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1.
PLoS Pathog ; 13(11): e1006696, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29112952

RESUMO

Klebsiella pneumoniae is a significant cause of nosocomial pneumonia and an alarming pathogen owing to the recent isolation of multidrug resistant strains. Understanding of immune responses orchestrating K. pneumoniae clearance by the host is of utmost importance. Here we show that type I interferon (IFN) signaling protects against lung infection with K. pneumoniae by launching bacterial growth-controlling interactions between alveolar macrophages and natural killer (NK) cells. Type I IFNs are important but disparate and incompletely understood regulators of defense against bacterial infections. Type I IFN receptor 1 (Ifnar1)-deficient mice infected with K. pneumoniae failed to activate NK cell-derived IFN-γ production. IFN-γ was required for bactericidal action and the production of the NK cell response-amplifying IL-12 and CXCL10 by alveolar macrophages. Bacterial clearance and NK cell IFN-γ were rescued in Ifnar1-deficient hosts by Ifnar1-proficient NK cells. Consistently, type I IFN signaling in myeloid cells including alveolar macrophages, monocytes and neutrophils was dispensable for host defense and IFN-γ activation. The failure of Ifnar1-deficient hosts to initiate a defense-promoting crosstalk between alveolar macrophages and NK cell was circumvented by administration of exogenous IFN-γ which restored endogenous IFN-γ production and restricted bacterial growth. These data identify NK cell-intrinsic type I IFN signaling as essential driver of K. pneumoniae clearance, and reveal specific targets for future therapeutic exploitations.


Assuntos
Interferon Tipo I/imunologia , Células Matadoras Naturais/imunologia , Infecções por Klebsiella/imunologia , Macrófagos Alveolares/imunologia , Transdução de Sinais/imunologia , Animais , Resistência a Múltiplos Medicamentos/imunologia , Klebsiella pneumoniae/crescimento & desenvolvimento , Klebsiella pneumoniae/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor Cross-Talk/imunologia , Infecções Respiratórias/imunologia
2.
Sci Adv ; 8(9): eabj7293, 2022 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-35235356

RESUMO

Interleukin-1α (IL-1α) and IL-1ß are inflammatory cytokines with important roles in health and disease. They trigger the same receptor and elicit comparable cellular responses but, for poorly understood reasons, are not redundant in vivo. Here, we decoupled IL-1α and IL-1ß functions that drive protective responses against invasive infection with group A Streptococcus. IL-1ß was essential for pathogen clearance, hence resistance to infection, by inducing granulocyte colony-stimulating factor at the infection site and establishing emergency granulopoiesis. In contrast, IL-1α governed reprogramming of liver metabolic pathways associated with tolerance to infection. The IL-1α-dominated hepatic regulation corresponded to high IL-1α levels in the liver during infection. Conversely, IL-1ß was critical for the regulation of the spleen transcriptome, which correlated with ample IL-1ß expression in this tissue. The results identify distinct and organ-specific roles of IL-1α versus IL-1ß and implicate spatial restriction of their expression and bioavailability during infection as the underlying mechanism.


Assuntos
Interleucina-1alfa , Interleucina-1alfa/genética , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo
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