RESUMEN

Background: Leishmaniasis results in a wide spectrum of clinical manifestations, ranging from skin lesions at the site of infection to disseminated lesions in internal organs, such as the spleen and liver. While the ability of Leishmania-infected host cells to migrate may be important to lesion distribution and parasite dissemination, the underlying mechanisms and the accompanying role of host cells remain poorly understood. Previously published work has shown that Leishmania infection inhibits macrophage migration in a 2-dimensional (2D) environment by altering actin dynamics and impairing the expression of proteins involved in plasma membrane-extracellular matrix interactions. Although it was shown that L. infantum induces the 2D migration of dendritic cells, in vivo cell migration primarily occurs in 3-dimensional (3D) environments. The present study aimed to investigate the migration of macrophages and dendritic cells infected by Leishmania using a 3-dimensional environment, as well as shed light on the mechanisms involved in this process. Methods: Following the infection of murine bone marrow-derived macrophages (BMDM), human macrophages and human dendritic cells by L. amazonensis, L. braziliensis, or L. infantum, cellular migration, the formation of adhesion complexes and actin polymerization were evaluated. Results: Our results indicate that Leishmania infection inhibited 3D migration in both BMDM and human macrophages. Reduced expression of proteins involved in adhesion complex formation and alterations in actin dynamics were also observed in Leishmania-infected macrophages. By contrast, increased human dendritic cell migration in a 3D environment was found to be associated with enhanced adhesion complex formation and increased actin dynamics. Conclusion: Taken together, our results show that Leishmania infection inhibits macrophage 3D migration, while enhancing dendritic 3D migration by altering actin dynamics and the expression of proteins involved in plasma membrane extracellular matrix interactions, suggesting a potential association between dendritic cells and disease visceralization.

RESUMEN

Zika virus (ZIKV), a member of the Flaviviridae family, was brought into the spotlight due to its widespread and increased pathogenicity, including Guillain-Barré syndrome and microcephaly. Neural progenitor cells (NPCs), which are multipotent cells capable of differentiating into the major neural phenotypes, are very susceptible to ZIKV infection. Given the complications of ZIKV infection and potential harm to public health, effective treatment options are urgently needed. Betulinic acid (BA), an abundant terpenoid of the lupane group, displays several biological activities, including neuroprotective effects. Here we demonstrate that Sox2+ NPCs, which are highly susceptible to ZIKV when compared to their neuronal counterparts, are protected against ZIKV-induced cell death when treated with BA. Similarly, the population of Sox2+ and Casp3+ NPCs found in ZIKV-infected cerebral organoids was significantly higher in the presence of BA than in untreated controls. Moreover, well-preserved structures were found in BA-treated organoids in contrast to ZIKV-infected controls. Bioinformatics analysis indicated Akt pathway activation by BA treatment. This was confirmed by phosphorylated Akt analysis, both in BA-treated NPCs and brain organoids, as shown by immunoblotting and immunofluorescence analyses, respectively. Taken together, these data suggest a neuroprotective role of BA in ZIKV-infected NPCs.

Asunto(s)

RESUMEN

Pathogenic bacteria, such as Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae and Moraxella catarrhalis, are important vaccine targets. The 10-valent pneumococcal conjugate vaccine (PCV10) acts on 10 differents S. pneumoniae serovars. However, this vaccine could also act on other bacteria genera, leading to dysbiosis. Moreover, the vaccination has also been associated with imbalances in the ratio between commensal and potentially pathogenic bacteria. Despite the wealth of studies assessing the influence of the microbiome on vaccine effects, how vaccination can influence the microbiome remains poorly understood. Herein, we assessed the effects of PCV10 on infant nasopharyngeal microbiome composition. Nasopharyngeal aspirates were collected from children with acute respiratory infection (ARI) aged 6-23 months. Two groups were composed of 48 vaccinated and 36 unvaccinated subjects. 16S ribosomal RNA sequencing was performed to assess bacterial composition and results were analyzed with QIIME. Similar bacterial compositions were observed in the unvaccinated and vaccinated samples. Principal component analysis also indicated a similar bacterial composition between the groups. In addition, bacterial diversity was not different between the vaccinated and unvaccinated samples. Accordingly, our results suggest that PCV10 vaccination promotes a specific response against its targets, thereby preserving the nosocomial microbiome. Although not statistically significant, Streptococcus and Haemophilus genera were increased in the vaccinated group, while Moraxella was decreased. Increases in Streptococcus may be associated with vaccine-target taxa replacement by non-pathogenic species. In sum, we observed that PCV10 vaccination acts by promoting a target-specific action against pathogenic bacteria and also induces commensal bacteria colonization without substantially changing the nasopharyngeal microbiome.

Asunto(s)