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

Iron Regulatory Protein 1 Sustains Mitochondrial Iron Loading and Function in Frataxin Deficiency

SummaryMitochondrial iron accumulation is a hallmark of diseases associated with impaired iron-sulfur cluster (Fe-S) biogenesis, such as Friedreich ataxia linked to frataxin (FXN) deficiency. The pathophysiological relevance of the mitochondrial iron loading and the underlying mechanisms are unknown. Using a mouse model of hepatic FXN deficiency in combination with mice deficient for iron regulatory protein 1 (IRP1), a key regulator of cellular iron metabolism, we show that IRP1 activation in conditions of Fe-S deficiency increases the available cytosolic labile iron pool. Surprisingly, our data indicate that IRP1 activation sustains mitochondrial iron supply and function rather than driving detrimental iron overload. Mitochondrial iron accumulation is shown to depend on mitochondrial dysfunction and heme-dependent upregulation of the mitochondrial iron importer mitoferrin-2. Our results uncover an unexpected protective role of IRP1 in pathological conditions associated with altered Fe-S metabolism

Supplementary Figure 5 from Thrombospondin-1 Triggers Cell Migration and Development of Advanced Prostate Tumors

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Thrombospondin-1 Triggers Cell Migration and Development of Advanced Prostate Tumors

Abstract The antitumor effects of pharmacologic inhibitors of angiogenesis are hampered in patients by the rapid development of tumor resistance, notably through increased invasiveness and accelerated metastasis. Here, we reevaluated the role of the endogenous antiangiogenic thrombospondin 1 (TSP1) in prostate carcinomas in which angiogenesis is an active process. In xenografted tumors, we observed that TSP1 altogether inhibited angiogenesis and fostered tumor development. Our results show that TSP1 is a potent stimulator of prostate tumor cell migration. This effect required CD36, which also mediates TSP1 antiangiogenic activity, and was mimicked by an antiangiogenic TSP1-derived peptide. As suspected for pharmacologic inhibitors of angiogenesis, the TSP1 capacities to increase hypoxia and to trigger cell migration are thus inherently linked. Importantly, although antiangiogenic TSP1 increases hypoxia in vivo, our data show that, in turn, hypoxia induced TSP1, thus generating a vicious circle in prostate tumors. In radical prostatectomy specimens, we found TSP1 expression significantly associated with invasive tumors and with tumors which eventually recurred. TSP1 may thus help select patients at risk of prostate-specific antigen relapse. Together, the data suggest that intratumor disruption of the hypoxic cycle through TSP1 silencing will limit tumor invasion. Cancer Res; 71(24); 7649–58. ©2011 AACR.</jats:p

Supplementary Figure Legends 1-5 from Thrombospondin-1 Triggers Cell Migration and Development of Advanced Prostate Tumors

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Supplementary Figure 5 from Thrombospondin-1 Triggers Cell Migration and Development of Advanced Prostate Tumors

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Epidermal hepcidin is required for neutrophil response to bacterial infection

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