Biology subjects

Pavenko, A.

Publications and source records attributed to Pavenko, A..

3 recordsLinked to original sources

bioRxiv2023

Integrated Organ Immunity: Antigen-specific CD4-T cell-derived IFN-γ induced by BCG imprints prolonged lung innate resistance against respiratory viruses

Bacille Calmette-Guerin (BCG) vaccination can confer non-specific protection against heterologous pathogens. However, the underlying mechanisms remain mysterious. Here, we show that mice immunized intravenously with BCG exhibited reduced weight loss and/or improved viral clearance when challenged with SARS-CoV-2 and influenza. Protection was first evident between 14 - 21 days post vaccination, and lasted for at least 42 days. Remarkably, BCG induced a biphasic innate response in the lung, initially at day 1 and a subsequent prolonged phase starting at [~]15 days post vaccination, and robust antigen-specific Th1 responses. MyD88-dependent TLR signaling was essential for the induction of the innate and Th1 responses, and protection against SARS-CoV-2. Depletion of CD4+ T cells or IFN-{gamma} activity prior to infection obliterated innate activation and protection. Single cell and spatial transcriptomics revealed CD4-dependent expression of interferon-stimulated genes (ISGs) in myeloid, type II alveolar and lung epithelial cells. Thus, BCG elicits "integrated organ immunity" where CD4+ T cells act on local myeloid and epithelial cells to imprint prolonged antiviral innate resistance.

immunology↗

bioRxiv2023

Spatial architecture of high-grade glioma reveals tumor heterogeneity within distinct domains

High-grade gliomas are aggressive primary brain cancers with poor response to standard regimens, driven by immense heterogeneity. In isocitrate dehydrogenase (IDH) wild-type high-grade glioma (glioblastoma, GBM), increased intra-tumoral heterogeneity is associated with more aggressive disease. Recently, spatial technologies have emerged to dissect this complex heterogeneity within the tumor ecosystem by preserving cellular organization in situ. Here, we construct a high-resolution molecular landscape of GBM and IDH-mutant high-grade glioma patient samples to investigate the cellular subtypes and spatial communities that compose high-grade glioma using digital spatial profiling and spatial molecular imaging. This uncovered striking diversity of the tumor and immune microenvironment, that is embodied by the heterogeneity of the inferred copy-number alterations in the tumor. Reconstructing the tumor architecture revealed two distinct niches, one composed of tumor cell states that most closely resemble normal glial cells, associated with microglia; and the other niche populated by monocytes and mesenchymal tumor cells. We further reveal that communication between tumor and immune cells is underpinned by tumor-specific ligands, such as TGF{beta} signaling in astrocyte-like tumor cells. This primary study reveals high levels of intra-tumoral heterogeneity in high-grade gliomas, associated with a diverse immune landscape within spatially localized regions.

cancer biology↗

bioRxiv2021

Spatial Analysis of Neural Cell Proteomic Profiles following Ischemic Stroke in Mice using High-Plex Digital Spatial Profiling

Stroke is ranked as the fifth leading cause of death and the leading cause of adult disability. The progression of neuronal damage after stroke is recognized to be a complex integration of glia, neurons, and the surrounding extracellular matrix, therefore potential treatments must target the detrimental effects created by these interactions. In this study, we examined the spatial cellular and neuroinflammatory mechanisms occurring early after ischemic stroke utilizing Nanostring Digital Spatial Profiling (DSP) technology. Male C57bl/6 mice were subjected to photothrombotic middle cerebral artery occlusion (MCAO) and sacrificed at three-days post-ischemia. Spatial distinction of the ipsilateral hemisphere was studied according to the regions of interest: the ischemic core, peri-infarct tissues, and peri-infarct normal tissue (PiNT) in comparison to the contralateral hemisphere. We demonstrated that the ipsilateral hemisphere initiates distinct spatial regulatory proteomic profiles with DSP technology that can be identified consistently with the immunohistochemical markers, FJB, GFAP, and Iba-1. The core border profile demonstrated an induction of neuronal death, apoptosis, autophagy, immunoreactivity, and early degenerative proteins. Most notably, the core border resulted in a decrease of the neuronal proteins Map2 and NeuN, an increase in the autophagy proteins BAG3 and CTSD, an increase in the microglial and peripheral immune invasion proteins Iba1, CD45, CD11b, and CD39, and an increase in the neurodegenerative proteins BACE1, APP, {beta} 1-42, ApoE, and hyperphosphorylated tau protein S-199. The peri-infarct region demonstrated increased astrocytic immunoreactivity, apoptotic, and neurodegenerative proteomic profile, with an increase in BAG3, GFAP, and hyperphosphorylated tau protein S-199. The PiNT region displayed minimal changes compared to the contralateral cortex with only an increase in GFAP. Overall, our data highlight the importance of identifying ischemic mechanisms in a spatial manner to understand the complex, dynamic interactions throughout ischemic progression and repair as well to introduce potential targets for successful therapeutic interventions.

neuroscience↗