COVID-19, Ebola virus disease, and Nipah virus infection reclassification as novel acute immune dysrhythmia syndrome (n-AIDS): potential crucial role for immunomodulators.

In this manuscript, COVID-19, Ebola virus disease, Nipah virus infection, SARS, and MERS are suggested to be considered for a novel immunological reclassification as acute onset immune dysrhythmia syndrome (n-AIDS) due to altered monocytic, Th1/Th2, as well as cytokines and chemokines balances. n-AIDs is postulated to be the cause of the acute respiratory distress and multi-inflammatory syndromes which are described with fatal COVID-19, and immunomodulators are suggested to effectively manage the mentioned diseases as well as for other disorders caused by Th1/Th2 imbalance. Meanwhile, para COVID syndrome is suggested to describe various immune-related complications, whether before or after recovery, and to embrace a potential of a latent infection, that might be discovered later, as occurred with Ebola virus disease. Finally, our hypothesis has evolved out of our real-life practice that uses immunomodulatory drugs to manage COVID-19 safely and effectively.

Distinct transcriptional responses to fatal Ebola virus infection in cynomolgus and rhesus macaques suggest species-specific immune responses.

Ebola virus (EBOV) is a negative single-stranded RNA virus within the Filoviridae family and the causative agent of Ebola virus disease (EVD). Nonhuman primates (NHPs), including cynomolgus and rhesus macaques, are considered the gold standard animal model to interrogate mechanisms of EBOV pathogenesis. However, despite significant genetic similarity (>90%), NHP species display different clinical presentation following EBOV infection, notably a ∼1-2 days delay in disease progression. Consequently, evaluation of therapeutics is generally conducted in rhesus macaques, whereas cynomolgus macaques are utilized to determine efficacy of preventative treatments, notably vaccines. This observation is in line with reported differences in disease severity and host responses between these two NHP following infection with simian varicella virus, influenza A and SARS-CoV-2. However, the molecular underpinnings of these differential outcomes following viral infections remain poorly defined. In this study, we compared published transcriptional profiles obtained from cynomolgus and rhesus macaques infected with the EBOV-Makona Guinea C07 using bivariate and regression analyses to elucidate differences in host responses. We report the presence of a shared core of differentially expressed genes (DEGs) reflecting EVD pathology, including aberrant inflammation, lymphopenia, and coagulopathy. However, the magnitudes of change differed between the two macaque species. These findings suggest that the differential clinical presentation of EVD in these two species is mediated by altered transcriptional responses.

Sex Differences in Immunity: Implications for the Development of Novel Vaccines Against Emerging Pathogens.

Vaccines are one of the greatest public health achievements and have saved millions of lives. They represent a key countermeasure to limit epidemics caused by emerging infectious diseases. The Ebola virus disease crisis in West Africa dramatically revealed the need for a rapid and strategic development of vaccines to effectively control outbreaks. Seven years later, in light of the SARS-CoV-2 pandemic, this need has never been as urgent as it is today. Vaccine development and implementation of clinical trials have been greatly accelerated, but still lack strategic design and evaluation. Responses to vaccination can vary widely across individuals based on factors like age, microbiome, co-morbidities and sex. The latter aspect has received more and more attention in recent years and a growing body of data provide evidence that sex-specific effects may lead to different outcomes of vaccine safety and efficacy. As these differences might have a significant impact on the resulting optimal vaccine regimen, sex-based differences should already be considered and investigated in pre-clinical and clinical trials. In this Review, we will highlight the clinical observations of sex-specific differences in response to vaccination, delineate sex differences in immune mechanisms, and will discuss the possible resulting implications for development of vaccine candidates against emerging infections. As multiple vaccine candidates against COVID-19 that target the same antigen are tested, vaccine development may undergo a decisive change, since we now have the opportunity to better understand mechanisms that influence vaccine-induced reactogenicity and effectiveness of different vaccines.

Innate Immune Responses to Acute Viral Infection During Pregnancy.

Immunological adaptations in pregnancy allow maternal tolerance of the semi-allogeneic fetus but also increase maternal susceptibility to infection. At implantation, the endometrial stroma, glands, arteries and immune cells undergo anatomical and functional transformation to create the decidua, the specialized secretory endometrium of pregnancy. The maternal decidua and the invading fetal trophoblast constitute a dynamic junction that facilitates a complex immunological dialogue between the two. The decidual and peripheral immune systems together assume a pivotal role in regulating the critical balance between tolerance and defense against infection. Throughout pregnancy, this equilibrium is repeatedly subjected to microbial challenge. Acute viral infection in pregnancy is associated with a wide spectrum of adverse consequences for both mother and fetus. Vertical transmission from mother to fetus can cause developmental anomalies, growth restriction, preterm birth and stillbirth, while the mother is predisposed to heightened morbidity and maternal death. A rapid, effective response to invasive pathogens is therefore essential in order to avoid overwhelming maternal infection and consequent fetal compromise. This sentinel response is mediated by the innate immune system: a heritable, highly evolutionarily conserved system comprising physical barriers, antimicrobial peptides (AMP) and a variety of immune cells-principally neutrophils, macrophages, dendritic cells, and natural killer cells-which express pattern-receptors that detect invariant molecular signatures unique to pathogenic micro-organisms. Recognition of these signatures during acute infection triggers signaling cascades that enhance antimicrobial properties such as phagocytosis, secretion of pro-inflammatory cytokines and activation of the complement system. As well as coordinating the initial immune response, macrophages and dendritic cells present microbial antigens to lymphocytes, initiating and influencing the development of specific, long-lasting adaptive immunity. Despite extensive progress in unraveling the immunological adaptations of pregnancy, pregnant women remain particularly susceptible to certain acute viral infections and continue to experience mortality rates equivalent to those observed in pandemics several decades ago. Here, we focus specifically on the pregnancy-induced vulnerabilities in innate immunity that contribute to the disproportionately high maternal mortality observed in the following acute viral infections: Lassa fever, Ebola virus disease (EVD), dengue fever, hepatitis E, influenza, and novel coronavirus infections.

Ethics of Conducting Clinical Research in an Outbreak Setting.

The conduct of clinical trials during the West Africa Ebola outbreak in 2014 highlighted many ethical challenges. How these challenges were addressed, what clinical studies were conducted during that outbreak, and the lessons learned for dealing with future outbreaks were the subject of a National Academy of Medicine committee report titled Integrating Clinical Research into Epidemic Response: The Ebola Experience. This report suggested improvements for research during subsequent emerging or re-emerging outbreaks and is summarized in this review. We also discuss the current Ebola outbreak in the Democratic Republic of the Congo and highlight how the dialogue has changed and how successful clinical trials have been implemented. We conclude with a description of productive efforts to include pregnant women and children in therapeutic and vaccine trials during outbreaks that are currently ongoing.

MHC class II transactivator CIITA induces cell resistance to Ebola virus and SARS-like coronaviruses.

Recent outbreaks of Ebola virus (EBOV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have exposed our limited therapeutic options for such diseases and our poor understanding of the cellular mechanisms that block viral infections. Using a transposon-mediated gene-activation screen in human cells, we identify that the major histocompatibility complex (MHC) class II transactivator (CIITA) has antiviral activity against EBOV. CIITA induces resistance by activating expression of the p41 isoform of invariant chain CD74, which inhibits viral entry by blocking cathepsin-mediated processing of the Ebola glycoprotein. We further show that CD74 p41 can block the endosomal entry pathway of coronaviruses, including SARS-CoV-2. These data therefore implicate CIITA and CD74 in host defense against a range of viruses, and they identify an additional function of these proteins beyond their canonical roles in antigen presentation.

Modelling the pandemic: attuning models to their contexts.

The evidence produced in mathematical models plays a key role in shaping policy decisions in pandemics. A key question is therefore how well pandemic models relate to their implementation contexts. Drawing on the cases of Ebola and influenza, we map how sociological and anthropological research contributes in the modelling of pandemics to consider lessons for COVID-19. We show how models detach from their implementation contexts through their connections with global narratives of pandemic response, and how sociological and anthropological research can help to locate models differently. This potentiates multiple models of pandemic response attuned to their emerging situations in an iterative and adaptive science. We propose a more open approach to the modelling of pandemics which envisages the model as an intervention of deliberation in situations of evolving uncertainty. This challenges the 'business-as-usual' of evidence-based approaches in global health by accentuating all science, within and beyond pandemics, as 'emergent' and 'adaptive'.

Working Hard or Hardly Working? Regulatory Bottlenecks in Developing a COVID-19 Vaccine.

Vaccine solutions rarely reach the public until after an outbreak abates; an Ebola vaccine was approved 5 years after peak outbreak and SARS, MERS, and Zika vaccines are still in clinical development. Despite massive leaps forward in rapid science, other regulatory bottlenecks are hamstringing the global effort for pandemic vaccines.