Link between Heat Shock Protein 90 and the Mitochondrial Respiratory Chain in the Caspofungin Stress Response of Aspergillus fumigatus.

Aspergillus fumigatus is an opportunistic mold responsible for invasive aspergillosis. Triazoles (e.g., voriconazole) represent the first-line treatment, but emerging resistance is of concern. The echinocandin drug caspofungin is used as second-line treatment but has limited efficacy. The heat shock protein 90 (Hsp90) orchestrates the caspofungin stress response and is the trigger of an adaptive phenomenon called the paradoxical effect (growth recovery at increasing caspofungin concentrations). The aim of this study was to elucidate the Hsp90-dependent mechanisms of the caspofungin stress response. Transcriptomic profiles of the wild-type A. fumigatus strain (KU80) were compared to those of a mutant strain with substitution of the native hsp90 promoter by the thiA promoter (pthiA-hsp90), which lacks the caspofungin paradoxical effect. Caspofungin induced expression of the genes of the mitochondrial respiratory chain (MRC), in particular, NADH-ubiquinone oxidoreductases (complex I), in KU80 but not in the pthiA-hsp90 mutant. The caspofungin paradoxical effect could be abolished by rotenone (MRC complex I inhibitor) in KU80, supporting the role of MRC in the caspofungin stress response. Fluorescent staining of active mitochondria and measurement of oxygen consumption and ATP production confirmed the activation of the MRC in KU80 in response to caspofungin, but this activity was impaired in the pthiA-hsp90 mutant. Using a bioluminescent reporter for the measurement of intracellular calcium, we demonstrated that inhibition of Hsp90 by geldanamycin or MRC complex I by rotenone prevented the increase in intracellular calcium shown to be essential for the caspofungin paradoxical effect. In conclusion, our data support a role of the MRC in the caspofungin stress response which is dependent on Hsp90.

Efficacy of Antifungal Monotherapies and Combinations against Aspergillus calidoustus.

Invasive fungal infections due to Aspergillus calidoustus with decreased azole susceptibility are emerging in the setting of azole prophylaxis and are associated with poor outcomes. We assessed the in vitro activity of antifungal drugs used alone or in combinations against A. calidoustus and found a synergistic effect between voriconazole and terbinafine at concentrations within the therapeutic range. An invertebrate Galleria mellonella model of A. calidoustus infection tended to support the potential benefit of this combination.

Impact of the SARS-CoV-2 pandemic on the administration of vaccines as per the national immunization schedule in children younger than 2 years. / Impacto de la pandemia por SARS-CoV-2 en la administración de vacunas del Calendario Nacional de Inmunizaciones en menores de 2 años.

INTRODUCTION: The reduction in the number of visits to health care centers since the onset of the SARS-CoV-2 pandemic may affect mandatory vaccination. OBJECTIVE: To assess the impact of the SARS-CoV-2 pandemic on the administration of the pentavalent and the measles, mumps, and rubella (MMR) vaccines to children younger than 2 years at the vaccination center of a children's hospital in the Autonomous City of Buenos Aires. METHOD: Cross-sectional study using the vaccination center's digital records from January to May 2019 and 2020. Results. In the second fortnight of March 2020, vaccinations dropped by 64.2 %. When examining the first dose of the pentavalent and MMR vaccines, such reduction was 74.9 % and 55.1 %, respectively. CONCLUSION: As of the second fortnight of March 2020, vaccinations dropped by 64.2 % compared to the same period of the previous year.

Introducción. El menor número de consultas a los centros de atención desde el comienzo de la pandemia por SARS-CoV-2 podría afectar la vacunación obligatoria. Objetivo. Evaluar el impacto de la pandemia por SARS-CoV-2 en la administración de vacunas pentavalente y triple viral a niños menores de 2 años en el vacunatorio de un hospital pediátrico de la Ciudad de Buenos Aires. Método. Estudio transversal, que utilizó registros informatizados del vacunatorio, de enero a mayo de 2019 y 2020. Resultados. Desde la segunda quincena de marzo de 2020, se observó un 64,2 % de disminución en la aplicación de vacunas. Al examinar la primera dosis de pentavalente y triple viral, la reducción fue del 74,9 % y del 55,1 %, respectivamente. Conclusión. A partir de la segunda quincena de marzo de 2020, se observó una disminución del 64,2 % en las vacunas aplicadas respecto del mismo período en el año anterior.

Impacto de la pandemia por SARS-CoV-2 en la administración de vacunas del Calendario Nacional de Inmunizaciones en menores de 2 años / Impact of the SARS-CoV-2 pandemic on the administration of vaccines as per the national immunization schedule in children younger than 2 years

Introducción. El menor número de consultas a los centros de atención desde el comienzo de la pandemia por SARS-CoV-2podría afectar la vacunación obligatoria.Objetivo. Evaluar el impacto de la pandemia por SARS-CoV-2en la administración de vacunas pentavalente y triple viral a niños menores de 2 años en el vacunatorio de un hospital pediátrico de la Ciudad de Buenos Aires.Método. Estudio transversal, que utilizó registros informatizados del vacunatorio, de enero a mayo de 2019 y 2020.Resultados. Desde la segunda quincena de marzo de 2020, se observó un 64,2 % de disminución en la aplicación de vacunas. Al examinar la primera dosis de pentavalente y triple viral, la reducción fue del 74,9 % y del 55,1 %, respectivamente.Conclusión. A partir de la segunda quincena de marzo de 2020, se observó una disminución del 64,2 % en las vacunas aplicadas respecto del mismo período en el año anterio

Introduction. The reduction in the number of visits to health care centers since the onset of the SARS-CoV-2 pandemic may affect mandatory vaccination.Objective. To assess the impact of the SARS-CoV-2 pandemic on the administration of the pentavalent and the measles, mumps, and rubella (MMR) vaccines to children younger than 2 years at the vaccination center of a children's hospital in the Autonomous City of Buenos Aires.Method. Cross-sectional study using the vaccination center's digital records from January to May 2019 and 2020.Results. In the second fortnight of March 2020, vaccinations dropped by 64.2 %. When examining the first dose of the pentavalent and MMR vaccines, such reduction was 74.9 % and 55.1 %, respectively.Conclusion. As of the second fortnight of March 2020, vaccinations dropped by 64.2 % compared to the same period of the previous year.