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Although accumulating data have investigated the effect of SARS-CoV-2 mutations on antibody neutralizing activity, less is known about T cell immunity. In this work, we found that the ancestral (Wuhan strain) Spike protein can efficaciously reactivate CD4+ T cell memory in subjects with previous Alpha variant infection. This finding has practical implications, as in many countries only one vaccine dose is currently administered to individuals with previous COVID-19, independently of which SARS-CoV-2 variant was responsible of the infection. We also found that only a minority of Spike-specific CD4+ T cells targets regions mutated in Alpha, Beta and Delta variants, both after natural infection and vaccination. Finally, we found that the vast majority of Spike-specific CD4+ T cell memory response induced by natural infection or mRNA vaccination is conserved also against Omicron variant. This is of importance, as this newly emerged strain is responsible for a sudden rise in COVID-19 cases worldwide due to its increased transmissibility and ability to evade antibody neutralization. Collectively, these observations suggest that most of the memory CD4+ T cell response is conserved against SARS-CoV-2 variants of concern, providing an efficacious line of defense that can protect from the development of severe forms of COVID-19. [ABSTRACT FROM AUTHOR]

The current pandemic emergence of novel coronavirus disease (COVID-19) poses a relevant threat to global health. SARS-CoV-2 infection is characterized by a wide range of clinical manifestations, ranging from absence of symptoms to severe forms that need intensive care treatment. Here, plasma-EDTA samples of 30 patients compared with age- and sex-matched controls were analyzed via untargeted nuclear magnetic resonance (NMR)-based metabolomics and lipidomics. With the same approach, the effect of tocilizumab administration was evaluated in a subset of patients. Despite the heterogeneity of the clinical symptoms, COVID-19 patients are characterized by common plasma metabolomic and lipidomic signatures (91.7% and 87.5% accuracy, respectively, when compared to controls). Tocilizumab treatment resulted in at least partial reversion of the metabolic alterations due to SARS-CoV-2 infection. In conclusion, NMR-based metabolomic and lipidomic profiling provides novel insights into the pathophysiological mechanism of human response to SARS-CoV-2 infection and to monitor treatment outcomes. Author summary: The current COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is markedly affecting the world population. Here we report about the small-molecule profile of patients hospitalized during the first wave of the COVID-19 pandemic in Florence (Italy). Using magnetic resonance spectroscopy, we showed that the infection induces profound changes in the metabolome. The analysis of the specific metabolite changes and correlations with clinical data enabled the identification of potential biochemical determinants of the disease fingerprint. We also followed how metabolic alterations revert towards those of the control group upon treatment with tocilizumab, a recombinant humanized monoclonal antibody against the interleukin-6 receptor. These results open up possibilities for the monitoring of novel patients and their individual response to treatment. [ABSTRACT FROM AUTHOR]

• A dysregulation in the immune response against SARS-CoV-2 occurs in severe COVID-19 patients. • 6 hallmarks define abnormalities of innate and adaptive immunity in COVID-19. • Innate immunity alterations include hyperinflammation and dysregulation of type I interferon activity and myeloid response. • Lymphocyte alterations include reduced cell counts, impaired functionality and heterogeneous specific response to SARS-CoV-2. • Understanding immune dysregulation in COVID-19 will be crucial to design appropriate therapeutic interventions. One and half year following the occurrence of COVID-19 pandemic, significant efforts from laboratories all over the world generated a huge amount of data describing the prototypical features of immunity in the course of SARS-CoV-2 infection. In this Review, we rationalize and organize the main observations, trying to define a "core" signature of immunity in COVID-19. We identified six hallmarks describing the main alterations occurring in the early infection phase and in the course of the disease, which predispose to severe illness. The six hallmarks are dysregulated type I IFN activity, hyperinflammation, lymphopenia, lymphocyte impairment, dysregulated myeloid response, and heterogeneous adaptive immunity to SARS-CoV-2. Dysregulation and exhaustion came out as the trait d'union, connecting abnormalities affecting both innate and adaptive immunity, humoral and cellular responses. [ABSTRACT FROM AUTHOR]

COVID-19 pandemia is affecting Countries worldwide with a gendered death excess as being a male represents, especially in the 50–69 years age group, an unfavourable factor. Females are constitutionally prone to defend themselves against pathogens with a stronger efficiency than males. As a fact, several genes involved into the regulation of the innate and adaptive immune response are strategically placed on the X-chromosome and, among them, pathogen-related receptors (PRRs), such as Toll-like receptor 7, suitable to recognize ssRNAs and trigger a gendered successful anti-viral fight. On the other hand, a more regulated IL-6 production and a more contained inflammation after the encounter of a pathogen supply score points in favour of the female sex in the view that an abnormal and exaggerated cytokine release does represent the hallmark of the deathful SARS-CoV-2 infection. The sex-prevalent expression of the attachment and permissive molecules ACE2 and TMPRSS2 further supports the concept of a male-oriented vulnerability. In this review, the possible role of biological and immunological sex differences into the higher morbidity and mortality of SARS-CoV-2 between females and males are discussed. [ABSTRACT FROM AUTHOR]