Daniels, N. J. | Search bioRxiv

bioRxiv2026

Lineage 2-Beijing Mycobacterium tuberculosis strains suppress BCG-trained innate immunity early after infection

Genetically distinct lineages of Mycobacterium tuberculosis differ in their virulence, transmissibility, and immune evasion capacity. The modern Lineage 2-Beijing (L2-B) clade of Mtb, which is highly prevalent in Asia and now globally distributed, is associated with resistance to the bacille Calmette Guerin (BCG) vaccine. Using a murine BCG vaccination model followed by aerosol challenge with geographically matched L2-B or Lineage 4 clinical isolates, we examined how L2-B circumvents vaccine-induced immunity. BCG-trained alveolar macrophages showed impaired control of L2-B growth in vitro. Spatial transcriptomic profiling of infected lungs revealed broad transcriptional reprogramming, including selective suppression of pathways essential for macrophage activation and trained innate immunity. Similar immune dysregulation was observed in peripheral blood from BCG-vaccinated household contacts of L2-B smear-positive TB patients. Together, these findings suggest mechanisms of lineage-specific immune evasion in TB, highlight key components of BCG-induced protection, and support re-evaluation of current TB vaccine strategies.

immunology↗

bioRxiv2022

MOPD I patient-derived cerebral organoids model microcephaly showing premature neurogenesis due to disrupted mitotic spindle orientation.

Mutations in the single-copy RNU4ATAC gene, which encodes U4atac snRNA of the minor spliceosome are linked to the developmental disorder microcephalic osteodysplastic primordial dwarfism type I (MOPD I). Partial loss-of-function mutations of U4atac snRNA lead to a poor prognosis, with less than three year survival. The most prominent characteristic of MOPD I is disrupted central nervous system development resulting in severe microcephaly and lissencephaly. In this study, we used self-organizing 3D cerebral organoids from patient-derived induced pluripotent stem cells (iPSCs) to investigate defective cellular events that disturb the laminar organization of the cortex and influence brain topology. We analyzed organoids from iPSCs homozygous for the partial loss-of-function U4atac snRNA 51G>A mutation and compared them to isogenic organoids obtained from iPSCs expressing wild-type U4atac snRNA, using immunostaining and 10X Genomics single-cell RNA sequencing. In our MOPD I organoids, we observed: a) reduced proliferation accompanied by premature neurogenesis depleting the neuro-progenitor pool due to an increased frequency of horizontal cell divisions in the ventricular zone; b) reduced numbers of intermediate progenitor and outer radial glial cells in the outer sub-ventricular zone; and c) defective radial neuronal migration, which is critical for cortical expansion in humans. Our findings therefore provide insight into MOPD I cellular pathogenesis and underline the value of these cerebral organoids as model systems for human neurodevelopmental disorders.

neuroscience↗