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Michael Novakhov’s favorite articles on Inoreader: Role of spike in the pathogenic and antigenic behavior of SARS-CoV-2 BA.1 Omicron


The recently identified, globally predominant SARS-CoV-2 Omicron variant (BA.1) is highly transmissible, even in fully vaccinated individuals, and causes attenuated disease compared with other major viral variants recognized to date17. The Omicron spike (S) protein, with an unusually large number of mutations, is considered the major driver of these phenotypes3,8. We generated chimeric recombinant SARS-CoV-2 encoding the S gene of Omicron in the backbone of an ancestral SARS-CoV-2 isolate and compared this virus with the naturally circulating Omicron variant. The Omicron S-bearing virus robustly escapes vaccine-induced humoral immunity, mainly due to mutations in the receptor-binding motif (RBM), yet unlike naturally occurring Omicron, efficiently replicates in cell lines and primary-like distal lung cells. In K18-hACE2 mice, while Omicron causes mild, non-fatal infection, the Omicron S-carrying virus inflicts severe disease with a mortality rate of 80%. This indicates that while the vaccine escape of Omicron is defined by mutations in S, major determinants of viral pathogenicity reside outside of S.

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Mycobacterium tuberculosis (Mtb), the causative agent of the pulmonary ailment, tuberculosis (TB), continues to thrive owing to a disorganized immune response against it by the host. Among other factors, the rewiring of distinct host signaling pathways is effectuated by the intracellular bacterium, resulting in pathogen-favorable outcomes. Oxidative stress build-up is a key cellular manifestation that occurs during mycobacterial infection. Enhanced oxidative stress is brought about by the cumulative effect of elevated reactive oxygen species generation as well as the inept ability of the cell to mitigate ROS levels. Here, we report the increased expression of the neuronal ligand, SLIT2, during mycobacterial infection in macrophages. By employing loss of function analysis using specific inhibitors, we attribute the heightened expression of SLIT2 to the Mtb-mediated phosphorylation of the p38/JNK pathways. Also, using chromatin immunoprecipitation (ChIP) analysis, we found reduced levels of the repressive H3K27me3 signature on the Slit2 promoter during mycobacterial infection. Furthermore, SLIT2 was found to promote the expression of cellular pantetheinase, Vanin1 (VNN1), that contributed to copious levels of ROS within the macrophage cellular milieu. Thus, we dissect essential molecular details leading to the robust expression of SLIT2 during Mtb infection while outlining the potential consequences of SLIT2 upregulation in infected macrophages.

Michael Novakhov’s favorite articles on Inoreader