"Actionable" host genetic markers for repurposing "add-on therapy" in COVID-19

Background/Objectives: COVID-19 still represents a lifethreatening disease in individuals with a specific genetic background. We successfully applied a new Machine Learning method on WES data to extract a set of coding variants relevant for COVID- 19 severity. We aim to identify personalized add-on therapy. Method(s): A subset of identified variants, "actionable" by repurposed drugs, were functionally tested by in vitro and in vivo experiments. Result(s): Males with either rare loss of function variants in the TLR7 gene or L412F polymorphism in the TLR3 gene benefit from IFN-gamma, which is specifically defective in activated PBMCs, restoring innate immunity. Females heterozygous for rare variants in the ADAMTS13 gene and males with D603N homozygous polymorphism in the SELP gene benefit from Caplacizumab, which reduces vWF aggregation and thrombus formation. Males with either the low-frequency gain of function variant T201M in CYP19A1 gene or with poly-Q repeats >=23 in the AR gene benefit from Letrozole, an aromatase inhibitor, which restores normal testosterone levels, reducing inflammation and which rescues male golden hamsters from severe COVID-19. Conclusion(s): By adding these commonly used drugs to standard of care of selected patients, the rate of intubation is expected to decrease consistently, especially in patients with high penetrance rare genetic markers, mitigating the effect of the pandemic with a significant impact on the healthcare system.

Italian ancestral HLA haplotype predisposing to severe COVID-19 by low spike and high IFNalpha binding affinity

Background/Objectives: Validated association between COVID-19 and the most obvious candidate genes, e.g. HLA, is still missing. A weak association with class I HLA-C*04:01 was found for infection in Sardinians and for severity in another mixed population. Auto-antibodies to interferon type I have been implicated in the severity of COVID-19 in two studies. Method(s): The binding affinity between HLA molecules and SARS-CoV-2 spike protein and IFNalpha subunits was evaluated in silico. The presence of antibodies against one or more of the 12 IFNalpha subunits was evaluated in 160 hospitalized COVID-19 patients. The 10 most frequent haplotypes in the Italian population were tested in 1.997 SARS-CoV-2 infected patients (hospitalized versus not hospitalized). Result(s): The presence of auto-antibodies against at least one IFNalpha subunit was detected in 26% of patients. The haplotype A*24:02-B*35:02-C*04:01-DRB1*11:04-DQB1*03:01 was found to predispose to severity (p = 0.0018;p = 0.07 after Bonferroni correction) in patients <50 years. The haplotype includes alleles able to bind spike with low affinity (i.e. C*04:01 and DRB1*11:04) and IFNalpha with high affinity (i.e. DRB1*11:04). Conclusion(s): One of the 10 most frequent ancestral haplotype of the Italian population predisposes to severity likely reducing both innate immunity through IFNalpha auto-antibodies induction and adaptive immunity through weaker spike protein presentation.

Gain and loss of function CFTR alleles modulate COVID-19 clinical outcome

Background/Objectives: We previously demonstrated that carrying a single pathogenic CFTR allele increases the risk for COVID-19 severity and mortality rate. We now aim to clarify the role of several uncharacterized rare alleles, including complex (cis) alleles, and in trans combinations. Method(s): LASSO logistic regression was used for the association of sets of variants, stratified by MAF, with severity. Immortalized cystic fibrosis bronchial epithelial cell lines and Fischer Rat Thyroid cells were transfected by plasmid carrying specific CFTR mutations. YFP-based assays were used to measure CFTR activity. Result(s): Here we functionally demonstrate that the rare (MAF=0.007) complex G576V/R668C allelemitigates the disease by a gain of function mechanism. Several novel CFTR ultra-rare (MAF <0.001) alleles were proved to have a reduced function;they are associated with disease severity either alone (single or complex alleles) or with another hypomorphic allele in the second chromosome, with a global reduction of CFTR activity between 40 to 72%. Conclusion(s): CFTR is a bidirectional modulator of COVID-19 outcome. At-risk subjects do not have open cystic fibrosis before viral infection and therefore are not easily recognisable in the general population unless a genetic analysis is performed. As the CFTR activity is partially retained, CFTR potentiator drugs could be an option as add-on therapy for at-risk patients.

Polymorphism of HLA and KIR affects severity of COVID-19 by shaping innate and adaptive immunity to SARS-CoV-2

Extreme polymorphism of HLA and Killer-cell Immunoglobulin-like Receptors (KIR) differentiates immune responses across individuals. Additional to Tcell receptor interactions, subsets of HLA class I act as ligands for inhibitory and activating KIR, allowing natural killer (NK) cells to detect and kill infected cells. We investigated the impact of HLA and KIR polymorphism on the severity of COVID-19. High resolution HLA class I and II and KIR genotypes were determined from 403 non-hospitalized and 1,575 hospitalized SARS-CoV-2 infected patients from Italy collected in 2020. We observed that the activating KIR2DS4*001 allotype is associated with severe disease (OR = 3.74, 95% CI 1.75-9.29, pc = 0.003). KIR2DS4*001 in presence of its specific HLA ligands and inhibitory KIR3DL2*002 in absence its HLA ligand are also enriched in severe COVID-19 patients (OR = 1.64, 95% CI 1.09-2.50, p = 0.019), suggesting this combination acts in tandem to increase risk of developing severe COVID-19. We also observed the HLA class II allotype, HLA-DPB1*13:01 protects SARS-CoV-2 infected patients from hospitalization (OR = 0.49, 95% CI 0.33-0.74, pc = 0.019). These association analyses were replicated using logistic regression with sex and age as covariates. Autoantibodies against IFN-alpha associated with COVID-19 severity were detected in 26% of hospitalized patients. HLA-C*08:02 was more frequent in patients with IFN-alpha autoantibodies than those without, and KIR3DL1*01502 was only present in patients lacking IFN- alpha antibodies. We intend to expand this analysis in Greek and Spanish COVID-19 cohorts. These findings show that KIR and HLA polymorphism may play important roles in determining the clinical outcome following SARS-CoV-2 infection, by influencing the course both of innate and adaptive immunity.

Ongoing adaptive reuse: patterns of heritage resilience before and after COVID-19

Purpose The paper aims to assess the impact and responses to coronavirus disease 2019 in six European heritage labs (Horizon 2020 Framework Programme) selected for their adaptive heritage re-use practices based on participation, self-organisation and self-management. As they are naturally oriented towards building resilient urban systems, the hypothesis is that the co-production of cultural values and places promoted by these projects could create the conditions for equitable perspectives of resilience in the normality of contemporary urban life. Design/methodology/approach The paper draws on data collected through a survey of six European Living Labs between January and May 2021. The survey results are framed by a literature review that defines adaptive reuse in terms of resilience. The five resilience characteristics described by Judith Rodin (awareness, diversification, integration, self-regulation and adaptability) are used to navigate the literature and organise the survey results. Findings Combining survey results and insights from the literature, some modes and elements (territorial, social, financial) are presented that contribute to creating the conditions for resilience through adaptive heritage reuse according to community-based approaches. Without claiming to be exhaustive, this evidence should be considered in the design phase of resilience programmes, policies or projects related to cultural heritage. Originality/value The concepts of community and resilience are becoming increasingly important in the field of cultural heritage. This paper makes a creative contribution to the ongoing debate by presenting and evaluating the contribution of adaptive reuse practices to resilience building.

A regional approach to drought index-insurance in Intergovernmental Authority on Development (IGAD) countries: volume 2 - intergovernmental authority on development country annexes

The objectives of this report are to review for each IGAD country the overall environment for the operational feasibility of implementing IBLI. The operational feasibility areas are summarized and scored at the end of each country chapter. They include the following;Importance of pastoral livestock for economy;Impact of drought on livestock;Pastoralist demand for livestock insurance;Effective distribution channels for micro-level IBLI;Existing pastoralist beneficiary registries;Pastoralist financial literacy;Legal and regulatory insurance environment;Insurance market development;Interest from insurers in IBLI;Finance available for premiums;and Interest from government stakeholders in IBLI. This report was conducted combining a desk-based study with key informant interviews. As for Volume I, given the travel restrictions due to COVID-19, only a minimum of in-country stakeholder meetings have been possible. Instead, questionnaires were shared with more than 50 in-country expert stakeholders (of which 21 replied), including ministries of agriculture, ministries of humanitarian affairs, ministries of finance, insurance regulators, development partners, livestock associations and non-governmental organizations (NGOs), inquiring about the status quo of drought risk financing initiatives in IGAD countries, the status of needed operational infrastructure for a regional approach, and the interest of stakeholders to support such an approach. Where applicable, results from these questionnaires and from other stakeholder consultations were included in the country annexes (as indicated).

Corrigendum to “A framework for assessing the effects of shock events on livestock and environment in sub-Saharan Africa: The COVID-19 pandemic in Northern Kenya” [Agricultural Systems Vol. 192 (2021) 103203](S0308521X21001566)(10.1016/j.agsy.2021.103203)

The authors regret that the following text should be added : “We gratefully acknowledge funding support from the Agricultural Technology Adoption Initiative (ATAI), grant number S5081.” The authors would like to apologise for any inconvenience caused. © 2021 The Author(s)