An extended haplotype on chromosome 3 is the major genetic risk factor for severe COVID-19. The risk haplotype, which was inherited from Neanderthals, decreases the expression of several cytokine receptors, including CCR5. Recently, a study based on three general population cohorts indicated that the minor allele of one of the variants in the haplotype (rs17713054) protects against HIV infection. We thus expected this allele to be over-represented in highly exposed individuals who remain uninfected (exposed seronegative individuals, ESN). To perform a meta-analysis, we genotyped rs17713054 in three ESN cohorts of European ancestry exposed to HIV through different routes. No evidence of association was detected in the single cohorts. The meta-analysis also failed to detect any effect of the variant on protection from HIV-1. The same results were obtained in a Cox-regression analysis for the time to seroconversion. An in-vitro infection assay did not detect differences in viral replication as a function of rs17713054 genotype status. We conclude that the rs17713054 minor allele is not associated with the ESN phenotype and does not modulate HIV infection in vitro.
The potential virucidal effects of UV-C irradiation on SARS-CoV-2 were experimentally evaluated for different illumination doses and virus concentrations (1000, 5, 0.05 MOI). Both virus inactivation and replication inhibition were investigated as a function of these parameters.At a virus density comparable to that observed in SARS-CoV-2 infection, an UV-C dose of just 3.7 mJ/cm2 was sufficient to achieve a 3-log inactivation,and complete inhibition of all viral concentrations was observed with 16.9 mJ/cm2. These results could explain the epidemiological trends of COVID-19 and are important for the development of novel sterilizing methods to contain SARS-CoV-2 infection.
Abstract Background Increasing evidence suggests a double-faceted role of alpha-synuclein (α-syn) following infection by a variety of viruses, including SARS-CoV-2. Although α-syn accumulation is known to contribute to cell toxicity and the development and/or exacerbation of neuropathological manifestations, it is also a key to sustaining anti-viral innate immunity. Consistently with α-syn aggregation as a hallmark of Parkinson's disease, most studies investigating the biological function of α-syn focused on neural cells, while reports on the role of α-syn in periphery are limited, especially in SARS-CoV-2 infection. Results Results herein obtained by real time qPCR, immunofluorescence and western blot indicate that α-syn upregulation in peripheral cells occurs as a Type-I Interferon (IFN)-related response against SARS-CoV-2 infection. Noteworthy, this effect mostly involves α-syn multimers, and the dynamic α-syn multimer:monomer ratio. Administration of excess α-syn monomers promoted SARS-CoV-2 replication along with downregulation of IFN-Stimulated Genes (ISGs) in epithelial lung cells, which was associated with reduced α-syn multimers and α-syn multimer:monomer ratio. These effects were prevented by combined administration of IFN-β, which hindered virus replication and upregulated ISGs, meanwhile increasing both α-syn multimers and α-syn multimer:monomer ratio in the absence of cell toxicity. Finally, in endothelial cells displaying abortive SARS-CoV-2 replication, α-syn multimers, and multimer:monomer ratio were not reduced following exposure to the virus and exogenous α-syn, suggesting that only productive viral infection impairs α-syn multimerization and multimer:monomer equilibrium. Conclusions Our study provides novel insights into the biology of α-syn, showing that its dynamic conformations are implicated in the innate immune response against SARS-CoV-2 infection in peripheral cells. In particular, our results suggest that promotion of non-toxic α-syn multimers likely occurs as a Type-I IFN-related biological response which partakes in the suppression of viral replication. Further studies are needed to replicate our findings in neuronal cells as well as animal models, and to ascertain the nature of such α-syn conformations.
The potential virucidal effects of UV-C irradiation on SARS-CoV-2 were experimentally evaluated for different illumination doses and virus concentrations (1000, 5, 0.05 MOI). At a virus density comparable to that observed in SARS-CoV-2 infection, an UV-C dose of just 3.7 mJ/cm 2 was sufficient to achieve a more than 3-log inactivation without any sign of viral replication. Moreover, a complete inactivation at all viral concentrations was observed with 16.9 mJ/cm 2 . These results could explain the epidemiological trends of COVID-19 and are important for the development of novel sterilizing methods to contain SARS-CoV-2 infection.
While the risk of SARS-CoV-2 infection and/or COVID-19 disease progression in the general population has been largely assessed, its impact on HIV-positive individuals remains unclear. We present clinical and immunological data collected in a cohort of HIV-infected young individuals during the first wave of COVID-19 pandemic. SARS-CoV-2 RNA, virus-specific antibodies, as well as the expression of factors involved in the anti-viral immune response were analyzed. Moreover, we set up an in vitro coinfection assay to study the mechanisms correlated to the coinfection process. Our results did not show any increased risk of severe COVID-19 in HIV-positive young individuals. In those subjects who contracted SARS-CoV-2 infection, an increase in IL-10 expression and production was observed. Furthermore, in the in vitro coinfection assay, we revealed a reduction in SARS-CoV-2 replication associated to an upregulation of IL-10. We speculate that IL-10 could play a crucial role in the course of SARS-CoV-2 infection in HIV-positive individuals. These results might help defining clinical management of HIV/SARS-CoV-2 co-infected young individuals, or putative indications for vaccination schedules in this population.
Recent evidence suggests that SARS-CoV-2 hinders immune responses via dopamine (DA)-related mechanisms. Nonetheless, studies addressing the specific role of DA in the frame of SARS-CoV-2 infection are still missing. In the present study, we investigate the role of DA in SARS-CoV-2 replication along with potential links with innate immune pathways in CaLu-3 human epithelial lung cells. We document here for the first time that, besides DA synthetic pathways, SARS-CoV-2 alters the expression of D1 and D2 DA receptors (D1DR, D2DR), while DA administration reduces viral replication. Such an effect occurs at non-toxic, micromolar-range DA doses, which are known to induce receptor desensitization and downregulation. Indeed, the antiviral effects of DA were associated with a robust downregulation of D2DRs both at mRNA and protein levels, while the amount of D1DRs was not significantly affected. While halting SARS-CoV-2 replication, DA, similar to the D2DR agonist quinpirole, upregulates the expression of ISGs and Type-I IFNs, which goes along with the downregulation of various pro-inflammatory mediators. In turn, administration of Type-I IFNs, while dramatically reducing SARS-CoV-2 replication, converges in downregulating D2DRs expression. Besides configuring the CaLu-3 cell line as a suitable model to study SARS-CoV-2-induced alterations at the level of the DA system in the periphery, our findings disclose a previously unappreciated correlation between DA pathways and Type-I IFN response, which may be disrupted by SARS-CoV-2 for host cell invasion and replication.
Abstract COVID‐19 commonly leads to respiratory issues, yet numerous patients also exhibit a diverse range of neurological conditions, suggesting a detrimental impact of SARS‐CoV‐2 or the viral Spike protein on the central nervous system. Nonetheless, the molecular pathway behind neurological pathology and the presumed neurotropism of SARS‐CoV‐2 remains largely unexplored. We generated human cortical organoids (HCOs) derived from human induced pluripotent stem cells (hiPSC) to assess: (1) the expression of SARS‐CoV‐2 main entry factors; (2) their vulnerability to SARS‐CoV‐2 infection; and (3) the impact of SARS‐CoV‐2 infection and exposure to the Spike protein on their transcriptome. Results proved that (1) HCOs express the main SARS‐CoV‐2 receptors and co‐receptors; (2) HCOs may be productively infected by SARS‐CoV‐2; (3) the viral particles released by SARS‐CoV‐2‐infected HCOs are able to re‐infect another cellular line; and (4) the infection resulted in the activation of apoptotic and stress pathways, along with inflammatory processes. Notably, these effects were recapitulated when HCOs were exposed to the Spike protein alone. The data obtained demonstrate that SARS‐CoV‐2 likely infects HCOs probably through the binding of ACE2, CD147, and NRP1 entry factors. Furthermore, exposure to the Spike protein alone proved sufficient to disrupt their homeostasis and induce neurotoxic effects, potentially contributing to the onset of long‐COVID symptoms.
Event Abstract Back to Event The Vitamin D reduces HIV-1 infection of CD4+ T cells in an in vitro model Simon Villegas-Ospina1, Wbeimar Aguilar-Jiménez1*, Sandra M. Gonzalez1, Wildeman Zapata1, 2, Irma Saulle3, Mara Biasin3, Mario Clerici4, 5 and Maria T. Rugeles1 1 Universidad de Antioquia, Facultad de Medicina, Colombia 2 Universidad Cooperativa de Colombia, Facultad de Medicina, Colombia 3 Università Degli Studi di Milano., Dipartimento di Scienze Biomediche e Cliniche, Italy 4 Università degli Studi di Milano, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Italy 5 Fondazione Don C. Gnocchi IRCCS., Italy Beyond its role in mineral metabolism, the Vitamin D (VitD) has anti-inflammatory properties that may influence the level of immune activation, reducing the risk of HIV-1 infection upon viral exposure. It also increases the production of molecules with anti-HIV-1 activity, further supporting its potential protective role. Indeed, we reported higher levels of VitD and VitD receptor (VDR) in sexually HIV-1-exposed but seronegative (HESN) individuals compared to non-exposed healthy controls (HCs), suggesting that the VitD pathway is associated with natural resistance to HIV-1 infection; interestingly, these higher levels were correlated with mucosal expression of human beta defensin (HBD)-2, HBD-3 and IL-10. However, the role of the VitD during HIV-1 infection remains largely unexplored and available studies have reported contradictory or unclear results to this regard. In this study, we explored the effect of the VitD in an in vitro model of acute HIV-1 infection; for this, peripheral blood mononuclear cells (PBMC) from 7 HCs were treated with three different concentrations of the active form of VitD (1x10-11, 1x10-9 [physiological] and 1x10-7 M), and later infected with an X4 laboratory adapted HIV-1 virus. We quantified the intracellular p24 protein, and the activation markers CD38 and HLA-DR in CD8+ and CD4+ T lymphocytes by flow cytometry, as well as the levels of p24 antigen and the pro- and anti-inflammatory cytokines in supernatants by ELISA. All comparisons were carried-out against the ethanol treatment as vehicle control using the Friedman and Dunn post-test, p<0.05 was considered significant. We observed that VitD reduced in a dose dependent manner the proportion of HIV-1-infected cells (4, 13, and 32%* of reduction; *p<0.05) and the amount of p24 viral protein in supernatants (52%, 58%*, and 66%+ of reduction; *p<0.05 and +p<0.001). Compared to ethanol, the VitD treatment at 1x10-7 M also decreased significantly the percentage of hyperactivated CD8+CD38+HLA-DR+ (0,72 vs 0,18%; p<0.05), and activated CD4+CD38-HLA-DR+ cells (60,08 vs 41,11%; p<0.05). No significant changes were found in the secretion of pro and anti-inflammatory cytokines upon VitD treatment. Interestingly, in a pilot experiment (n=4), we observed that physiological concentrations of the inactive form of VitD also decreased the HIV-1 infection observed as an average of 50% reduction of the p24 viral protein in supernatants, but these effects not reach the statistical significance. These preliminary results show that VitD has anti-HIV-1 effects. The reduction in the percentage of hyper and activated T cells might be the plausible mechanism behind this viral control. It has been well established that activated cells are more susceptible to HIV infection and viral replication; in fact, it has been correlated with higher viral loads and AIDS progression. Further studies, increasing the sample size and including functional analysis are currently underway. Acknowledgements This investigation was supported by CODI-Universidad de Antioquia (Code: 255. 2013); Estrategia de Sostenibilidad 2014-2015 de la Universidad de Antioquia; Banco de la República (convenio 201414 Universidad Cooperativa de Colombia - Proyecto 3377) and COLCIENCIAS (Code:111565740508). Keywords: HIV-1 Infection, Vitamin D, Immunomodulatory molecules, T lymphocytes, immune activation, Anti-HIV-1 activity. Conference: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015. Presentation Type: Oral Presentation Topic: Infectious and parasitic diseases Citation: Villegas-Ospina S, Aguilar-Jiménez W, Gonzalez SM, Zapata W, Saulle I, Biasin M, Clerici M and Rugeles MT (2015). The Vitamin D reduces HIV-1 infection of CD4+ T cells in an in vitro model. Front. Immunol. Conference Abstract: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología. doi: 10.3389/conf.fimmu.2015.05.00311 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 15 May 2015; Published Online: 15 Sep 2015. * Correspondence: Mr. Wbeimar Aguilar-Jiménez, Universidad de Antioquia, Facultad de Medicina, Medellin, Antioquia, 050010, Colombia, aguilar.wb@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Simon Villegas-Ospina Wbeimar Aguilar-Jiménez Sandra M Gonzalez Wildeman Zapata Irma Saulle Mara Biasin Mario Clerici Maria T Rugeles Google Simon Villegas-Ospina Wbeimar Aguilar-Jiménez Sandra M Gonzalez Wildeman Zapata Irma Saulle Mara Biasin Mario Clerici Maria T Rugeles Google Scholar Simon Villegas-Ospina Wbeimar Aguilar-Jiménez Sandra M Gonzalez Wildeman Zapata Irma Saulle Mara Biasin Mario Clerici Maria T Rugeles PubMed Simon Villegas-Ospina Wbeimar Aguilar-Jiménez Sandra M Gonzalez Wildeman Zapata Irma Saulle Mara Biasin Mario Clerici Maria T Rugeles Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.
