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1.
Microb Drug Resist ; 27(12): 1677-1684, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34129401

RESUMEN

The rapid increased multidrug resistance in Klebsiella pneumoniae has led to a renewed interest in polymyxin antibiotics, such as colistin, as antibiotics of last resort, not least in low/middle income countries. We conducted a genomic survey of clinical polymyxin-resistant K. pneumoniae to investigate the genetic alterations in isolates harboring blaKPC-2. Whole-genome sequencing was performed using an Illumina NextSeq 500 paired-end reads. Mutations and insertion sequence detection were analyzed to seven isolates recovered from clinical specimens of patients hospitalized in Brazil, focusing on key genes associated with polymyxin resistance. Furthermore, the levels of mRNA expression of genes associated with resistance to polymyxin B and other antimicrobials were evaluated by quantitative real-time PCR. Eighty-five percent of the isolates were assigned to clonal complex 258, with a minimum inhibitory concentration range of 4 to >256 mg/L for polymyxin B. It was possible to observe the presence of one important insertion element, ISKpn13, in a strain recovered from the blood that have blaKPC-2. Deleterious mutations reported in PmrB (R256G), YciM (N212T), and AcrB (T598A) were common, and mobile colistin resistance (mcr) genes were absent in all the isolates. RT-qPCR analysis revealed an overexpression of the pmrC (1.160-fold), pmrD (2.258-fold), and kpnE (1.530-fold) genes in the polymyxin B-resistant isolates compared with the expression of the polymyxin B-susceptible K. pneumoniae isolate. Overall, these results demonstrate the diversity of genetic variations in polymyxin-resistant populations derived from the different clonal strains, but the same sequence types, and suggest that there are still unknown mechanisms of polymyxin resistance in K. pneumoniae.


Asunto(s)
Antibacterianos/farmacología , Farmacorresistencia Bacteriana/genética , Polimixina B/farmacología , beta-Lactamasas/genética , Brasil , Genes Bacterianos , Humanos , Pruebas de Sensibilidad Microbiana , Secuenciación Completa del Genoma
2.
Front Immunol ; 11: 1010, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32655546

RESUMEN

Trypanosoma cruzi P21 protein (P21) is a putative secreted and immunomodulatory molecule with potent bioactive properties such as induction of phagocytosis and actin cytoskeleton polymerization. Despite the bioactive properties described so far, the action of P21 on parasite replication in muscle cell lineage or T. cruzi parasitism during acute experimental infection is unclear. We observed that recombinant P21 (rP21) decreased the multiplication of T. cruzi in C2C12 myoblasts, phenomenon associated with greater actin polymerization and IFN-γ and IL-4 higher expression. During experimental infection, lower cardiac nests, inflammatory infiltrate and fibrosis were observed in mice infected and treated with rP21. These results were correlated with large expression of IFN-γ counterbalanced by high levels of IL-10, which was consistent with the lower cardiac tissue injury found in these mice. We have also observed that upon stress, such as that induced by the presence of the IFN-γ cytokine, T. cruzi produced more P21. The effect of P21 in controlling the replication of T. cruzi, may indicate an evolutionary mechanism of survival developed by the parasite. Thus, when subjected to different stress conditions, the protozoan produces more P21, which induces T. cruzi latency in the host organism, enabling the protozoan to evade the host's immune system.


Asunto(s)
Péptidos y Proteínas de Señalización Intercelular/metabolismo , Malaria/parasitología , Mioblastos/parasitología , Miocardio/patología , Proteínas Protozoarias/metabolismo , Trypanosoma cruzi/fisiología , Enfermedad Aguda , Animales , Línea Celular , Interacciones Huésped-Parásitos , Humanos , Evasión Inmune , Péptidos y Proteínas de Señalización Intercelular/genética , Interferón gamma/metabolismo , Malaria/inmunología , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Carga de Parásitos , Proteínas Protozoarias/genética
3.
Immunobiology, v. 225,n. 3, 151904, jan. 2020
Artículo en Inglés | Sec. Est. Saúde SP, SESSP-IBPROD, Sec. Est. Saúde SP | ID: bud-2906

RESUMEN

B cells contribute to the immune system in many ways such as antigen presentation to CD4+ T cells, secretion of cytokines and lymphoid tissue organogenesis. Furthermore, they are the only cell type capable of producing immunoglobulins. B cells also account for critical aspects of the resistance against intracellular pathogens. Trypanosoma cruzi is an intracellular parasite that sabotages humoral response by depletion of immature B cells. Polyclonal activation and secretion of non-specific antibodies are also other mechanisms used by T cruzi to evade and subvert the mammalian host immune system, leading to increased parasitemia and susceptibility to Chagas’ disease. It remained unclear whether B cell depletion occurs due to direct contact with T. cruzi or results from a global increase in inflammation. Unlike previous reports, we demonstrated in this study that T. cruzi infects human B cells, resulting in parasite-induced activation of caspase-7 followed by proteolytic cleavage of phospholipase Cgama1 and cell death. These data contribute to explain the mechanisms ruling B-cell depletion and evasion of the immune response by T. cruzi.

4.
PLoS One ; 13(6): e0198643, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29889876

RESUMEN

The emergence of infections associated to new antimicrobial resistance in Acinetobacter baumannii (Ab) genotypes represents a major challenge. In this context, this study aimed to determine the diversity of resistance mechanisms and investigate clonal dissemination and predominant sequence types (STs) in multidrug-resistant Ab strains of clinical (tracheal aspirate, n = 17) and environmental (surface, n = 6) origins. Additionally, the major clones found in clinical (A) and environmental (H) strains had their complete genomes sequenced. All strains were submitted to polymerase chain reactions (PCR) for the detection of the ISAba1/blaOXA-51-like and ISAba1/blaOXA-23-like genes, while the expression of genes encoding the carO porin, AdeABC (adeB), AdeFGH (adeG), and AdeIJK (adeJ) efflux pumps was determined by real time PCR (qPCR). Most of the strains were characterized as extensively drug-resistant (XDR) with high minimal inhibitory concentrations (MICs) detected for tigecycline and carbapenems. Associations between ISAba1/OXA-51 and ISAba1/OXA-23 were observed in 91.3% and 52.2% of the strains, respectively. Only the adeB gene was considered hyper-expressed. Furthermore, most of the strains analyzed by the MuLtilocus Sequence-Typing (MLST) were found to belong to the clonal complex 113 (CC113). In addition, a new ST, ST1399, belonging to CC229, was also discovered herein. Strains analyzed by whole genome sequencing presented resistance genes linked to multidrug-resistance phenotypes and confirmed the presence of Tn2008, which provides high levels carbapenem-resistance.


Asunto(s)
Acinetobacter baumannii/enzimología , Proteínas Bacterianas/metabolismo , beta-Lactamasas/metabolismo , Acinetobacter baumannii/genética , Secuencia de Aminoácidos , Antibacterianos/farmacología , Proteínas de la Membrana Bacteriana Externa/química , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas Bacterianas/genética , Carbapenémicos/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Farmacorresistencia Bacteriana/genética , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Pruebas de Sensibilidad Microbiana , Tipificación de Secuencias Multilocus , Porinas/química , Porinas/genética , Alineación de Secuencia , Tigeciclina/farmacología , Secuenciación Completa del Genoma , beta-Lactamasas/genética
5.
Sci Rep ; 7: 44978, 2017 03 21.
Artículo en Inglés | MEDLINE | ID: mdl-28322302

RESUMEN

Chronic chagasic cardiomyopathy (CCC) is arguably the most important form of the Chagas Disease, caused by the intracellular protozoan Trypanosoma cruzi; it is estimated that 10-30% of chronic patients develop this clinical manifestation. The most common and severe form of CCC can be related to ventricular abnormalities, such as heart failure, arrhythmias, heart blocks, thromboembolic events and sudden death. Therefore, in this study, we proposed to evaluate the anti-angiogenic activity of a recombinant protein from T. cruzi named P21 (rP21) and the potential impact of the native protein on CCC. Our data suggest that the anti-angiogenic activity of rP21 depends on the protein's direct interaction with the CXCR4 receptor. This capacity is likely related to the modulation of the expression of actin and angiogenesis-associated genes. Thus, our results indicate that T. cruzi P21 is an attractive target for the development of innovative therapeutic agents against CCC.


Asunto(s)
Inhibidores de la Angiogénesis/metabolismo , Enfermedad de Chagas/etiología , Proteínas Protozoarias/metabolismo , Trypanosoma cruzi/metabolismo , Actinas/metabolismo , Inhibidores de la Angiogénesis/farmacología , Animales , Línea Celular , Proliferación Celular , Enfermedad de Chagas/metabolismo , Enfermedad de Chagas/parasitología , Citoesqueleto/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Matriz Extracelular , Regulación de la Expresión Génica , Humanos , Ratones , Modelos Biológicos , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Multimerización de Proteína , Proteínas Protozoarias/farmacología , Receptores CXCR4 , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacología
6.
Acta Trop ; 174: 153-157, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27288707

RESUMEN

Plasma membrane injury and repair is particularly prevalent in muscle cells. Here, we aimed to verify dysferlin, acid sphingomyelinase and transcriptional factor EB gene expression during Trypanosoma cruzi infection in vitro and in vivo. Our results showed that the parasite modulates gene expression of these proteins in a way dependent on the number of plasma membrane interacting parasites and in a rapamycin-sensitive manner.


Asunto(s)
Membrana Celular/fisiología , Enfermedad de Chagas/genética , Enfermedad de Chagas/fisiopatología , Disferlina/metabolismo , Proteínas de la Membrana/metabolismo , Esfingomielina Fosfodiesterasa/metabolismo , Trypanosoma cruzi/genética , Animales , Membrana Celular/genética , Disferlina/genética , Regulación de la Expresión Génica , Proteínas de la Membrana/genética , Esfingomielina Fosfodiesterasa/genética , Factores de Transcripción
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