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The outbreak of coronavirus disease 2019 (COVID-19), triggered by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the disruptive global consequences in terms of mortality and social and economic crises, have taught lessons that may help define strategies to better face future pandemics. Innate and intrinsic immunity form the front-line natural antiviral defense. They involve both tissue-resident and circulating cells, which can produce anti-viral molecules shortly after viral infection. Prototypes of these factors are type I interferons (IFN), antiviral cytokines with a long record of clinical use. During the last two years, there has been an impressive progress in understanding the mechanisms of both SARS-CoV-2 infection and the cellular and soluble antiviral responses occurring early after viral exposure. However, this information was not sufficiently translated into therapeutic approaches. Insufficient type I IFN activity probably accounts for disease progression in many patients. This results from both the multiple interfering mechanisms developed by SARS-CoV-2 to decrease type I IFN response and various pre-existing human deficits of type I IFN activity, inherited or auto-immune. Emerging data suggest that IFN-I-mediated boosting of patients' immunity, achieved directly through the exogenous administration of IFN-β early post viral infection, or indirectly following inoculation of heterologous vaccines (e.g., Bacillus Calmette Guerin), might play a role against SARS-CoV-2. We review how recent insights on the viral and human determinants of critical COVID-19 pneumonia can foster clinical studies of IFN therapy. We also discuss how early therapeutic use of IFN-β and prophylactic campaigns with live attenuated vaccines might prevent a first wave of new pandemic viruses. • COVID-19 experience calls global attempts to exploit knowledge on innate antiviral immunity for future pandemics. • IFN-β plays an early protective role in Sars-COV-2 infection and can mitigate disease progression. • LAV and agents fostering innate immunity, including IFN-β, may represent first-line strategy for controlling viral pandemics. • Clinical trials with IFN-β in COVID-19 patients should include personalized therapies based on novel biomarkers. • Research on mechanisms of antiviral innate immunity should be encouraged for its potential impact on public health prevention strategies. [ABSTRACT FROM AUTHOR]

• IFN-I, in particular IFN-β, are promising drugs for SARS-CoV2 infection. • Early infection in elderly patients is the best setting to exploit IFN-I immunomodulatory activity. • Caution should be given in using continuous IFN-I treatments at high doses. • Mucosal IFN-I delivery is promising but deserves further clinical investigation. • Attention should be paid to IFN-I treatment in patients with severe COVID-19. Coronavirus disease 2019 (COVID-19) first emerged in late 2019 in China. At the time of writing, its causative agent SARS-CoV-2 has spread worldwide infecting over 9 million individuals and causing more than 460,000 deaths. In the absence of vaccines, we are facing the dramatic challenge of controlling COVID-19 pandemic. Among currently available drugs, type I Interferons (IFN-I) – mainly IFN-α and β –represent ideal candidates given their direct and immune-mediated antiviral effects and the long record of clinical use. However, the best modalities of using these cytokines in SARS-CoV-2 infected patients is a matter of debate. Here, we discuss how we can exploit the current knowledge on IFN-I system to tailor the most promising dosing, timing and route of administration of IFN-I to the disease stage, with the final aim of making these cytokines a valuable therapeutic strategy in today's fight against COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Abstract: Human gammaherpesviruses such as Epstein–Barr virus (EBV) cause lifelong infections and associated diseases, by virtue of their ability to establish latent infection. Many studies performed in the past years in murine herpesvirus 68 (MHV-68) model of infection suggested that the limited immunity generated against isolated viral components by subunit vaccines cannot counteract the multiple immune evasion strategies operated by gammaherpesviruses. Indeed, a significant inhibition of long-term latency establishment could be observed in mice vaccinated with strains of genetically modified MHV-68 defective in reactivation or establishment of latency. In this study, we focused on the effects of interferon-α (IFN-α) on both the lytic and latent phase of MHV-68 infection, as exerted by the constitutive release of IFN-α1 by a clone of MHV-68 genetically modified to produce this cytokine (MHV-68mIFNα1). Although the MHV-68mIFNα1 recombinant virus exhibited in vitro replication features indistinguishable from those of the wild type MHV-68, its pathological properties were severely attenuated in vivo in immunocompetent mice and not in mice rendered genetically unresponsive to type I IFN, suggesting that a stronger immune response was primed in the presence of the cytokine. Notably, MHV-68mIFNα1 attenuation did not result in a reduced level of long-term spleen latency establishment. These results prompted us to evaluate the efficacy of MHV-68mIFNα1 in a prophylactic vaccination regimen aimed at inhibiting the symptoms of acute virus infection and the establishment of long-term latency after MHV-68 challenge. Our results show that mice vaccinated with MHV-68mIFNα1, administered as a live-attenuated or partially inactivated (by Psoralen and UV treatment) vaccine, were protected against the challenge with wt MHV-68 from all phases of infection. The ability of MHV-68mIFNα1 to produce IFN-α at the site of the infection, thus efficiently stimulating the immune system in case of virus reactivation from latency, makes this recombinant virus a safer live-attenuated vaccine as compared to the previously reported latency-deficient clones. [Copyright &y& Elsevier]

Human gammaherpesviruses such as Epstein-Barr virus (EBV) cause lifelong infections and associated diseases, including malignancies, and the development of an effective vaccine against this class of viral infections is of considerable interest. The murine herpesvirus 68 (MHV-68) model provides a useful experimental setting to investigate the immune response to gammaherpesvirus infections and to evaluate the efficacy of vaccination strategies. In this study, we tested a heat-inactivated MHV-68 vaccine in immunocompetent mice as well as in B cell-deficient or type I IFN receptor knockout mice. Vaccination with heat-inactivated MHV-68 protected immunocompetent mice from the acute MHV-68 infection in the lung and strongly reduced the expansion of latently infected cells in the spleen and the development of splenomegaly. A similar inhibition of the acute viral replication in the lung was also observed in vaccinated B cell-deficient mice. Of note, the inactivated MHV-68 vaccine completely protected type I IFN receptor knockout mice from the infection with a lethal dose of MHV-68. [Copyright &y& Elsevier]

Abstract Background Experiencing traumatic childhood is a risk factor for developing substance use disorder, but the mechanisms that underlie this relationship have not been determined. Adverse childhood experiences affect the immune system, and the immune system mediates the effects of psychostimulants. However, whether this system is involved in the etiology of substance use disorder in individuals who have experienced early life stress is unknown. Methods In this study, we performed a series of ex vivo and in vivo experiments in mice and humans to define the function of the immune system in the early life stress–induced susceptibility to the neurobehavioral effects of cocaine. Results We provide evidence that exposure to social stress at an early age permanently sensitizes the peripheral (splenocytes) and brain (microglia) immune responses to cocaine in mice. In the brain, microglial activation in the ventral tegmental area of social-stress mice was associated with functional alterations in dopaminergic neurotransmission, as measured by whole-cell voltage clamp recordings in dopamine neurons. Notably, preventing immune activation during the social-stress exposure reverted the effects of dopamine in the ventral tegmental area and the cocaine-induced behavioral phenotype to control levels. In humans, cocaine modulated toll-like receptor 4–mediated innate immunity, an effect that was enhanced in those addicted to cocaine who had experienced a difficult childhood. Conclusions Collectively, our findings demonstrate that sensitization to cocaine in early life–stressed individuals involves brain and peripheral immune responses and that this mechanism is shared between mice and humans. [ABSTRACT FROM AUTHOR]