Gunsch, G. | bioRxiv Science

bioRxiv2022

The Presence of Myelinated Nerves and Schwann Cells in White Adipose Tissue: Proximity to Synaptic Vesicle Containing Nerve Terminals and Potential Role in BTBR ob/ob Demyelinating Diabetic Neuropathy

Peripheral neuropathy is a pathophysiological state of nerve degeneration and loss of tissue innervation. The most prominent cause of small fiber neuropathy is diabetes which can be demyelinating in nature, but this has not yet been explored in adipose tissue. Both demyelinating neuropathies and axonopathies implicate Schwann cells (SCs), the peripheral glial required for nerve myelination and regeneration after injury. Here, we perform a comprehensive assessment of SCs and myelination patterns of subcutaneous white adipose tissue (scWAT) nerves, including changes that occur with obesity and other imbalanced energy states in mice and humans. We found that mouse scWAT is densely innervated by both myelinated and unmyelinated sensory and sympathetic nerves. Accordingly, scWAT is home to both myelinating and non-myelinating SCs - the greater proportion of which are myelinating. Furthermore, SCs were found closely associated with synaptic vesicle-containing nerve terminals in scWAT. Obese BTBR ob/ob mice exhibit diabetic peripheral neuropathy in scWAT, and display concordant demyelination specific to small fibers, which was also associated with a decrease in the pan-SC marker Sox10 and compensatory increase in Krox20 gene expression. Together this suggests that adipose SCs may be involved in regulating the plasticity or the neuropathy of adipose tissue nerves.

neuroscience↗

bioRxiv2022

Prime-pull immunization of mice with a BcfA-adjuvanted vaccine elicits mucosal immunity and prevents SARS CoV-2 infection and pathology

Vaccines against SARS-CoV-2 that induce mucosal immunity capable of preventing infection and disease remain urgently needed. We show that intramuscular priming of mice with an alum and BcfA-adjuvanted Spike subunit vaccine, followed by a BcfA-adjuvanted mucosal booster, generated Th17 polarized tissue resident CD4+ T cells, and mucosal and serum antibodies. The serum antibodies efficiently neutralized SARS-CoV-2 and its Delta variant, suggesting cross-protection against a recent variant of concern (VOC). Immunization with this heterologous vaccine prevented weight loss following challenge with mouse-adapted SARS-CoV-2 and reduced viral replication in the nose and lungs. Histopathology showed a strong leukocyte and polymorphonuclear (PMN) cell infiltrate without epithelial damage in mice immunized with BcfA-containing vaccines. In contrast, viral load was not reduced in the upper respiratory tract of IL-17 knockout mice immunized with the same formulation, suggesting that the Th17 polarized T cell responses are critical for protection. We show that vaccines adjuvanted with alum and BcfA, delivered through a heterologous prime-pull regimen, protect against SARS-CoV-2 infection without causing enhanced respiratory disease. SIGNIFICANCEThere remains a need for SARS CoV-2 booster vaccines that generate mucosal immunity and prevent transmission. We show that systemic priming followed by a mucosal booster with a BcfA-adjuvanted subunit vaccine generates neutralizing antibodies and Th17 polarized systemic and tissue-resident immune responses that provide sterilizing immunity against wildtype SARS CoV-2, and a variant of concern. Importantly, in contrast to alum alone, the addition of BcfA prevents respiratory pathology. These results suggest that a BcfA-adjuvanted mucosal booster may elicit mucosal immunity in individuals previously immunized systemically with approved vaccines. This foundational study in mice sets the stage for testing our vaccine regimen in larger animal models as a booster vaccine.

immunology↗