Re-examining rotavirus innate immune evasion: Potential applications of the reverse genetics system

Rotaviruses represent one of the most successful pathogens in the world, with high infectivity and efficient transmission between the young of many animal species, including humans. To overcome host defenses, rotaviruses have evolved a plethora of strategies to effectively evade the innate immune response, establish initial infection in the small intestine, produce progeny, and shed into the environment. Previously, studying the roles and relative contributions of specific rotaviral factors in innate immune evasion had been challenging without a plasmid-only reverse genetics system. Although still in its infancy, current reverse genetics technology will help address important research questions regarding rotavirus innate immune evasion, host range restriction, and viral pathogenesis. In this review, we summarize the current knowledge about the antiviral host innate immune defense mechanisms, countermeasures of rotavirus-encoded factors, and strategies to better understand these interactions using the rotavirus reverse genetics system

To B or Not to B: Mechanisms of Protection Conferred by rVSV-EBOV-GP and the Roles of Innate and Adaptive Immunity

Zaire Ebola virus (EBOV) is a member of the Filoviridae family of negative sense, single-stranded RNA viruses. EBOV infection causes Ebola virus disease (EVD), characterized by coagulopathy, lymphopenia, and multi-organ failure, which can culminate in death. In 2019, the FDA approved the first vaccine against EBOV, a recombinant live-attenuated viral vector wherein the G protein of vesicular stomatitis virus is replaced with the glycoprotein (GP) of EBOV (rVSV-EBOV-GP, Ervebo® by Merck). This vaccine demonstrates high efficacy in nonhuman primates by providing prophylactic, rapid, and post-exposure protection. In humans, rVSV-EBOV-GP demonstrated 100% protection in several phase III clinical trials in over 10,000 individuals during the 2013–2016 West Africa epidemic. As of 2020, over 218,000 doses of rVSV-EBOV-GP have been administered to individuals with high risk of EBOV exposure. Despite licensure and robust preclinical studies, the mechanisms of rVSV-EBOV-GP-mediated protection are not fully understood. Such knowledge is crucial for understanding vaccine-mediated correlates of protection from EVD and to aid the further design and development of therapeutics against filoviruses. Here, we summarize the current literature regarding the host response to vaccination and EBOV exposure, and evidence regarding innate and adaptive immune mechanisms involved in rVSV-EBOV-GP-mediated protection, with a focus on the host transcriptional response. Current data strongly suggest a protective synergy between rapid innate and humoral immunity

Obesity Correlates With Pronounced Aberrant Innate Immune Responses in Hospitalized Aged COVID-19 Patients

Both age and obesity are leading risk factors for severe coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Specifically, although most infections occur in individuals under the age of 55 years, 95% of hospitalizations, admissions to the intensive care unit, and deaths occur in those over the age of 55 years. Moreover, hospitalized COVID-19 patients have a higher prevalence of obesity. It is generally believed that chronic low-grade inflammation and dysregulated innate and adaptive immune responses that are associated with aging and obesity are responsible for this elevated risk of severe disease. However, the impact of advanced age and obesity on the host response to SARS-CoV-2 infection remains poorly defined. In this study, we assessed changes in the concentration of soluble immune mediators, IgG antibody titers, frequency of circulating immune cells, and cytokine responses to mitogen stimulation as a function of BMI and age. We detected significant negative correlations between BMI and myeloid immune cell subsets that were more pronounced in aged patients. Similarly, inflammatory cytokine production by monocytes was also negatively correlated with BMI in aged patients. These data suggest that the BMI-dependent impact on host response to SARS-CoV-2 is more pronounced on innate responses of aged patients

Transcriptional profiling of immune responses in NHPs after low-dose, VSV-based vaccination against Marburg virus

ABSTRACTInfection with Marburg virus (MARV), the causative agent of Marburg virus disease (MVD), results in haemorrhagic disease and high case fatality rates (>40%) in humans. Despite its public health relevance, there are no licensed vaccines or therapeutics to prevent or treat MVD. A vesicular stomatitis virus (VSV)-based vaccine expressing the MARV glycoprotein (VSV-MARV) is currently in clinical development. Previously, a single 10 million PFU dose of VSV-MARV administered 1–5 weeks before lethal MARV challenge conferred uniform protection in nonhuman primates (NHPs), demonstrating fast-acting potential. Additionally, our group recently demonstrated that even a low dose VSV-MARV (1000 PFU) protected NHPs when given 7 days before MARV challenge. In this study, we longitudinally profiled the transcriptional responses of NHPs vaccinated with this low dose of VSV-MARV either 14 or 7 days before lethal MARV challenge. NHPs vaccinated 14 days before challenge presented with transcriptional changes consistent with an antiviral response before challenge. Limited gene expression changes were observed in the group vaccinated 7 days before challenge. After challenge, genes related to lymphocyte-mediated immunity were only observed in the group vaccinated 14 days before challenge, indicating that the length of time between vaccination and challenge influenced gene expression. Our results indicate that a low dose VSV-MARV elicits distinct immune responses that correlate with protection against MVD. A low dose of VSV-MARV should be evaluated in clinical rails as it may be an option to deliver beneficial public health outcomes to more people in the event of future outbreaks