Host genetics impact on SARS-CoV-2 vaccine-induced immunoglobulin levels and dynamics: The role of TP53, ABO, APOE, ACE2, HLA-A, and CRP genes.

Background: Development and worldwide availability of safe and effective vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to fight severe symptoms of coronavirus disease 2019 (COVID-19) and block the pandemic have been a great achievement and stimulated researchers on understanding the efficacy and duration of different vaccine types. Methods: We investigated the levels of anti-SARS-CoV-2 antibodies (IgG) and neutralizing antibodies (NAbs) in 195 healthy adult subjects belonging to the staff of the University-Hospital of Ferrara (Italy) starting from 15 days up to 190 days (about 6 months) after the second dose of the BNT162b2 (Pfizer-BioNTech) mRNA-based vaccine (n = 128) or ChAdOx1 (AstraZeneca) adenovirus-based vaccine (n = 67) using a combined approach of serological and genomics investigations. Results: A strong correlation between IgG and NAb levels was detected during the 190 days of follow-up (r 2 = 0.807; p < 0.0001) and was confirmed during the first 90 days (T1) after vaccination (r 2 = 0.789; p = 0.0001) and 91-190 days (T2) after vaccination (r 2 = 0.764; p = 0.0001) for both vaccine types (r 2 = 0.842; p = 0.0001 and r 2 = 0.780; p = 0.0001 for mRNA- and adenovirus-based vaccine, respectively). In addition to age (p < 0.01), sex (p = 0.03), and type of vaccine (p < 0.0001), which partially accounted for the remarkable individual differences observed in the antibody levels and dynamics, interesting genetic determinants appeared as significant modifiers of both IgG and NAb responses among the selected genes investigated (TP53, rs1042522; APOE, rs7412/rs429358; ABO, rs657152; ACE2, rs2285666; HLA-A rs2571381/rs2499; CRP, rs2808635/rs876538; LZTFL1, rs35044562; OAS3, rs10735079; SLC6A20, rs11385942; CFH, rs1061170; and ACE1, ins/del, rs4646994). In detail, regression analysis and mean antibody level comparison yielded appreciable differences after genotype stratification (P1 and P2, respectively, for IgG and NAb distribution) in the whole cohort and/or in the mRNA-based vaccine in the following genes: TP53, rs1042522 (P1 = 0.03; P2 = 0.04); ABO, rs657152 (P1 = 0.01; P2 = 0.03); APOE, rs7412/rs429358 (P1 = 0.0018; P2 = 0.0002); ACE2, rs2285666 (P1 = 0.014; P2 = 0.009); HLA-A, rs2571381/rs2499 (P1 = 0.02; P2 = 0.03); and CRP, rs2808635/rs876538 (P1 = 0.01 and P2 = 0.09). Conclusion: High- or low-responsive subjects can be identified among healthy adult vaccinated subjects after targeted genetic screening. This suggests that favorable genetic backgrounds may support the progression of an effective vaccine-induced immune response, though no definite conclusions can be drawn on the real effectiveness ascribed to a specific vaccine or to the different extent of a genotype-driven humoral response. The interplay between data from the polygenic predictive markers and serological screening stratified by demogeographic information can help to recognize the individual humoral response, accounting for ethnic and geographical differences, in both COVID-19 and anti-SARS-CoV-2 vaccinations.

Cell cycle block by p53 activation reduces SARS-CoV-2 release in infected alveolar basal epithelial A549-hACE2 cells.

SARS-CoV viruses have been shown to downregulate cellular events that control antiviral defenses. They adopt several strategies to silence p53, key molecule for cell homeostasis and immune control, indicating that p53 has a central role in controlling their proliferation in the host. Specific actions are the stabilization of its inhibitor, MDM2, and the interference with its transcriptional activity. The aim of our work was to evaluate a new approach against SARS-CoV-2 by using MDM2 inhibitors to raise p53 levels and activate p53-dependent pathways, therefore leading to cell cycle inhibition. Experimental setting was performed in the alveolar basal epithelial cell line A549-hACE2, expressing high level of ACE2 receptor, to allow virus entry, as well as p53 wild-type. Cells were treated with several concentrations of Nutlin-3 or RG-7112, two known MDM2 inhibitors, for the instauration of a cell cycle block steady-state condition before and during SARS-CoV-2 infection, and for the evaluation of p53 activation and impact on virus release and related innate immune events. The results indicated an efficient cell cycle block with inhibition of the virion release and a significant inhibition of IL-6, NF-kB and IFN-λ expression. These data suggest that p53 is an efficient target for new therapies against the virus and that MDM2 inhibitors deserve to be further investigated in this field.

Therapeutic potential of the MDM2 inhibitor Nutlin-3 in counteracting SARS-CoV-2 infection of the eye through p53 activation.

Starting from the beginning of the severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) global pandemic, most of the published data has concentrated on the respiratory signs and symptoms of Covid-19 infection, underestimating the presence and importance of ocular manifestations, such as conjunctivitis, usually reported in SARS-CoV-2 infected patients. With the present review we intend to resume the ocular involvement in SARS-CoV-2 infection and the recent discoveries about the different cell types and tissues of the eye that can be directly infected by SARS-CoV-2 and propagate the infection. Moreover, reviewing literature data about p53 expression in normal and diseased eye tissues, we hypothesize that the pleiotropic protein p53 present at high levels in cornea, conjunctiva and tear film might play a protective role against SARS-CoV-2 infection. Since p53 can be easily up-regulated by using small molecule non-genotoxic inhibitors of MDM2, we propose that topical use of Nutlin-3, the prototype member of MDM2 inhibitors, might protect the anterior surface of the eye from SARS-CoV-2 infection, reducing the spreading of the virus.

COVID-19 Vaccination May Not Increase Rates of Corneal Graft Rejection.

PURPOSE: The aim of the study was to present the rates of rejection from 2018 to 2021 and evaluate the purported association between COVID-19 vaccination and corneal graft rejection. METHODS: Cases of corneal graft rejection diagnosed between January 2018 and December 2021 were reviewed. The conditional Poisson regression model of the self-controlled case series method was used to estimate the incidence risk ratio of graft rejection after COVID-19 vaccination risk period compared with the control period. Based on outcomes of eyes that underwent keratoplasty from January 2018 to December 2020, Cox proportional hazard models were fitted with previous COVID-19 vaccination as a time-varying covariate. RESULTS: Over the past 4 years, the annual tally of diagnosed cases of graft rejection (19 cases in year 2018, 19 cases in year 2019, 21 cases in year 2020, and 18 cases in year 2021) has remained relatively stable. Using the conditional Poisson regression analysis, no significant increase in the incidence rate of rejection in the risk period after COVID-19 vaccination was found (incidence risk ratio = 0.56, 95% confidence interval [CI] = 0.13-2.28, P = 0.70). Fitted as a time-varying covariate, previous COVID-19 vaccination was not associated with graft rejection in both unadjusted (hazard ratio =0.77, 95% CI = 0.29-5.46, P = 0.77) and adjusted Cox models (hazard ratio = 0.75, 95% CI = 0.10-5.52, P = 0.78). CONCLUSIONS: No notable increase in rates of corneal graft rejection was noted in year 2021 when COVID-19 vaccination was broadly implemented. The apparent temporal relationship between COVID vaccination and corneal graft rejection may not represent a causative association.

Therapeutic potential of the MDM2 inhibitor Nutlin-3 in counteracting SARS-CoV-2 infection of the eye through p53 activation

Starting from the beginning of the severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) global pandemic, most of the published data has concentrated on the respiratory signs and symptoms of Covid-19 infection, underestimating the presence and importance of ocular manifestations, such as conjunctivitis, usually reported in SARS-CoV-2 infected patients. With the present review we intend to resume the ocular involvement in SARS-CoV-2 infection and the recent discoveries about the different cell types and tissues of the eye that can be directly infected by SARS-CoV-2 and propagate the infection. Moreover, reviewing literature data about p53 expression in normal and diseased eye tissues, we hypothesize that the pleiotropic protein p53 present at high levels in cornea, conjunctiva and tear film might play a protective role against SARS-CoV-2 infection. Since p53 can be easily up-regulated by using small molecule non-genotoxic inhibitors of MDM2, we propose that topical use of Nutlin-3, the prototype member of MDM2 inhibitors, might protect the anterior surface of the eye from SARS-CoV-2 infection, reducing the spreading of the virus.

p53/NF-kB Balance in SARS-CoV-2 Infection: From OMICs, Genomics and Pharmacogenomics Insights to Tailored Therapeutic Perspectives (COVIDomics).

SARS-CoV-2 infection affects different organs and tissues, including the upper and lower airways, the lung, the gut, the olfactory system and the eye, which may represent one of the gates to the central nervous system. Key transcriptional factors, such as p53 and NF-kB and their reciprocal balance, are altered upon SARS-CoV-2 infection, as well as other key molecules such as the virus host cell entry mediator ACE2, member of the RAS-pathway. These changes are thought to play a central role in the impaired immune response, as well as in the massive cytokine release, the so-called cytokine storm that represents a hallmark of the most severe form of SARS-CoV-2 infection. Host genetics susceptibility is an additional key side to consider in a complex disease as COVID-19 characterized by such a wide range of clinical phenotypes. In this review, we underline some molecular mechanisms by which SARS-CoV-2 modulates p53 and NF-kB expression and activity in order to maximize viral replication into the host cells. We also face the RAS-pathway unbalance triggered by virus-ACE2 interaction to discuss potential pharmacological and pharmacogenomics approaches aimed at restoring p53/NF-kB and ACE1/ACE2 balance to counteract the most severe forms of SARS-CoV-2 infection.

Autoinflammatory Diseases and Cytokine Storms-Imbalances of Innate and Adaptative Immunity.

Innate and adaptive immune responses have a well-known link and represent the distinctive origins of several diseases, many of which may be the consequence of the loss of balance between these two responses. Indeed, autoinflammation and autoimmunity represent the two extremes of a continuous spectrum of pathologic conditions with numerous overlaps in different pathologies. A common characteristic of these dysregulations is represented by hyperinflammation, which is an exaggerated response of the immune system, especially involving white blood cells, macrophages, and inflammasome activation with the hyperproduction of cytokines in response to various triggering stimuli. Moreover, hyperinflammation is of great interest, as it is one of the main manifestations of COVID-19 infection, and the cytokine storm and its most important components are the targets of the pharmacological treatments used to combat COVID-19 damage. In this context, the purpose of our review is to provide a focus on the pathogenesis of autoinflammation and, in particular, of hyperinflammation in order to generate insights for the identification of new therapeutic targets and strategies.