Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity

The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and has multiple mutations in its spike protein2. Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron’s evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis of spike-pseudotyped virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis

An integrative approach to assess non-native iguana presence on Saba and Montserrat: Are we losing all native Iguana populations in the Lesser Antilles

Invasive alien species are among the main drivers of the ongoing sixth mass extinction wave, especially affecting island populations. Although the Caribbean is well-known for its high species richness and endemism, also for reptiles, equally important is the regional contribution of non-native species to island biodiversity. The Lesser Antilles encompass high genetic diversity in Iguana, though most native populations either have gone extinct or are declining following competitive hybridization with invasive non-native green iguanas. Here, we assessed non-native presence in two poorly-studied native melanistic Iguana iguana populations using available genetic tools and explored utilizing size-dependent body measurements to discriminate between native and non-native iguanas. Genetic samples from Saba and Montserrat were genotyped across 17 microsatellite loci with STRUCTURE, and multivariate analyses indicating non-native iguana presence only on Saba. This was corroborated by mtDNA and nDNA sequences, highlighting a non-native origin in Central America and the ABC islands. We identified preliminary evidence suggestive of hybridization. Morphological variation among size-dependent characteristics showed that non-native iguanas have significantly larger subtympanic plates than native iguanas. Non-native individuals also differed in scalation and coloration patterns. Overall, our findings demonstrate the need for continuous monitoring of non-native iguanas within remaining native Iguana populations in the Lesser Antilles, as those not directly threatened by non-native green iguanas are restricted to only 8.7% of the historic range. Although genetic data allow for the identification of non-native or hybrid iguana presence, this field-to-lab workflow is time-consuming. Rapid in-situ identification of non-native individuals is crucial for conservation management. In addition to patterns of scalation and coloration, we have highlighted the utility of size-dependent variables for rapid diagnosis. We urge regional partners to build morphometric databases for native Iguana populations allowing the quick detection of future incursions of non-native green iguanas and the rapid implementation of effective countermeasures during the early phase of invasion

IFITM3 regulates virus-induced inflammatory cytokine production by titrating Nogo-B orchestration of TLR responses

SummaryInterferon induced transmembrane protein 3 (IFITM3) is an important viral restriction factor in viral pathogenesis that also exhibits poorly understood immune regulatory functions. Here, using human and mouse models, we demonstrate that IFITM3 regulates MyD88-dependent TLR-mediated cytokine production following dendritic cell exposure to cytomegalovirus (CMV), and this process limits viral pathogenesisin vivo. IFITM3 also restricted pro-inflammatory (IL-6) cytokine production in response to influenza. IFITM3 bound to and promoted ubiquitination and proteasomal degradation of the reticulon 4 isoform Nogo-B. We reveal that Nogo-B mediates TLR-dependent pro-inflammatory cytokine production and promotes viral pathogenesisin vivo, and this process involved alteration of TLR dynamics. The anti-inflammatory function of IFITM3 was intrinsically linked to its ability to regulate Nogo-B. Thus, we uncover Nogo-B as an unappreciated driver of viral pathogenesis and highlight a novel immune regulatory pathway where IFITM3 fine-tunes TLR responsiveness of myeloid cells to viral stimulation.</jats:p