Protective role of the HSP90 inhibitor, STA-9090, in lungs of SARS-CoV-2-infected Syrian golden hamsters.

INTRODUCTION: The emergence of new SARS-CoV-2 variants, capable of escaping the humoral immunity acquired by the available vaccines, together with waning immunity and vaccine hesitancy, challenges the efficacy of the vaccination strategy in fighting COVID-19. Improved therapeutic strategies are urgently needed to better intervene particularly in severe cases of the disease. They should aim at controlling the hyperinflammatory state generated on infection, reducing lung tissue pathology and inhibiting viral replication. Previous research has pointed to a possible role for the chaperone HSP90 in SARS-CoV-2 replication and COVID-19 pathogenesis. Pharmacological intervention through HSP90 inhibitors was shown to be beneficial in the treatment of inflammatory diseases, infections and reducing replication of diverse viruses. METHODS: In this study, we investigated the effects of the potent HSP90 inhibitor Ganetespib (STA-9090) in vitro on alveolar epithelial cells and alveolar macrophages to characterise its effects on cell activation and viral replication. Additionally, the Syrian hamster animal model was used to evaluate its efficacy in controlling systemic inflammation and viral burden after infection. RESULTS: In vitro, STA-9090 reduced viral replication on alveolar epithelial cells in a dose-dependent manner and lowered significantly the expression of proinflammatory genes, in both alveolar epithelial cells and alveolar macrophages. In vivo, although no reduction in viral load was observed, administration of STA-9090 led to an overall improvement of the clinical condition of infected animals, with reduced oedema formation and lung tissue pathology. CONCLUSION: Altogether, we show that HSP90 inhibition could serve as a potential treatment option for moderate and severe cases of COVID-19.

Autoimmune-mediated intestinal inflammation-impact and regulation of antigen-specific CD8+ T cells.

BACKGROUND & AIMS: Few data exist regarding mechanisms of mucosal CD8+ T-cell reactivity to epithelial-specific antigen. To dissect the immunologic mechanisms underlying CD8+ T-cell dysregulation, reactivity to a self-antigen expressed in intestinal epithelium of mice bearing a major histocompatibility complex class I-restricted T-cell receptor specific for this antigen was studied. In addition, antigen-specific regulatory CD4+ T cells induced in vivo were tested to control these autoreactive CD8+ T cells. METHODS: Transgenic VILLIN-HA mice were mated with CL4-TCR transgenic mice. Alternatively, adoptive transfer of CL4-TCR transgenic CD8+ T cells into VILLIN-HA transgenic mice was performed to mimic spontaneous encounter of neoantigen. Mucosal CD8+ T cells were characterized under different conditions of tolerance, immunopathology, and active immunosuppression. RESULTS: Transgenic CD8+ T cells from VILLIN-HA x CL4-TCR transgenic mice preferentially migrated and expanded in mucosal lymphoid tissues. Although transgenic CD8+ T cells showed signs of T-cell activation, they failed to cause tissue damage. This was accompanied by the induction/expansion of CD4+ and CD8+, Foxp3-expressing T cells. In contrast, adoptive transfer of naive transgenic CD8+ T cells from CL4-TCR transgenic mice into VILLIN-HA transgenic mice induced severe intestinal inflammation with poor clinical course of disease. Transgenic CD8+ T cells secreted vigorous amounts of proinflammatory cytokines like interferon gamma/tumor necrosis factor alpha. Strikingly, this acute wasting disease was significantly ameliorated by cotransfer of antigen-specific regulatory CD4+ T cells. CONCLUSIONS: Epithelial-specific antigen expression is sufficient to trigger severe antigen-specific CD8+ T-cell-mediated intestinal inflammation; this might be controlled by antigen-specific regulatory T cells under physiological conditions.