The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Rôle de la voie de la cyclooxygénase dans le contrôle du tonus vasculaire lors de situations normales et inflammatoires

L inhibition de l activité de la cyclooxygénase-2 par les Coxib est associée à des risques d accidents cardiovasculaires. Ces observations ont révélé l importance de la voie de la cyclooxygénase dans le système vasculaire. Le travail présenté dans cette thèse décrit le rôle des prostanoïdes dans le contrôle du tonus des vaisseaux isolés lors de situations normales et inflammatoires. Nous avons étudié les activités des cyclooxygénases et nous avons caractérisé les différents récepteurs aux prostanoïdes impliqués dans ces réponses. Ainsi nous avons induit l expression de la cyclooxygénase-2 in vitro dans des artères mammaires humaines et in vivo dans l aorte de lapin. L induction de la cyclooxygénase-2 provoque une réduction des vasoconstrictions induites par la noradrénaline. Cet effet est accompagné par une augmentation de la synthèse des prostaglandines I2 et E2. Les inhibiteurs sélectifs de la cyclooxygénase-2 diminuent la production de ces prostaglandines, restaurent et potentialisent le tonus vasculaire induit par la noradrénaline. Lors de situations normales, la prostaglandine E2 provoque des effets vasoactifs différents. Nous avons montré pharmacologiquement que la prostaglandine E2 induit la contraction des artères mammaires via le récepteur EP3 et qu elle provoque la relaxation des veines pulmonaires et saphènes humaines en activant des récepteurs EP4. Dans ces vaisseaux comme dans la plupart des vaisseaux sanguins humains, la stimulation des récepteurs IP par la prostaglandine I2 entraîne des relaxations. Dans les conditions inflammatoires, seule la relaxation induite par un analogue de la prostaglandine I2 est réduite tandis que celles provoquées par les autres prostanoïdes ne sont pas altérées. Par ailleurs, cet effet est compensé par la production élevée de prostaglandine I2, puisque l antagonisme des récepteurs IP augmente la contraction induite par la noradrénaline comme cela a été observé avec les Coxib. Ce travail montre que les complications cardiovasculaires liées à l utilisation des Coxib est en partie liées à un mécanisme localisé dans les cellules de muscle lisse de la paroi vasculaire, indépendamment des plaquettes et des cellules. sanguines. Enfin, la forte production de prostaglandine I2, et non pas celle de prostaglandine E2, est responsable de la baisse de la réactivité vasculaire à la noradrénaline observée lors de l induction de la cyclooxygénase-2. Ce travail de thèse pourrait avoir des applications cliniques dans le cadre des traitements anti-inflammatoires afin de limiter les accidents cardiovasculaires.The inhibition of cyclooxygenase-2 activity by Coxib is associated with adverse cardiovascular events suggesting the importance of the cyclooxygenase pathway in the vascular system. This thesis describes the role of this pathway in the control of vascular tone of isolated vessels under normal and inflammatory conditions. In the first part, we have examined the cyclooxygenase activities and in the second part we have characterized the prostanoid receptors involved in these responses. For this purpose, we have induced cyclooxygenase-2 expression in vitro in human mammary arteries and in vivo in rabbit aorta. Cyclooxygenase-2 induction causes a reduction in the vasoconstriction induced by norepinephrine. This effect is accompanied by an increase in the release of prostaglandins E2 and I2. Selective cyclooxygenase-2 inhibitors decrease the synthesis of these prostaglandins, restore and potentiate vascular tone induced by norepinephrine. In normal conditions, prostaglandin E2 mediates different vasoactive effects. We have demonstrated pharmacologically that prostaglandin E2 induces contraction in mammary arteries via the EP3 receptor and relaxation in human pulmonary and saphenous veins via EP4 receptor activation. In these vessels, as in most other human vessels, IP receptor stimulation by prostaglandin I2 produces relaxations. Under inflammatory conditions, the relaxation of mammary artery induced by an analogue of prostaglandin I2 is reduced while that induced by the activation of the other prostanoids receptors was not altered. In addition, this effect is compensated by the high production of prostaglandin I2, since the IP antagonist restores the norepinephrine reactivity as observed with the Coxib.This work shows that cardiovascular complications related to the use of Coxib are partly due to a mechanism located in the smooth muscle cells of the vascular wall, independently of platelets and blood cells. Finally, the high level of prostaglandin I2 synthesis and not prostaglandin E2 is responsible for the reduced vascular reactivity observed when cyclooxygenase-2 is induced. The use of a prostaglandin I2 analogue with Coxib could have clinical applications, as a novel strategy of anti-inflammatory treatment in order to reduce cardiovascular side effects.PARIS13-BU Sciences (930792102) / SudocSudocFranceF

Effects of physical activity on cell‐to‐cell communication during type 2 diabetes: A focus on miRNA signaling

International audienceType 2 diabetes (TD2) is a progressive disease characterized by hyperglycemia that results from alteration in insulin secretion, insulin resistance, or both. A number of alterations involving different tissues and organs have been reported to the development and the progression of T2D, and more relevantly, through cell-to-cell communication pathways. Recent studies demonstrated that miRNAs are considerably implicated to cell-to-cell communication during T2D. Physical activity (PA) is associated with decreasing risks of developing T2D and acts as insulin-like factor. Cumulative evidence suggest that this effect could be mediated in part through improving insulin sensitivity in T2D and obese patients and modulating miRNAs synthesis and release in healthy patients. Therefore, the practice of PA should ideally be established before the initiation of T2D. This review describes cell-to-cell communications involved in the pathophysiology of T2D during PA

Arterial Remodelling in Chronic Kidney Disease: Impact of Uraemic Toxins and New Pharmacological Approaches

Chronic kidney disease (CKD) is a major public health concern that affects around 10 percent of the world’s population. The severity of CKD is mainly due to the high prevalence of cardiovascular (CV) complications in this population. The aim of this review is to describe the arterial remodelling associated with CKD, to provide a quick overview of the mechanisms involved and to review the recent pharmacological approaches aimed at improving vascular health in CKD. CKD patients are exposed to metabolic and haemodynamic disorders that may affect the CV system. Large artery functional and geometric abnormalities have been well documented in CKD patients and are associated with an increase in arterial stiffness and a maladaptive remodelling. Uraemic toxins, such as indoxyl sulphate, p-cresyl sulphate, protein carbamylation and advanced glycation products, exert various effects on vascular smooth muscle cell functions. The low-grade inflammation associated with CKD may also affect arterial wall composition and remodelling. It is worth noting that the CV risk for CKD patients remains high despite the pharmacological control of traditional CV risk factors, suggesting the need for innovative therapeutic strategies. An interventional study targeting the NLRP3 inflammasome has provided some interesting preliminary results that need to be confirmed, especially in terms of safety

Prostaglandin E-2 induced contraction of human intercostal arteries is mediated by the EP3 receptor

Arterial vascularization of the spinal cord may be mechanically or functionally altered during thoracoabdominal surgery/ intravascular procedures. Increased arterial pressure has been shown to restore spinal perfusion and function probably by increasing the blood flow through the intercostal arteries. The regulation of human intercostal artery (HICA) vascular tone is not well documented. Prostaglandin (PG) E-2 concentration is increased during inflammatory conditions and has been shown to regulate vascular tone in many preparations. In this context, the pharmacological response of HICA to PGE2 and the characterization of the PGE(2) receptor subtypes (EP1, EP2, EP3 or EP4) involved are of importance and that is the aim of this study. Rings of HICA were prepared from 29 patients and suspended in organ baths for isometric recording of tension. Cumulative concentration-response curves were performed in these preparations with various EP receptor agonists in the absence or presence of different receptor antagonists or inhibitors. PGE(2) induced the contraction of HICA (E-max=7.28 +/- 0.16 g; pEC(50) value=0.79 +/- 0.18; n=17); contractions were also observed with the EP3 receptor agonists, sulprostone, 17-phenyl-PGE(2), misoprostol or ONO-AE-248. In conclusion, PGE(2) induced vasoconstriction of HICA via EP3 receptor subtypes and this result was confirmed by the use of selective EP receptor antagonists (L-826266, ONO-8713, SC-51322) and by a strong detection of EP3 mRNA. These observations suggest that in the context of perioperative inflammation, increased PGE2 concentrations could trigger vasoconstriction of HICA and possibly alter spinal vascularization. (C) 2012 Elsevier B.V. All rights reserved

Decreased vasorelaxation induced by iloprost during acute inflammation in human internal mammary artery

Cyclooxygenase-2 (COX-2) induction in human internal mammary arteries (IMA) under inflammatory conditions has been associated with attenuated norepinephrine (NE)-induced vasoconstriction. This effect was associated with increased prostaglandin (PG) E-2 and prostacyclin (PGI(2)) releases. The present study was designed to assess the role of these PG and their receptors (EP and IP, respectively) on the vascular reactivity during acute inflammation. Isolated IMA were cultured in the absence (Control conditions) or presence (Inflammatory conditions) of both interleukin-1 beta (IL-1 beta) and lipopolysaccharide (LPS). The vasorelaxation and the increased content of cyclic adenosine monophosphate (cAMP) induced by iloprost, a PGI(2) analogue, were significantly reduced under inflammatory conditions and restored in preparations cultured with the IP antagonist (CAY10441). Decreased cAMP levels under inflammatory conditions are due to at least increased phosphodiesterase (PDE) 4B expression. On the other hand, PGE(2), thromboxane analogues and EP agonistsinduced vasoconstrictions were not affected under inflammatory conditions. No vasorelaxation was observed with PGD(2), PGE(2) or the EP2/4 agonists in pre-contracted IMA. Finally, using RT-qPCR and immunohistochemistry, the COX-2, IP receptor and PGI(2) synthase (PGIS) were detected. A significant increase of COX-2 and moderate increase of IP mRNA expression was observed under inflammatory conditions, whereas PGIS mRNA level was not affected. This study demonstrates that PGI(2)/IP receptor signalling and PGI(2)-induced relaxation are impaired in human IMA during acute inflammation, whereas the responses induced by other prostanoids are not affected. These results could explain some of the mechanisms of vascular dysfunction reported in inflammatory conditions

Involvement of prostaglandin F-2 alpha in preeclamptic human umbilical vein vasospasm: a role of prostaglandin F and thromboxane A(2) receptors

Objective Preeclampsia is characterized by hypertension and proteinuria developing after 20 weeks of gestation. Increased vasoconstriction can be one of the major underlying pathophysiological event in this syndrome. We examined the role of vasoconstrictor prostanoid, prostaglandin F-2 alpha (PGF(2 alpha)) in preeclamptic and normotensive human umbilical veins