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The cytoskeleton not only deals with numerous interaction and communication mechanisms at the cellular level but also has a crucial role in the viral infection cycle. Although numerous aspects of SARS-CoV-2 virus interaction at the cellular level have been widely studied, little has been reported about the structural and functional response of the cytoskeleton. This work aims to characterize, at the ultrastructural level, the modifications in the cytoskeleton of infected cells, namely, its participation in filopodia formation, the junction of these nanostructures forming bridges, the viral surfing, and the generation of tunnel effect nanotubes (TNT) as probable structures of intracellular viral dissemination. The three-dimensional reconstruction from the obtained micrographs allowed observing viral propagation events between cells in detail for the first time. More profound knowledge about these cell-cell interaction models in the viral spread mechanisms could lead to a better understanding of the clinical manifestations of COVID-19 disease and to find new therapeutic strategies.

Intravesical administration of BCG was the first immunotherapy approved by the FDA and it is still nowadays the treatment of choice for a subset of non-muscle invasive bladder cancer patients. Considering this precedent and the strong capabilities of BCG to trigger cellular responses, we hypothesized that systemic administration of BCG by the intravenous route (IV BCG), a vaccination strategy that has been found well-tolerated, highly immunogenic and effective at preventing tuberculosis infection in non-human primates, could result effective against lung tumors. Our data revealed that IV BCG, administered in a therapeutic scenario, slowed tumor growth and extended mouse survival in models of B16-F10 lung metastasis and in an orthotopic LLC lung cancer model, by enhancing both antitumoral innate and adaptive immune responses. IV BCG administration induced tumor-specific CD8+ T cell responses with enhanced cytotoxic function, in a process dependent on conventional type 1 Dendritic Cells (cDC1s). In addition, we found that BCG strongly activated both human and mouse NK cells. Remarkably, NK cell depletion prevented BCG-induced cDC1 recruitment to the tumor-bearing lung and reduced cDC1 upload with tumor-derived antigens, as well as the subsequent induction of tumor-specific CD8+ T cell responses and tumor control. Of note, IV BCG strongly synergized with the immune checkpoint inhibitor (ICI) anti-PD-L1 in lung tumors which were otherwise resistant to immune checkpoint blockade given as monotherapy, suggesting the IV BCG could represent a promising ICI-resensitizing cancer immunotherapy.

Bacillus Calmette-Guerin (BCG) is an attenuated bacterial vaccine used to protect against Mycobacterium tuberculosis (Mtb) in regions where infections are highly prevalent. BCG is currently deliver...

Intravesical BCG is the gold-standard therapy for non-muscle invasive bladder cancer (NMIBC); however, it still fails in a significant proportion of patients, so improved treatment options are urgently needed. Here, we compared BCG antitumoral efficacy with another live attenuated mycobacteria, MTBVAC, in an orthotopic mouse model of bladder cancer (BC). We aimed to identify both bacterial and host immunological factors to understand the antitumoral mechanisms behind effective bacterial immunotherapy for BC. We found that the expression of the BCG-absent proteins ESAT6/CFP10 by MTBVAC was determinant in mediating bladder colonization by the bacteria, which correlated with augmented antitumoral efficacy. We further analyzed the mechanism of action of bacterial immunotherapy and found that it critically relied on the adaptive cytotoxic response. MTBVAC enhanced both tumor antigen-specific CD4+ and CD8+ T-cell responses, in a process dependent on stimulation of type 1 conventional dendritic cells. Importantly, improved intravesical bacterial immunotherapy using MBTVAC induced eradication of fully established bladder tumors, both as a monotherapy and specially in combination with the immune checkpoint inhibitor antiprogrammed cell death ligand 1 (anti PD-L1). These results contribute to the understanding of the mechanisms behind successful bacterial immunotherapy against BC and characterize a novel therapeutic approach for BCG-unresponsive NMIBC cases. This study was supported by Spanish Science and Innovation Ministry (RETOS COLABORACIÓN RTC-2017-6379-1 and RETOS INVESTIGACIÓN RTI2018- 097625-B-I00); and 'Gobierno de Aragón-Fondo Europeo de Desarrollo Regional (FEDER) 2014-2020: Construyendo Europa Desde Aragón'. The funders had no role in study design, data collection and analysis, and decision to publish or preparation of the manuscript. Sí

Jasonia glutinosa (L.) DC., known as rock tea (RT), is traditionally used in Spain as a digestive due to its beneficial properties in bowel disorders. The pharmacological nature of these properties has not been established yet. The aim of this work was to evaluate the therapeutic utility of RT in experimental colitis and to identify chemical constituents with anti-inflammatory and/or anti-oxidative properties. RT extract was prepared with ethanol in a Soxhlet apparatus and analysed by HPLC–DAD. Superoxide radical scavenging properties, xanthine oxidase and lipoxygenase (5-LOX) inhibitory activity, and capability to lower nitric oxide (NO) and tumor necrosis factor a (TNF-a) levels were measured in cell-free and cell-based assays. In the 2.5%-dextran-sodium sulphate (DSS) injury-repair model of ulcerative colitis (UC), mice were daily treated with sulfasalazine (SSZ, as reference drug, 100 mg/kg bw), RT (5, 25 and 50 mg/kg bw, p.o.), or vehicle over 20 days. Colitis was scored daily. Colon samples were examined macroscopically and histopathologically. Protein levels of myeloperoxidase (MPO), interleukins 6, and 10 (IL-6, IL-10), inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2) were studied as markers of oxidative stress and inflammatory activity. The integrity of the apical epithelial layer was assessed by immunofluorescence staining of zonula ocludens-1 (ZO-1). Finally, intestinal contractility was also evaluated by isometric myography. Fifteen phenolic compounds and three pigments were identified and quantified, of which caffeoylquinic acids, and the flavonoid, quercetin-3-O-galactoside, were the most abundant. RT extract significantly scavenged superoxide radicals, inhibited 5-LOX activity, and lowered NO and TNF-a levels. DSS-treated mice receiving RT scored clinically lower than controls during the first 3 days of DSS treatment and during the recovery period. SSZ was less effective than RT. Anatomical and histological examination of colon samples revealed that RT significantly prevented colon shortening, increased colon thickness, and lowered the macroscopic damage score. RT also significantly prevented the increase of MPO activity, IL-6 levels, iNOS and COX-2 expression, the loss of ZO-1 apical expression, and normalized contractility disturbances. In conclusion, daily administration of RT showed therapeutic properties in the DSS-model of UC. The benefits of RT can likely be attributed to its anti-inflammatory and antioxidant phenolic and flavonoid constituents.