Biology subjects

Soares-Schanoski, A.

Publications and source records attributed to Soares-Schanoski, A..

5 recordsLinked to original sources

bioRxiv2022

Intratumoral mregDC and CXCL13 T helper niches enable local differentiation of CD8 T cells following PD-1 blockade

Here, we leveraged a large neoadjuvant PD-1 blockade trial in patients with hepatocellular carcinoma (HCC) to search for correlates of response to immune checkpoint blockade (ICB) within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13+ CH25H+ IL-21+ PD-1+ CD4 T helper cells (CXCL13+ Th) and Granzyme K+ PD-1+ effector-like CD8 T cells, whereas terminally exhausted CD39hi TOXhi PD-1hi CD8 T cells dominated in non-responders. Strikingly, most T cell receptor (TCR) clones that expanded post-treatment were found in pre-treatment biopsies. Notably, PD-1+ TCF-1+ progenitor-like CD8 T cells were present in tumors of responders and non-responders and shared clones mainly with effector-like cells in responders or terminally differentiated cells in non-responders, suggesting that local CD8 T cell differentiation occurs upon ICB. We found that these progenitor CD8 T cells interact with CXCL13+ Th cells within cellular triads around dendritic cells enriched in maturation and regulatory molecules, or "mregDC". Receptor-ligand analysis revealed unique interactions within these triads that may promote the differentiation of progenitor CD8 T cells into effector-like cells upon ICB. These results suggest that discrete intratumoral niches that include mregDC and CXCL13+ Th cells control the differentiation of tumor-specific progenitor CD8 T cell clones in patients treated with ICB.

immunology↗

bioRxiv2019

Differential gene expression elicited by ZIKV infection in trophoblasts from congenital Zika syndrome discordant twins

Zika virus (ZIKV) causes congenital Zika syndrome (CZS), which is characterized by fetal demise, microcephaly and other abnormalities. ZIKV in the pregnant woman circulation must cross the placental barrier that includes fetal endothelial cells and trophoblasts, in order to reach the fetus. CZS occurs in [~]1-40% of cases of pregnant women infected by ZIKV, suggesting that mothers infection by ZIKV during pregnancy is not deterministic for CZS phenotype in the fetus. Therefore, other susceptibility factors might be involved, including the host genetic background. We have previously shown that in three pairs of dizygotic twins discordant for CZS, neural progenitor cells (NPCs) from the CZS-affected twins presented differential in vitro ZIKV susceptibility compared with NPCs from the non-affected. Here, we analyzed human-induced-pluripotent-stem-cell-derived (hiPSC-derived) trophoblasts from these twins and compared by RNA-Seq the trophoblasts from CZS-affected and non-affected twins. Following in vitro exposure to a Brazilian ZIKV strain (ZIKVBR), trophoblasts from CZS-affected twins were significantly more susceptible to ZIKVBR infection when compared with trophoblasts from the non-affected. Transcriptome profiling revealed no differences in gene expression levels of ZIKV candidate attachment factors, IFN receptors and IFN in the trophoblasts, either before or after ZIKVBR infection. Most importantly, ZIKVBR infection caused, only in the trophoblasts from CZS-affected twins, the downregulation of genes related to extracellular matrix organization and to leukocyte activation, which are important for trophoblast adhesion and immune response activation. In addition, only trophoblasts from non-affected twins secreted significantly increased amounts of chemokines RANTES/CCL5 and IP10 after infection with ZIKVBR. Overall, our results showed that trophoblasts from non-affected twins have the ability to more efficiently activate genes that are known to play important roles in cell adhesion and in triggering the immune response to ZIKV infection in the placenta, and this may contribute to predict protection from ZIKV dissemination into fetuses tissues. Author summaryThe Zika virus (ZIKV) infection in adults is usually characterized by mild flu-like symptoms, with most cases remaining asymptomatic. However, in the last years, widespread ZIKV infection was shown for the first time to be associated with congenital Zika syndrome (CZS) and death of neonates. CZS is a very debilitating condition that includes microcephaly and mental retardation, leading to a strong social and health impact. This dramatic condition calls for a careful evaluation of the molecular mechanisms involved in ZIKV infection in the maternal-fetal interface. It is estimated that CZS occurs in [~]1-40% of cases of pregnant women infected by ZIKV, which suggests that different susceptibility factors might be involved, including the host genetic background. By analyzing trophoblast cells that recapitulate the placenta from three pairs of dizygotic twins discordant for CZS, we were able to show that trophoblasts from CZS-affected twins were significantly more susceptible to ZIKV infection when compared with trophoblasts from the non-affected twins. We also provide a detailed picture of genes differentially expressed by trophoblasts from the discordant twins after infection with ZIKV. These genes can be further investigated as possible therapeutic targets to avoid viral dissemination into developing fetus tissues.

microbiology↗

bioRxiv2019

Defining mucosal immunity using mass cytometry following experimental human pneumococcal challenge

Streptococcus pneumoniae (Spn) is a common cause of respiratory infection, but also frequently colonises the nasopharynx in the absence of disease. We used mass cytometry to study immune cells from nasal biopsy samples, collected following experimental human pneumococcal challenge, in order to identify immunological changes that follow and control spn colonisation. Using 37 markers, we characterized 293 nasal immune cell clusters, of which 7 were associated with Spn colonisation. B cell and CD8+CD161+ T cell clusters were significantly higher in non-colonised than in colonised subjects. Spn colonization led to recirculation of not only Spn-specific but also aspecific nasal B cells. This associated with increased numbers of circulating plasmablasts and increased antibody levels against the unrelated bacterium Haemophilus influenzae. In addition, we demonstrated that baseline functionality of blood mucosal associated invariant T (MAIT) cells associated with protection against Spn. These results identify new host-pathogen interactions at the mucosa upon Spn colonisation.

immunology↗

bioRxiv2019

Systems Analysis of Subjects Acutely Infected with Chikungunya Virus

The largest ever recorded epidemic of the chikungunya virus (CHIKV) began in 2004 and affected four continents. Acute symptomatic infections are typically associated with the onset of fever and often debilitating polyarthralgia/polyarthritis. In this study, a systems biology approach was used to analyze the blood transcriptomes of adults acutely infected with CHIKV. Gene signatures that were associated with viral RNA amounts and to the onset of symptoms were identified. Among those genes, the putative role of Eukaryotic Initiation Factor (eIF) family genes and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC3A) in the CHIKV replication process were displayed. We further compared these signatures with those induced by dengue virus infection and rheumatoid arthritis. Finally, we demonstrated that CHIKV infection in mice induced IL-1 beta production in a mechanism highly dependent on the inflammasome NLRP3 activation. The findings provided valuable insights into the virus-host interactions during the acute phase and could be useful in the investigation of new and effective therapeutic interventions.

immunology↗

bioRxiv2018

Experimental Human Challenge Reveals Distinct Mechanisms of Acquisition or Protection Against Pneumococcal Colonization

Colonization of the upper respiratory tract with Streptococcus pneumoniae is the precursor of pneumococcal pneumonia and invasive disease. Following exposure, however, it is unclear which human immune mechanisms determine whether a pathogen will colonize. We used a human challenge model to investigate host-pathogen interactions in the first hours and days following intranasal exposure to Streptococcus pneumoniae. Using a novel home sampling method, we measured early immune responses and bacterial density dynamics in the nose and saliva after pneumococcal exposure. We found that nasal colonization can take up to 24 hours to become established. Also, two distinct bacterial clearance profiles were associated with protection: nasal clearers with immediate clearance of bacteria in the nose by the activity of pre-existent mucosal neutrophils and saliva clearers with detectable pneumococcus in saliva at one-hour post challenge and delayed clearance mediated by an inflammatory response and increased neutrophil activity 24 hours post bacterial encounter.

immunology↗