Many viruses utilize the host endo-lysosomal network for infection. Tracing the endocytic itinerary of SARS-CoV-2 can provide insights into viral trafficking and aid in designing new therapeutic strategies. Here, we demonstrate that the receptor binding domain (RBD) of SARS-CoV-2 spike protein is internalized via the pH-dependent CLIC/GEEC (CG) endocytic pathway in human gastric-adenocarcinoma (AGS) cells expressing undetectable levels of ACE2. Ectopic expression of ACE2 (AGS-ACE2) results in RBD traffic via both CG and clathrin-mediated endocytosis. Endosomal acidification inhibitors like BafilomycinA1 and NH4Cl, which inhibit the CG pathway, reduce the uptake of RBD and impede Spike-pseudoviral infection in both AGS and AGS-ACE2 cells. The inhibition by BafilomycinA1 was found to be distinct from Chloroquine which neither affects RBD uptake nor alters endosomal pH, yet attenuates Spike-pseudovirus entry. By screening a subset of FDA-approved inhibitors for functionality similar to BafilomycinA1, we identified Niclosamide as a SARS-CoV-2 entry inhibitor. Further validation using a clinical isolate of SARS-CoV-2 in AGS-ACE2 and Vero cells confirmed its antiviral effect. We propose that Niclosamide, and other drugs which neutralize endosomal pH as well as inhibit the endocytic uptake, could provide broader applicability in subverting infection of viruses entering host cells via a pH-dependent endocytic pathway.

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PurposeThis research analyses the simultaneous relationship between perceived risks, destination image and destination loyalty as well as the mediating role of two components of destination image (cognitive and affective) in the relationship between perceived risks and destination loyalty.Design/methodology/approachThe current study used a convenience sampling method for collecting data from 413 respondents using a self-administered questionnaire. Furthermore, the two-step approach for structural equation modelling (SEM) was used to assess the model's psychometric properties and test the proposed structural model.FindingsThe results revealed that only socio-psychological and political risks negatively affected destination loyalty. In contrast, performance risk, physical risk and financial risk did not show a significant direct effect on tourists' destination loyalty. Each type of perceived risk significantly contributed to cognitive and affective image formation. However, the financial risk did not significantly affect the affective image. Moreover, the affective component of the image was found to have a higher impact on establishing destination loyalty than the cognitive component of the image. Finally, cognitive and affective facets of the image were found to act as significant mediators between perceived risks and destination loyalty.Practical implicationsThe study provides a better understanding of how perceived risks and destination image, if properly managed, exert a better influence on destination loyalty. Moreover, the affective dimension of destination image must be actively used to position Kashmir in the domestic tourism market and connect with individuals, especially those who have negative feelings regarding risky destinations.Originality/valueThis is likely to be the first study to investigate the relationships between various dimensions of perceived risk, destination image and destination loyalty in the context of a volatile destination, i.e. Kashmir Valley (India). Furthermore, the role of two facets of destination image (cognitive and affective) in mediating the relationship between perceived risks and destination loyalty extends and contributes to the theoretical foundation for the destination perception concept.