SARS-CoV-2 Omicron BA.2.86 & JN.1 shifting tropism from airway to intestine

Abstract

Omicron has emerged into various sub-lineages. However, the immune landscape against Omicron variants masks their intrinsic phenotypes. We compared replication competence of SARS-CoV-2 variants from BA.1 to JN.1 in explants of human bronchus and lung. Cell entry routes, extrapulmonary infection and innate immune responses were assessed using human airway organoids and intestinal enteroids. BA.5, XBB.1.5 and EG.5.1 replicate to higher titres than BA.2.86 and JN.1 in bronchus and lung explants. Replication of BA.2.86 but not EG.5.1 is inhibited by TMPRSS2 inhibitor. Interestingly, BA.2.86 and JN.1 replicate to higher titres in intestinal enteroids than EG.5.1, which is not seen in colon cells and high expression of ACE2 is found in the intestinal epithelium. BA.5, XBB.1.5 and EG.5.1 intrinsically have higher potential for efficient transmission and causing more severe disease among all tested variants. Dual-pathway cell entry of EG.5.1 contributes to its lung tropism and pathogenicity over BA.2.86. We demonstrate that human airway organoids and intestinal enteroids are more clinically relevant models than cell lines for studying host cell entry and gut tropism, respectively. ACE2 binding affinity is associated with intestinal tropism rather than respiratory tropism. This study reveals the switching from respiratory to intestinal tropism of the BA.2.86 and JN.1.