Biology subjects

Carballido, J. M.

Publications and source records attributed to Carballido, J. M..

3 recordsLinked to original sources

bioRxiv2026

Deep CyTOF immune profiles of ex vivo granulomatous responses to Mycobacterium tuberculosis differ with European and African geographical origin

Genetic and environmental factors influence human immunity and modulate responses to infection. Accounting for immune heterogeneity across human populations is critical to the design of novel vaccines and host-directed interventions that would optimally benefit populations experiencing the highest disease burden. Tuberculosis (TB) burden is unevenly distributed across geographical regions and our understanding of the differential immune response to Mycobacterium tuberculosis (Mtb) across human populations remains limited. Here, we sought to evaluate the impact of geographical origin on ex vivo granulomatous responses to Mtbinfection. We found that peripheral blood mononuclear cells (PBMCs) from healthy African donors exhibited greater control of Mtbgrowth ex vivo than those isolated from European individuals. High-dimensional single-cell profiling of the granulomatous responses by cytometry by time-of-flight (CyTOF) revealed divergent profiles based on the specimens' geographical origin. Monocytes from European donors displayed a pro-inflammatory phenotype - correlating with Mtbgrowth -, whereas PBMCs of African individuals were enriched in activated, cytotoxic T cells - correlating with Mtbcontrol. Reduced inflammatory response in African monocytes following various microbial stimulations was confirmed. Taken together, our comprehensive immune profiling indicates that environmental and genetic factors shape a cytotoxic-regulatory response that promotes bacterial control. Against the current "one-treatment-fits-all" approach, our findings support the use of specimens from intervention-relevant settings to inform the targeted design of TB vaccines and host-directed interventions.

immunology↗

bioRxiv2026

Bovine AAV - a promising vector for pulmonary gene therapy

Efficient systemic delivery to the lung remains a major barrier for adeno-associated virus (AAV)-mediated pulmonary gene therapy, particularly when pre-existing immunity limits the use of conventional capsids. Here, we evaluated Bovine AAV, a phylogenetically divergent capsid, as candidate vector for lung-directed gene transfer. In adult C57BL/6J mice, intravenous delivery of Bovine AAV resulted in robust and preferential lung transduction comparable to AAV4, with predominant targeting of alveolar type I pneumocytes and pulmonary endothelial cells. In primary human lung-resident cells, Bovine AAV was particularly effective in microvascular endothelial cells, a target poorly transduced by AAV4 in vitro. Bovine AAV demonstrated scalable production with yield, purification performance, capsid quality, and genome integrity comparable to AAV9. In sera from healthy adults from the United States and Switzerland, Bovine AAV showed intermediate neutralization frequencies, lower than AAV2 and AAV4 but higher than AAV5 and AAV9. Of relevance, Bovine AAV maintained in vivo transduction efficiency in mice previously immunized with a pool of human and non-human primate-derived AAV capsids, including AAV4. Together, these results position Bovine AAV as a promising lung-tropic and immune-distinct vector for pulmonary gene therapy, with particular relevance for applications requiring systemic delivery in the presence of pre-existing immunity to conventional serotypes.

molecular biology↗

bioRxiv2024

Granulysin antimicrobial activity promotes dormancy in Mycobacterium tuberculosis

Human tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) remains a global public health threat. Granulomas constitute a hallmark of TB pathogenesis that can clear, contain or exacerbate an infection. Containment is exploited by Mtb as a hideout to persist in a dormant, antibiotic-tolerant state only to resuscitate upon immunosuppression. The immune determinants of a granulomatous response driving Mtb persistence remain elusive. We here combined an ex vivo granuloma model with peripheral blood mononuclear cell (PBMC) specimens from TB patients and a high-dimensional mass cytometry (CyTOF) approach to shed light on the immune factors prompting Mtb dormancy. Compared to healthy controls, patient-derived ex vivo granulomas rapidly force Mtb to adopt a dormant-like state; an observation that correlates with the presence of activated innate (-like) cytotoxic lymphocytes. We further demonstrate that Mtb dormancy is induced by direct exposure to granulysin, thereby unravelling an immune escape mechanism to cytotoxic lymphocyte activity.

immunology↗