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1.
Int J Med Microbiol ; 309(5): 307-318, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31178418

RESUMEN

Mycobacterium abscessus (MAB) is an emerging, rapidly growing non-tuberculous Mycobacterium causing therapy-resistant pulmonary disease especially in patients with cystic fibrosis (CF). Smooth and rough colony type MAB can be isolated from infected patients whereby rough colony type MAB are more often associated with severe disease. Disease severity is also associated with an alternated type I interferon (IFN-I) response of the MAB-infected patients. However the relevance of this response for the outcome of MAB infection is still unknown. In this study, we analyzed the IFNß expression of murine macrophages infected with a MAB rough colony strain (MAB-R) isolated from a patient with progressive CF and compared it to macrophages infected with the MAB smooth colony type reference strain (MAB-S). We found that MAB-R infected macrophages expressed significantly more IFNß mRNA and protein than MAB-S infected macrophages. Higher IFNß induction by MAB-R was associated with higher TNF expression and intracellular killing while low IFNß induction was associated with lower TNF expression and persistence of MAB-S. IFNß induction was independent of the intracellular cGAS-STING recognition pathway. MAB appeared to be recognized extracellularly and induced IFNß expression via TLR2-TLR4-MyD88-TRIF-IRF3 dependent pathways. By using macrophages lacking the IFN-I receptor we demonstrate that MAB induced IFN-I response essentially contributed to restricting MAB-R and MAB-S infections by activating macrophage Nos2 expression and nitric oxide production. Thus IFN-I seem to influence the intrinsic ability of macrophages to control MAB infections. As MAB persists over long time periods in susceptible patients, our findings suggest that virulence of MAB strains is promoted by an insufficient IFN-I response of the host.


Asunto(s)
Interferón beta/inmunología , Macrófagos/microbiología , Mycobacterium abscessus/inmunología , Factor 88 de Diferenciación Mieloide/inmunología , Óxido Nítrico/inmunología , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 4/inmunología , Animales , Interacciones Huésped-Patógeno/inmunología , Humanos , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Infecciones por Mycobacterium no Tuberculosas/inmunología , Infecciones por Mycobacterium no Tuberculosas/microbiología , Óxido Nítrico Sintasa de Tipo II/genética , Esputo/microbiología
2.
Biochim Biophys Acta ; 1849(8): 966-78, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26066982

RESUMEN

Interleukin (IL)-36α - one of the novel members of the IL-1 family of cytokines - is a potent regulator of dendritic and T cells and plays an important role in inflammatory processes like experimental skin inflammation in mice and in mouse models for human psoriasis. Here, we demonstrate that C/EBPß, a transcription factor required for the selective expression of inflammatory genes, is a key activator of the Il36A gene in murine macrophages. RNAi-mediated suppression of C/EBPß expression in macrophages (C/EBPß(low) cells) significantly impaired Il36A gene induction following challenge with LPS. Despite the presence of five predicted C/EBP binding sites, luciferase reporter assays demonstrated that C/EBPß confers responsiveness to LPS primarily through a half-CRE•C/EBP element in the proximal Il36A promoter. Electrophoretic mobility shift assays showed that C/EBPß but not CREB proteins interact with this critical half-CRE•C/EBP element. In addition, overexpression of C/EBPß in C/EBPß(low) cells enhanced the expression of Il36A whereas CREB-1 had no effect. Finally, chromatin immunoprecipitation confirmed that C/EBPß but neither CREB-1, ATF-2 nor ATF4 is directly recruited to the proximal promoter region of the Il36A gene. Together, these findings demonstrate an essential role of C/EBPß in the regulation of the Il36A gene via the proximal half-CRE•C/EBP element in response to inflammatory stimuli.


Asunto(s)
Proteína beta Potenciadora de Unión a CCAAT/fisiología , Inflamación/genética , Interleucina-1/genética , Macrófagos/metabolismo , Animales , Secuencia de Bases , Sitios de Unión/genética , Células Cultivadas , Codón Iniciador/genética , Regulación de la Expresión Génica/efectos de los fármacos , Interleucina-1/metabolismo , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Psoriasis/genética , Elementos Reguladores de la Transcripción
3.
Virulence ; 11(1): 465-481, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32408806

RESUMEN

Mycobacterium avium subspecies paratuberculosis (MAP) causes Johne's disease (JD), an incurable chronic intestinal bowel disease in ruminants. JD occurs worldwide and causes enormous economic burden in dairy industry. Research on JD pathobiology is hampered by its complexity which cannot completely be mimicked by small animal models. As a model the mouse allows dissecting some pathogenicity features of MAP. However, for unknown reasons MAP exhibits reduced growth in granulomas of infected mice compared to other Mycobacterium avium subspecies. Here, we characterized immune reactions of MAP-infected C57BL/6 mice. After infection, mice appeared fully immunocompetent. A strong antigen-specific T cell response was elicited indicated by IFNγ production of splenic T cells re-stimulated with MAP antigens. Function of splenic dendritic cells and proliferation of adoptively transferred antigen-specific CD4+ T cells was unaltered. Isolated splenic myeloid cells from infected mice revealed that MAP resides in CD11b+ macrophages. Importantly, sorted CD11b+CD11c- cells expressed high level of type 2 nitric oxide synthase (NOS2) but only low levels of pro- and anti-inflammatory cytokines. Correspondingly, MAP-infected MAC2 expressing myeloid cells in spleen and liver granuloma displayed strong expression of NOS2. In livers of infected Nos2-/-mice higher bacterial loads, more granuloma and larger areas of tissue damage were observed 5 weeks post infection compared to wild type mice. In vitro, MAP was sensitive to NO released by a NO-donor. Thus, a strong T cell response and concomitant NOS2/NO activity appears to control MAP infection, but allows development of chronicity and pathogen persistence. A similar mechanism might explain persistence of MAP in ruminants.


Asunto(s)
Citocinas/inmunología , Óxido Nítrico Sintasa de Tipo II/inmunología , Paratuberculosis/inmunología , Animales , Femenino , Inmunidad Celular , Hígado/microbiología , Hígado/patología , Macrófagos/inmunología , Macrófagos/microbiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mycobacterium avium subsp. paratuberculosis , Óxido Nítrico Sintasa de Tipo II/genética , Bazo/microbiología , Bazo/patología , Linfocitos T/inmunología
4.
Front Immunol ; 9: 2317, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30386330

RESUMEN

Myeloid-derived suppressor cells (MDSC) are immature myeloid cells with immunomodulatory function. To study the mechanism by which MDSC affect antimicrobial immunity, we infected mice with two M. avium strains of differential virulence, highly virulent Mycobacterium avium subsp. avium strain 25291 (MAA) and low virulent Mycobacterium avium subsp. hominissuis strain 104 (MAH). Intraperitoneal infection with MAA, but not MAH, caused severe disease and massive splenic infiltration of monocytic MDSC (M-MDSC; Gr-1intCD11bhiCD11cint) expressing inducible NO synthase (Nos2) and bearing high numbers of mycobacteria. Depletion experiments demonstrated that M-MDSC were essential for disease progression. NO production by M-MDSC influenced antigen-uptake and processing by dendritic cells and proliferation of CD4+ T cells. M-MDSC were also induced in MAA-infected mice lacking Nos2. In these mice CD4+ T cell expansion and control of infection were restored. However, T cell inhibition was only partially relieved and arginase (Arg) 1-expressing M-MDSC were accumulated. Likewise, inhibition of Arg1 also partially rescued T cell proliferation. Thus, mycobacterial virulence results in the induction of M-MDSC that block the T cell response in a Nos2- and Arg1-dependent manner.


Asunto(s)
Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Mycobacterium avium/inmunología , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Tuberculosis/veterinaria , Animales , Biomarcadores , Antígeno CD11b/metabolismo , Antígeno CD11c/metabolismo , Femenino , Interacciones Huésped-Patógeno/inmunología , Inmunofenotipificación , Activación de Linfocitos/inmunología , Ratones , Óxido Nítrico/metabolismo , Receptores de Quimiocina/metabolismo , Bazo/inmunología , Bazo/metabolismo
5.
Virulence ; 8(7): 1303-1315, 2017 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-28422568

RESUMEN

Type I interferons (IFN-I), such as IFN-α and IFN-ß are important messengers in the host response against bacterial infections. Knowledge about the role of IFN-I in infections by nontuberculous mycobacteria (NTM) is limited. Here we show that macrophages infected with pathogens of the Mycobacterium avium complex produced significantly lower amounts of IFN-ß than macrophages infected with the opportunistic pathogen M. smegmatis. To dissect the molecular mechanisms of this phenomenon, we focused on the obligate pathogen Mycobacterium avium ssp paratuberculosis (MAP) and the opportunistic M. smegmatis. Viability of both bacteria was required for induction of IFN-ß in macrophages. Both bacteria induced IFN-ß via the cGAS-STING-TBK1-IRF3/7-pathway of IFN-ß activation. Stronger phosphorylation of TBK1 and higher amounts of extracellular bacterial DNA in the macrophage cytosol were found in M. smegmatis infected macrophages than in MAP infected macrophages. After intraperitoneal infection of mice, a strong Ifnb induction by M. smegmatis correlated with clearance of the bacteria. In contrast, MAP only induced weak Ifnb expression which correlated with bacterial persistence and increased number of granulomas in the liver. In mice lacking the type I interferon receptor we observed improved survival of M. smegmatis while survival of MAP was similar to that in wildtype mice. On the other hand, treatment of MAP infected wildtype mice with the IFN-I inducer poly(I:C) or recombinant IFN-ß impaired the survival of MAP. This indicates an essential role of IFN-I in clearing infections by MAP and M. smegmatis. The expression level of IFN-I is decisive for transient versus persistent NTM infection.


Asunto(s)
Factor 3 Regulador del Interferón/metabolismo , Factor 7 Regulador del Interferón/metabolismo , Interferón beta/metabolismo , Infecciones por Mycobacterium no Tuberculosas/metabolismo , Mycobacterium avium subsp. paratuberculosis/fisiología , Mycobacterium smegmatis/fisiología , Nucleotidiltransferasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Femenino , Interacciones Huésped-Patógeno , Humanos , Factor 3 Regulador del Interferón/genética , Factor 7 Regulador del Interferón/genética , Interferón beta/genética , Macrófagos/microbiología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Infecciones por Mycobacterium no Tuberculosas/genética , Infecciones por Mycobacterium no Tuberculosas/microbiología , Mycobacterium avium subsp. paratuberculosis/genética , Mycobacterium smegmatis/genética , Nucleotidiltransferasas/genética , Fosforilación , Proteínas Serina-Treonina Quinasas/genética , Transducción de Señal
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