Features of HLA class I expression and its clinical relevance in SARS-CoV-2: What do we know so far?

Modifications in HLA-I expression are found in many viral diseases. They represent one of the immune evasion strategies most widely used by viruses to block antigen presentation and NK cell response, and SARS-CoV-2 is no exception. These alterations result from a combination of virus-specific factors, genetically encoded mechanisms, and the status of host defences and range from loss or upregulation of HLA-I molecules to selective increases of HLA-I alleles. In this review, I will first analyse characteristic features of altered HLA-I expression found in SARS-CoV-2. I will then discuss the potential factors underlying these defects, focussing on HLA-E and class-I-related (like) molecules and their receptors, the most documented HLA-I alterations. I will also draw attention to potential differences between cells transfected to express viral proteins and those presented as part of authentic infection. Consideration of these factors and others affecting HLA-I expression may provide us with improved possibilities for research into cellular immunity against viral variants.

Hallmarks of the aging T-cell system.

The adaptive immune system has the enormous challenge to protect the host through the generation and differentiation of pathogen-specific short-lived effector T cells while in parallel developing long-lived memory cells to control future encounters with the same pathogen. A complex regulatory network is needed to preserve a population of naïve cells over lifetime that exhibit sufficient diversity of antigen receptors to respond to new antigens, while also sustaining immune memory. In parallel, cells need to maintain their proliferative potential and the plasticity to differentiate into different functional lineages. Initial signs of waning immune competence emerge after 50 years of age, with increasing clinical relevance in the 7th-10th decade of life. Morbidity and mortality from infections increase, as drastically exemplified by the current COVID-19 pandemic. Many vaccines, such as for the influenza virus, are poorly effective to generate protective immunity in older individuals. Age-associated changes occur at the level of the T-cell population as well as the functionality of its cellular constituents. The system highly relies on the self-renewal of naïve and memory T cells, which is robust but eventually fails. Genetic and epigenetic modifications contribute to functional differences in responsiveness and differentiation potential. To some extent, these changes arise from defective maintenance; to some, they represent successful, but not universally beneficial adaptations to the aging host. Interventions that can compensate for the age-related defects and improve immune responses in older adults are increasingly within reach.

Mini-Review on the Roles of Vitamin C, Vitamin D, and Selenium in the Immune System against COVID-19.

Low levels of micronutrients have been associated with adverse clinical outcomes during viral infections. Therefore, to maximize the nutritional defense against infections, a daily allowance of vitamins and trace elements for malnourished patients at risk of or diagnosed with coronavirus disease 2019 (COVID-19) may be beneficial. Recent studies on COVID-19 patients have shown that vitamin D and selenium deficiencies are evident in patients with acute respiratory tract infections. Vitamin D improves the physical barrier against viruses and stimulates the production of antimicrobial peptides. It may prevent cytokine storms by decreasing the production of inflammatory cytokines. Selenium enhances the function of cytotoxic effector cells. Furthermore, selenium is important for maintaining T cell maturation and functions, as well as for T cell-dependent antibody production. Vitamin C is considered an antiviral agent as it increases immunity. Administration of vitamin C increased the survival rate of COVID-19 patients by attenuating excessive activation of the immune response. Vitamin C increases antiviral cytokines and free radical formation, decreasing viral yield. It also attenuates excessive inflammatory responses and hyperactivation of immune cells. In this mini-review, the roles of vitamin C, vitamin D, and selenium in the immune system are discussed in relation to COVID-19.

COVID-19 pneumonia: CD8+ T and NK cells are decreased in number but compensatory increased in cytotoxic potential.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is posing a huge threat to human health worldwide. We aim to investigate the immune status of CD8+ T and NK cells in COVID-19 patients. METHODS: The count and immune status of lymphocytes were detected by flow cytometry in 32 COVID-19 patients and 18 healthy individuals. RESULTS: As the disease progression in COVID-19 patients, CD8+ T and NK cells were significantly decreased in absolute number but highly activated. After patients' condition improved, the count and immune status of CD8+ T and NK cells restored to some extent. GrA+CD8+ T and perforin+ NK cells had good sensitivity and specificity for assisting diagnosis of COVID-19. CONCLUSIONS: As the disease progression, the declined lymphocytes in COVID-19 patients might lead to compensatory activation of CD8+ T and NK cells. GrA+CD8+ T and perforin+ NK cells might be used as meaningful indicators for assisting diagnosis of COVID-19.

Can BCG vaccine protect against COVID-19 via trained immunity and tolerogenesis?

As the number of infections and mortalities from the SARS-CoV-2 pandemic continues to rise, the development of an effective therapy against COVID-19 becomes ever more urgent. A few reports showing a positive correlation between BCG vaccination and reduced COVID-19 mortality have ushered in some hope. BCG has been suggested to confer a broad level of nonspecific protection against several pathogens, mainly via eliciting "trained immunity" in innate immune cells. Secondly, BCG has also been proven to provide benefits in autoimmune diseases by inducing tolerogenicity. Being an acute inflammatory disease, COVID-19 requires a therapy that induces early priming of anti-viral immune responses and regulates aberrant hyperactivity of innate-immune cells. Here, we hypothesize that BCG can offer reliable spatiotemporal protection from COVID-19 by triggering trained immunity and tolerogenesis, through multiple cellular pathways. We propose further research on BCG-mediated immunoprotection, especially in vulnerable individuals, as a strategy to halt the progress of the SARS-CoV-2 pandemic. Also see the video abstract here https://youtu.be/P2D2RXfq6Vg.

Dynamics of SARS-CoV-2 infection model with two modes of transmission and immune response.

In this paper, we propose a new within-host model which describes the interactions between SARS-CoV-2, host pulmonary epithelial cells and cytotoxic T lymphocyte (CTL) cells. Furthermore, the proposed model takes into account the lytic and nonlytic immune responses and also incorporates both modes of transmission that are the virus-to-cell infection through extracellular environment and the cell-to-cell transmission via virological synapses. The well-posedness of the model as well as the existence of equilibria are established rigorously. Moreover, the dynamical behaviour of the model is further examined by two threshold parameters, and the biological aspects of the analytical results are further presented.

3CL hydrolase-based multiepitope peptide vaccine against SARS-CoV-2 using immunoinformatics.

The present study provides the first multiepitope vaccine construct using the 3CL hydrolase protein of SARS-CoV-2. The coronavirus 3CL hydrolase (Mpro) enzyme is essential for proteolytic maturation of the virus. This study was based on immunoinformatics and structural vaccinology strategies. The design of the multiepitope vaccine was built using helper T-cell and cytotoxic T-cell epitopes from the 3CL hydrolase protein along with an adjuvant to enhance immune response; these are joined to each other by short peptide linkers. The vaccine also carries potential B-cell linear epitope regions, B-cell discontinuous epitopes, and interferon-γ-inducing epitopes. Epitopes of the constructed multiepitope vaccine were found to be antigenic, nonallergic, nontoxic, and covering large human populations worldwide. The vaccine construct was modeled, validated, and refined by different programs to achieve a high-quality three-dimensional structure. The resulting high-quality model was applied for conformational B-cell epitope selection and docking analyses with toll-like receptor-3 for understanding the capability of the vaccine to elicit an immune response. In silico cloning and codon adaptation were also performed with the pET-19b plasmid vector. The designed multiepitope peptide vaccine may prompt the development of a vaccine to control SARS-CoV-2 infection.

The «moonlighting protein¼ able to explain the Th1 immune lockdown in severe COVID-19.

COVID-19 is a major public health issue around the world and new data about its etiological agent, SARS-CoV-2, are urgently necessary, also translating the scientific knowledge acquired on its more similar predecessors, SARS-CoV-1 and MERS-CoV, the coronaviruses responsible for SARS and MERS, respectively. Like SARS-CoV-1, SARS-CoV-2 exploits the ACE2 receptors to enter the host cells; nevertheless, recent bioinformatics insights suggest a potential interaction of SARS-CoV-2 with the «moonlighting protein¼ CD26/DPP4, exactly how MERS-CoV works. CD26/DPP4 is overexpressed on T-helper type 1 (Th1) cells and its expression increases with aging, all factors which could well explain the Th1 immune lockdown, especially in the elderly, during fatal SARS-CoV-2 infections. Facing with this scenario, it is possible that Th1 and T-cytotoxic lymphocytes are the immune cells most affected by SARS-CoV-2, and that the immune system is forced to mount a T-helper type 2 (Th2) response, the only one still mountable, in the attempt to counteract the viral load. However, in this way, the symptomatic patient experiences all the negative effects of the Th2 response, which can seriously aggravate the clinical picture.