RESUMO
In giardiasis, diarrhoea, dehydration, malabsorption, weight loss and/or chronic inflammation are indicative of epithelial barrier dysfunction. However, the pathogenesis of giardiasis is still enigmatic in many aspects. Here, we show evidence that a cysteine protease of Giardia duodenalis called giardipain-1, contributes to the pathogenesis of giardiasis induced by trophozoites of the WB strain. In an experimental system, we demonstrate that purified giardipain-1 induces apoptosis and extrusion of epithelial cells at the tips of the villi in infected jirds (Meriones unguiculatus). Moreover, jird infection with trophozoites expressing giardipain-1 resulted in intestinal epithelial damage, cellular infiltration, crypt hyperplasia, goblet cell hypertrophy and oedema. Pathological alterations were more pronounced when jirds were infected intragastrically with Giardia trophozoites that stably overexpress giardipain-1. Furthermore, Giardia colonization in jirds results in a chronic inflammation that could relate to the dysbiosis triggered by the protist. Taken together, these results reveal that giardipain-1 plays a key role in the pathogenesis of giardiasis.
Assuntos
Cisteína Proteases , Giardia lamblia , Giardíase , Animais , Cisteína Proteases/genética , Gerbillinae , Giardia , Trofozoítos , Mucosa Intestinal/patologia , Homeostase , InflamaçãoRESUMO
Abstract: Background: Tumor cell resistance to chemotherapy agents is one of the main problems in the eradication of different neoplasias. One of the mechanisms of this process is the overexpression of anti-apoptotic proteins such as Bcl-2 and Bcl-XL; blocking the activity of these proteins may contribute to the sensitization of tumor cells and allow the adequate effects of chemotherapeutic drugs. Methods and results: This study adressed the transfection of prostate cancer cells (PC3) with a plasmid encoding a recombinant protein with an antagonist peptide from the BH3 region of the Bax protein fused to the GFP reporter protein (BaxGFP). This protein induced apoptosis of these tumor cells; further, selective transport of this plasmid to the tumor cell with Salmonella enterica serovar Typhimurium (strain SL3261), a live-attenuated bacterial vector, can induce sensitization of the tumor cell to the action of drugs such as cisplatin, through a process known as bactofection. Conclusions: These results suggest that Salmonella enterica can be used as a carrier vector of nucleotide sequences encoding heterologous molecules used in antitumor therapy.
Resumen: Introducción: La resistencia a los agentes quimioterapéuticos por parte de las células tumorales es uno de los principales problemas para la erradicación de distintas neoplasias. Uno de los mecanismos involucrados en este proceso es la sobreexpresión de proteínas antiapoptóticas como Bcl-2 y Bcl-XL. El bloquear la actividad de estas proteínas puede contribuir a la sensibilización de las células tumorales, permitiendo que los fármacos quimioterapeúticos funcionen de forma adecuada. Métodos y resultados: En este trabajo se llevó a cabo la transfección de células de cáncer de próstata (PC3) por un plásmido que codifica para una proteína recombinante que contiene un péptido antagónico perteneciente a la región BH3 de la proteína Bax fusionada a la proteína reportera GFP (BaxGFP). Esta proteína fue capaz de inducir apoptosis en las células PC3. El transporte selectivo de este plásmido hacia la célula tumoral empleando Salmonella enterica serovar Typhimurium cepa SL3261, un vector bacteriano vivo atenuado, permitió la sensibilización de la célula tumoral a la acción de fármacos como el cisplatino mediante un proceso denominado bactofección. Conclusiones: Estos resultados sugieren que Salmonella enterica puede emplearse como un vector acarreador de secuencias nucleotídicas que codifican para moléculas heterólogas empleadas en la terapia antitumoral.
RESUMO
BACKGROUND: Tumor cell resistance to chemotherapy agents is one of the main problems in the eradication of different neoplasias. One of the mechanisms of this process is the overexpression of anti-apoptotic proteins such as Bcl-2 and Bcl-XL; blocking the activity of these proteins may contribute to the sensitization of tumor cells and allow the adequate effects of chemotherapeutic drugs. METHODS AND RESULTS: This study adressed the transfection of prostate cancer cells (PC3) with a plasmid encoding a recombinant protein with an antagonist peptide from the BH3 region of the Bax protein fused to the GFP reporter protein (BaxGFP). This protein induced apoptosis of these tumor cells; further, selective transport of this plasmid to the tumor cell with Salmonella enterica serovar Typhimurium (strain SL3261), a live-attenuated bacterial vector, can induce sensitization of the tumor cell to the action of drugs such as cisplatin, through a process known as bactofection. CONCLUSIONS: These results suggest that Salmonella enterica can be used as a carrier vector of nucleotide sequences encoding heterologous molecules used in antitumor therapy.
RESUMO
Salmonella enterica es una especie de bacterias anaeróbicas facultativas que han sido empleadas con gran éxito como vector bacteriano vivo atenuado con fines vacunales. Recientemente se ha documentado que S. enterica tiene propiedades importantes para ser considerada como agente terapéutico contra el cáncer. Estudios preclínicos y clínicos han demostrado que S. enterica coloniza tumores sólidos, semisólidos y metástasis, además de que contribuye a disminuir la resistencia a los tratamientos. En esta revisión se aborda la capacidad de S. enterica atenuada para eliminar células tumorales y su empleo como vector bacteriano vivo acarreador de moléculas heterólogas contra el cáncer.
Salmonella enterica, a species of facultative anaerobic bacteria, has demonstrated success as a live-attenuated bacterial vector for vaccination. S. enterica has also demonstrated promise as a therapeutic agent against cancer. Pre-clinical and clinical trials have shown that S. enterica is localized in both solid and semi-solid tumors as well as in metastatic tumors. Moreover, S. enterica reduces resistance to treatment with other agents. In this review we present the novel therapeutic anti-cancer approaches that use S. enterica both for its ability as a delivery system for heterologous moieties against cancer and for its direct anti-cancer properties.
RESUMO
Salmonella enterica, a species of facultative anaerobic bacteria, has demonstrated success as a live-attenuated bacterial vector for vaccination. S. enterica has also demonstrated promise as a therapeutic agent against cancer. Pre-clinical and clinical trials have shown that S. enterica is localized in both solid and semi-solid tumors as well as in metastatic tumors. Moreover, S. enterica reduces resistance to treatment with other agents. In this review we present the novel therapeutic anti-cancer approaches that use S. enterica both for its ability as a delivery system for heterologous moieties against cancer and for its direct anti-cancer properties.
