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

Studies on neuroimmune interactions in allergic inflammation with focus on neurotrophins

Allergic asthma is a chronic airway disease characterized by an eosinophilic inflammation, bronchoconstriction, increased mucus production and bronchial hyperreactivity. The disease involves several mediators and cell types and is associated with a Th2-mediated immune response. Stress is a factor reported to deteriorate the allergic inflammation. Stress can influence the immune system by activating the HPA axis, resulting in release of glucocorticoids which could effects functions such as leukocyte trafficking and mediator release. These functions could be important for the course of the allergic inflammation. NGF, BDNF and NT-3 are members of the neurotrophin family, and since they have important functions in both the nervous and immune systems they have been suggested to play a role as neuroimmune modulators. The neurotrophins are essential growth factors in the nervous system, and can also be produced by and activate inflammatory cells. Elevated neurotrophin levels have been found both in blood and locally in the airways of asthmatic subjects, and the levels have been shown to be elevated further following allergen exposure. The neurotrophins have also been linked to bronchial hyperreactivity. However, it is not completely established which cells in the airways that produce the elevated levels of neurotrophins. Further, the levels of NGF have been found to be elevated in healthy humans in response to stress, but it is unknown if stress affects other neurotrophins than NGF, such as BDNF, and whether the neurotrophins are regulated differently in allergic compared to healthy subjects in response to stress. The first major focus of this thesis was to determine if bronchial smooth muscle cells (SMC) could be a source of the neurotrophins in the human airways, and how inflammatory cytokines might influence such production. This was studied by using an in vitro cell culture model. The second focus was to determine how stress could influence immune regulation, allergic inflammation and neurotrophin release, and the possible involvement of glucocorticoids in stress-evoked neuroimmune interaction. This was performed by utilizing both human and in vivo animal stress models. It was shown that human bronchial SMC could produce NGF, BDNF and NT-3, and that the production was diffrentially regulated by inflammatory cytokines. In the human stress modell, stress increased the proportion of regulatory T-cells in both allergic and healthy subjects, whereas a decrease in blood NK cell numbers and Th1/Th2 cytokine ratio was observed in allergic subjects only. Furthermore, PBMC from asthmatic subjects released more BDNF than PBMC from healthy controls. In response to stress, the release of BDNF from PBMC increased in healthy controls, but not in asthmatic subjects. However, the levels of BDNF from asthmatic subjects at the stress period correlated positively to the levels of IL-5. In the allergic animal model, stress aggravated airway eosinophilia. The stress-induced eosinophilia was reduced when glucocorticoid release was inhibited. In response to stress, the levels of NGF decreased in the airways of non-allergic animals, whereas higher levels of NGF were detected in the airways of allergic compared to non-allergic animals during stress. In contrast to the eosinophils, the NGF levels were elevated when glueocorticoid release was inhibited. The results indicate that in inflammatory conditions, human bronchial SMC may be a source of neurotrophins. Also, PBMC may be a source of neurotrophins, especially in allergic inflammation. Further, atopic and non-atopic subjects shared some immune changes in response to stress. However, other stress-induced immune changes are unique to atopic individuals, indicating that some pathogenic mechanisms in atopics may be more strongly affected by stress than others. Data also supports an increased eosinophilic airway inflammation and increased neurotrophin production in response to stress, and an involvement of glucocorticoids in these responses. Altogether, it is suggested that stress could contribute to an aggravated allergic inflammation, and that neurotrophins may be suggested as messengers in this response

Keeping the blood flowing—plasminogen activator genes and feeding behavior in vampire bats

The blood feeding vampire bats emerged from New World leaf-nosed bats that fed on fruit and insects. Plasminogen activator, a serine protease that regulates blood coagulation, is known to be expressed in the saliva of Desmodus rotundus (common vampire bat) and is thought to be a key enzyme for the emergence of blood feeding in vampire bats. To better understand the evolution of this biological function, we studied the plasminogen activator (PA) genes from all vampire bat species in light of their feeding transition to bird and subsequently mammalian blood. We include the rare species Diphylla ecaudata and Diaemus youngi, where plasminogen activator had not previously been studied and demonstrate that PA gene duplication observed in Desmodus is not essential to the vampire phenotype, but relates to the emergence of predominant mammalian blood feeding in this species. Plasminogen activator has evolved through gene duplication, domain loss, and sequence evolution leading to change in fibrin-specificity and susceptibility to plasminogen activator inhibitor-1. Before undertaking this study, only the four plasminogen activator isoforms from Desmodus were known. The evolution of vampire bat plasminogen activators can now be linksed phylogenetically to the transition in feeding behavior among vampire bat species from bird to mammalian blood