FROM microRNAS TO MITOCHONDRIA IN THE MACROPHAGE RESPONSE TO MYCOBACTERIUM TUBERCULOSIS: AND INFLAMMASOME ACTIVATION IN COVID-19

Tuberculosis (TB) and COVID-19 are two major infectious disease problems. While TB is caused by a slow growing bacterium, Mycobacterium tuberculosis (Mtb), and COVID-19 is caused by a virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, SARS-COV-2), both diseases have widespread impact on human health and share many common pathologies. Outcome of infection with both pathogens is heavily influenced by the response of host macrophages. Here we use a combination of unbiased and targeted approaches, including transcriptomics, methylomics, and cytokine analysis to evaluate immunological responses in human macrophages exposed to Mtb and SARS-CoV-2. Using in vitro macrophage exposure models and both unbiased and targeted analysis approaches, we find that the macrophage response to Mtb is shaped by changes in the production of small non-coding RNAs, including microRNAs (miRNAs) and tRNA-derived fragments (tRFs), gene expression, methylation, mitochondrial responses, while host responses to SARS-CoV-2 are shaped by macrophage-mediated viral sensing and inflammasome activation. Using next generation sequencing, we show that certain miRNAs are consistently dysregulated in Mtb infection. These miRNAs target a number of differentially expressed genes involved in processes central to the anti-TB response, including immune cell activation, macrophage lipid metabolism, and blood vessel development. Many genes involved in immune cell activation and metabolic reprogramming were also subject to changes in methylation. Additionally, we investigate dysregulation of tRFs, a novel form of small non-coding RNA that have never before been studied in the context of bacterial infections. We find that tRFs are significantly dysregulated in infection with Mtb and that dysregulated tRFs derive primarily from the host mitochondrial genome. Fluorescent imaging shows that increased abundance of mitochondria-biased tRFs is linked to recruitment of a tRF cleaving enzyme Angiogenin (ANG) and the apoptotic suppressor x-linked inhibitor of apoptosis protein (XIAP) to host mitochondria. Finally, we investigate the role of the inflammasome in SARS-COV-2 infection and find that SARS-COV-2 stimulates activation of the NLRP3 inflammasome through MyD88-mediated direct sensing of extracellular virus in macrophages, but not nasal or lung epithelial cells. Taken together, our studies show that the macrophage plays a central role in the host response to both Mtb and SARS-COV-2 infection and that macrophage responses are shaped by a network of pre- and post-transcriptional molecular regulatory factors

Reinventing foreign aid for inclusive and sustainable development: a survey

This survey essay reviews over 200 papers in arguing that in order to achieve sustainable and inclusive development, foreign aid should not orient developing countries towards industrialisation in the perspective of Kuznets but in the view of Piketty. Abandoning the former’s view that inequality will fall with progress in industrialisation and placing more emphasis on inequality in foreign aid policy will lead to more sustainable development outcomes. Inter alia: mitigate short-term poverty; address concerns of burgeoning population growth; train recipient governments on inclusive development; fight corruption and mismanagement and; avoid the shortfalls of celebrated Kuznets’ conjectures. We discuss how the essay addresses post-2015 development challenges and provide foreign aid policy instruments with which discussed objectives can be achieved. In summary, the essay provides useful policy measures to avoid past pitfalls. ‘Output may be growing, and yet the mass of the people may be becoming poorer’ (Lewis, 1955). ‘Lewis led all developing countries to water, proverbially speaking, some African countries have so far chosen not to drink’ (Amavilah, 2014). Piketty (2014) has led all developing countries to the stream again and a challenging policy syndrome of our time is how foreign aid can help them to drink

Infectability of human BrainSphere neurons suggests neurotropism of SARS-CoV-2

Reports from Wuhan suggest that 36% of COVID-19 patients show neurological symptoms, and cases of viral encephalitis have been reported, suggesting that the virus is neurotropic under unknown circumstances. This is well established for other coronaviruses. In order to understand why some patients develop such symptoms and others do not, we address herein the infectability of the central nervous system (CNS). Reports that the ACE2 receptor – critical for virus entry into lung cells – is found in different neurons support this expectation. We employed a human induced pluripotent stem cell (iPSC)- derived BrainSphere model, which we used earlier for Zika, Dengue, HIV and John Cunningham virus infection studies. We detected the expression of the ACE2 receptor, but not TMPRSS2, in the model. Incubating the BrainSpheres for 6 hours with SARS-CoV-2 at a multiplicity of infection (MOI) of 0.1 led to infection of a fraction of neural cells with replication of the virus evident at 72 hpi. Virus particles were found in the neuronal cell body extending into apparent neurite structures. PCR measurements corroborated the replication of the virus, suggesting at least a tenfold increase in virus copies per total RNA. Leveraging state-of-the-art 3D organotypic cell culture, which has been shown to allow both virus infection and modeling of (developmental) neurotoxicity but is at the same time simple enough to be transferred and used in a BSL-3 environment, we demonstrate, for the first time, the potential critically important neurotropism of SARS-CoV-2.publishe

Efficacy, safety, and immunogenicity of a booster regimen of Ad26.COV2.S vaccine against COVID-19 (ENSEMBLE2) : results of a randomised, double-blind, placebo-controlled, phase 3 trial

Background Despite the availability of effective vaccines against COVID-19, booster vaccinations are needed to maintain vaccine-induced protection against variant strains and breakthrough infections. This study aimed to investigate the efficacy, safety, and immunogenicity of the Ad26.COV2.S vaccine (Janssen) as primary vaccination plus a booster dose. Methods ENSEMBLE2 is a randomised, double-blind, placebo-controlled, phase 3 trial including crossover vaccination after emergency authorisation of COVID-19 vaccines. Adults aged at least 18 years without previous COVID-19 vaccination at public and private medical practices and hospitals in Belgium, Brazil, Colombia, France, Germany, the Philippines, South Africa, Spain, the UK, and the USA were randomly assigned 1:1 via a computer algorithm to receive intramuscularly administered Ad26.COV2.S as a primary dose plus a booster dose at 2 months or two placebo injections 2 months apart. The primary endpoint was vaccine efficacy against the first occurrence of molecularly confirmed moderate to severe-critical COVID-19 with onset at least 14 days after booster vaccination, which was assessed in participants who received two doses of vaccine or placebo, were negative for SARS-CoV-2 by PCR at baseline and on serology at baseline and day 71, had no major protocol deviations, and were at risk of COVID-19 (ie, had no PCR-positive result or discontinued the study before day 71). Safety was assessed in all participants; reactogenicity, in terms of solicited local and systemic adverse events, was assessed as a secondary endpoint in a safety subset (approximately 6000 randomly selected participants). The trial is registered with ClinicalTrials.gov, NCT04614948, and is ongoing. Findings Enrolment began on Nov 16, 2020, and the primary analysis data cutoff was June 25, 2021. From 34 571 participants screened, the double-blind phase enrolled 31 300 participants, 14 492 of whom received two doses (7484 in the Ad26.COV2.S group and 7008 in the placebo group) and 11 639 of whom were eligible for inclusion in the assessment of the primary endpoint (6024 in the Ad26.COV2.S group and 5615 in the placebo group). The median (IQR) follow-up post-booster vaccination was 36 center dot 0 (15 center dot 0-62 center dot 0) days. Vaccine efficacy was 75 center dot 2% (adjusted 95% CI 54 center dot 6-87 center dot 3) against moderate to severe-critical COVID-19 (14 cases in the Ad26.COV2.S group and 52 cases in the placebo group). Most cases were due to the variants alpha (B.1.1.7) and mu (B.1.621); endpoints for the primary analysis accrued from Nov 16, 2020, to June 25, 2021, before the global dominance of delta (B.1.617.2) or omicron (B.1.1.529). The booster vaccine exhibited an acceptable safety profile. The overall frequencies of solicited local and systemic adverse events (evaluated in the safety subset, n=6067) were higher among vaccine recipients than placebo recipients after the primary and booster doses. The frequency of solicited adverse events in the Ad26.COV2.S group were similar following the primary and booster vaccinations (local adverse events, 1676 [55 center dot 6%] of 3015 vs 896 [57 center dot 5%] of 1559, respectively; systemic adverse events, 1764 [58 center dot 5%] of 3015 vs 821 [52 center dot 7%] of 1559, respectively). Solicited adverse events were transient and mostly grade 1-2 in severity. Interpretation A homologous Ad26.COV2.S booster administered 2 months after primary single-dose vaccination in adults had an acceptable safety profile and was efficacious against moderate to severe-critical COVID-19. Studies assessing efficacy against newer variants and with longer follow-up are needed. Funding Janssen Research & Development. Copyright (c) 2022 The Author(s). Published by Elsevier Ltd