Leishmania infection increased the expression of PKR and IFN‐β on induction of PKR‐promoter activity. The observed effects required the engagement of TLR2. TLR2‐KO macrophages expressed low IFN‐β and PKR levels postinfection with a reduced parasite load. We also revealed the requirement of PKR signaling for Leishmania‐ induced IFN‐1 expression, responsible for sustaining PKR expression and enhancing infection. Moreover, during infection, SOD1 transcripts increased and were also enhanced when IFN‐1 was added to the cultures. Remarkably, SOD1 expression was abrogated in infected, dominant‐negative PKR‐expressing cells. Finally, lesions of patients with anergic diffuse cutaneous leishmaniasis exhibited higher levels of PKR/IFN‐1‐expressing cells compared to those with single cutaneous leishmaniasis. In summary, we demonstrated the mechanisms and relevance of the IFN‐1/PKR axis in the Leishmania infection.—De Carvalho Vivarini, A., Pereira, R. M. S., Dias Teixeira, K. L., Calegari‐Silva, T. C., Bellio, M., Laurenti, M. D., Corbett, C. E. P., de Castro Gomes, C. M., Soares, R. P., Mendes Silva, A., Silveira, F. T., Lopes, U. G. Human cutaneous leishmaniasis: interferon‐dependent expression of double‐stranded RNA‐kinase (PKR) via TLR2. FASEB J. 25, 4162–4173 (2011). www.fasebj.org