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

doi:10.21203/rs.3.rs-4851361/v1

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

https://doi.org/10.21203/rs.3.rs-4851361/v1

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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.

Health sciences/Pathogenesis/Infection

Biological sciences/Microbiology/Virology/SARS-CoV-2

Biological sciences/Microbiology/Virology/Viral host response

Since the emergence of SARS-CoV-2 Omicron variants in November 2021, various descendent lineages including BA.5, XBB (XBB.1.5 and EG.5.1), BA.2 (BA.2.86 and JN.1) have subsequently appeared and replaced the precursor strains. These mutant variants are characterized by enhanced viral fitness and immune evasion, hence posing huge challenge to impede the transmission of COVID-19 ¹.

First reported in February 2023, EG.5 is a descendent lineage of XBB.1.9.2 with a spike protein F456L mutation. EG.5 and its sub-lineages including EG.5.1, which carries an additional spike protein mutation Q52H, were designated as a variant of interest (VOI) in August 2023 by WHO, and have been circulated worldwide as the major strains as of November 2023 ². EG.5.1 demonstrated an enhanced immune evasion from antibody neutralization, which was attributed to its spike protein F456L mutation ^3-5. The global prevalence of EG.5 variants was gradually outcompeted by the emergence of BA.2.86 and its sub-lineages including JN.1, which were subsequently classified as VOIs in November and December 2023 ⁶. BA.2.86 is a far descendant of the Omicron BA.2 lineage, and possesses 34 mutations in the spike protein relative to BA.2 and 36 mutations distinct from XBB.1.5 ⁷, whilst the JN.1 variant further carries a spike L455S mutation ⁸. Nonetheless, both BA.2.86 and JN.1 variants displayed unprecedented immune evasive ability to the humoral immunity elicited by pre-XBB breakthrough infections, the monovalent and BA.1/BA.5 bivalent vaccinations ^1,9-11 leading to their high estimated reproduction numbers ^11-13.

Various types of COVID-19 vaccines, number of vaccinations and repeated infections generate the complex landscape of neutralizing antibody levels and specificities of the community against Omicron variants making it difficult to evaluate the intrinsic phenotypes of the newly emerging SARS-CoV-2 variants solely based on clinical manifestations and epidemiological data.

Here, we used physiologically relevant models of ex-vivo explant cultures of the human respiratory tissues, human airway and intestinal organoids to evaluate the tissue tropism and viral replication of a number of dominant strains emerging between December 2021 and up to April 2024 including Omicron BA.1 to BA.5 (BA.1, BA.2, BA.4, BA.5), BA.2-lineage (BA.2.12.1, CH.1.1, BA.2.86 and JN.1), BA.5-lineage (BQ.1.22, BF.8) and XBB-lineage (XBB.1.5, XBB.1.16, XBB.1.9.1 and EG.5.1). The innate immune responses to the variants were studied in intestinal epithelium.

BA.5, XBB.1.5 and EG.5.1 replicate efficiently than BA.2.86 and JN.1 in human bronchial tissues

As shown in previous publication, the replication competence of viruses in the human bronchial tissues implies the transmissibility between humans. According to the emergence of Omicron variants, we first compared the virus replication of a number of Omicron BA variants (including BA.1, BA.2, BA.2.12.1, BA.4, BA.5 and BA.5.2.1) with wild-type (WT) strain as one batch, BA.5 together with several XBB variants, CH.1.1 and BQ.1.22 in another batch. Finally, we investigated the virus replication of EG.5.1, BA.2.86 and JN.1 in comparison with BA.5, XBB.1.16 and XBB.1.9.1 in the human ex-vivo cultures of bronchial tissues by quantitating infectious virus titres.

All BA variants replicated significantly to higher titres than WT at both 24 hpi and 48 hpi (Fig. 1a) and area-under-curve (AUC) values of all tested BA variants were significantly higher than that of WT (Fig. 1b). When comparing the XBB variants with BA.5, CH.1.1 and BQ.1.22, XBB.1.16 and XBB.1.9.1 had significantly lower titres than the other 4 variants (BA.5, XBB.1.5, CH.1.1 and BQ.1.22) at 24 hpi while BA.5, XBB.1.5 and BQ.1.22 had relatively higher titres than CH.1.1, XBB.1.16 and XBB.1.9.1 at 48 hpi (Fig. 1c). The AUC levels of BA.5, XBB.1.5 and BQ.1.22 show similar trends as the replication of 48 hpi, which were higher than that of CH.1.1, XBB.1.16 and XBB.1.9.1 (Fig. 1d). Direct comparison of EG.5.1, BA.2.86 and JN.1 demonstrates a similar replication competence of EG.5.1 to BA.5, which was significantly higher than that of BA.2.86, JN.1, XBB.1.16 and XBB.1.9.1 (Fig. 1e and 1f). Taken together the three batches of comparison, BA variants (BA.1, BA.2, BA.4, BA.5 and BA.5.2.1), XBB.1.5, BQ.1.22 and EG.5.1 demonstrated higher tropism in human bronchial tissues than the other tested variants including the currently dominated strains of BA.2.86 and JN.1, suggesting that these variants are able to transmit between humans more efficiently than the others.

BA.5, XBB.1.5 and EG.5.1 replicate efficiently than BA.2.86 and JN.1 in human lung tissues

In lung explants, WT replicated to the highest titres at 24 hpi, 48 hpi and 72 hpi than all the tested Omicron BA subvariants (Fig. 2a). We also observed that BA.2.12.1 replicated to lower titres than BA.5 at 24 and 72 hpi while lower than BA.5.2.1 at 48 and 72 hpi (Fig. 2a). The highest replication competence of WT was confirmed by the AUC level and both BA.5 and BA.5.2.1 had a significantly higher AUC levels than BA.1 and BA.2.12.1 (Fig. 2b). When comparing with XBB subvariants, BA.5 and XBB.1.5 replicated to higher titres than CH.1.1 at 48 and 72 hpi (Fig. 2c) while BA.5, XBB.1.5 and BQ.1.22 replicated to higher titres than XBB.1.9.1 at 72 hpi (Fig. 2c). AUC levels of BA.5 and XBB.1.5 confirmed the higher replication competence than CH.1.1 while XBB.1.5 had a higher AUC level than XBB.1.9.1 (Fig. 2d).

EG.5.1 consistently replicated to higher titres than BA.2.86 and JN.1 from 24 to 72 hpi (Fig. 2e). BA.2.86 replicated to lower titres than BA.5, XBB.1.16 and XBB.1.9.1 at 48 and 72 hpi while JN.1 had a lower titre than XBB.1.16 (Fig. 2e). Higher replication competence of EG.5.1, BA.5 and XBB.1.16 than BA.2.86 and JN.1 was confirmed by the AUC levels (Fig. 2f). Besides, EG.5.1 and BA.5 had a higher AUC level than XBB.1.9.1 (Fig. 2f). Taken together the findings on lung explants, WT has the highest replication competence in human lungs when compared to the Omicron subvariants. More importantly, among all the Omicron subvariants tested, BA.5, XBB.1.5, EG.5.1 and XBB.1.16 replicated to higher titres than BA.1, BA.2.12.1, CH.1.1, XBB.1.9.1, BA.2.86 and JN.1 while BQ.1.22 had the medium replication competence.

Cellular tropism of Omicron variants in human bronchial and lung tissues

Immunohistochemical staining of viral nucleoprotein shows that the subvariants had similar cellular tropism in the human bronchial and lung tissues (Fig. 3a and 3b). More cells stained with viral nucleocapsid protein were observed in Omicron BA subvariants (from BA.1, BA.2, BA.4, BA.5 and BF.8), XBB.1.5, BQ.1.22 and EG.5.1 than WT, BA.2.86 and JN.1 in human bronchial tissues while more positive cells were observed in BA.5, XBB.1.5, EG.5.1 and XBB.1.16 infection than the other variants in human lung tissues (Fig. 3). The extensiveness of viral protein staining was in concordance with the replication competence of the subvariants.

BA.2.86 but not EG.5.1 enters cell via TMPRSS2-dependent pathways in airway organoids

In order to investigate the preference of entry route of BA.2.86 and EG.5.1, we applied camostat (CAM) and E64d to inhibit the activities of TMPRSS2 and cathepsins, respectively in both Vero E6-T2 cells and human AO. In Vero E6-T2 cells, BA.2.86 replicated to lower titres in CAM-treated cells than vehicle- or E64d-treated cells at 24 hpi (Fig. 4a), but there were no significant differences of AUC values of BA.2.86 and EG.5.1 in the presence of CAM or E64d (Fig. 4b). In contrast, significant reduction of viral titres of BA.2.86 was observed in AO treated with CAM when compared to titres in AO treated with vehicle of E64d at both 24 and 48 hpi (Fig. 4c). The AUC levels of BA.2.86 dramatically reduced by the treatment of CAM while titres of EG.5.1 was reduced by CAM treatment at 24 hpi compared to vehicle and E64d treatment and a lesser extent of reduction of AUC levels was observed in AO infected with EG.5.1 in the presence of CAM (Fig. 4d).

BA.2.86 and JN.1 replicated efficiently in intestinal enteroids

The replication competence and immune responses of EG.5.1, BA.2.86 and JN.1 were compared in both human colorectal cancer (Caco-2) cells and tissue-derived intestinal enteroids. Infection of Caco-2 cells with EG.5.1, BA.2.86 and JN.1 showed that EG.5.1 replicated to the highest titres among the three at 48 hpi (Fig. 5a) and EG.5.1 had a higher AUC value than BA.2.86 and JN.1 (Fig. 5b). Similar to EG.5.1, XBB.1.5 replicated to higher titres than XBB.1.16, BA.2.86 and JN.1 at both 24, and 48 hpi (Fig. 5a). The AUC level of XBB.1.5 was significantly higher than XBB.1.16, BA.2.86 and JN.1 (Fig. 5b). Besides, EG.5.1 had the highest level of viral ORF1b gene expression (Fig. 5c). XBB.1.16 induced higher levels of proinflammatory cytokines and chemokines in Caco-2 cells except TNF-α and ACE2-L, than all the other tested viruses (Fig. 5d). EG.5.1 and XBB.1.5 induced similar and higher levels of cytokines and chemokines than BA.2.86 and JN.1, while only EG.5.1 induced higher TNF-α levels than XBB.1.5. Moreover, EG.5.1 infection led to the lowest level of ACE2-L among all the viruses tested.

In intestinal enteroids, BA.2.86 and JN.1 replicated to higher titres than EG.5.1 at 48 and 72 hpi, which was confirmed by the values of AUC and the IHC staining of viral protein (Fig. 6a and 6b). JN.1 infection led to higher mRNA expression of viral ORF1b gene than the other two viruses (Fig. 6c). However, BA.2.86 infection induced higher mRNA expression of IFN-β, IFN-λ1, IFN-λ2/3, IP-10, ISG15 and MDA5 than EG.5.1 and JN.1 infection, while BA.2.86 induced higher TNF-α expression than EG.5.1 (Fig. 6c).

The tropism of Omicron variants in the human intestinal enteroids were visualized through immunofluorescence staining of the SARS-CoV-2 nucleoprotein and different cell markers of intestinal enteroids, including cytosol lysozyme C (LYZ C) for Paneth cells, mucin-2 (Muc2) for goblet cells, and cell surface Villin for enterocytes (Fig. 6d). Co-localization of SARS-CoV-2 NP foci were observed in the Paneth cells and enterocytes under infections of EG.5.1, BA.2.86, and JN.1, while there was absence of goblet cell staining in JN.1-infected cells. The extent of cells with positive staining of viral protein by immunohistochemistry in the enteroids confirmed the replication competence of the subvariants in terms of AUC levels (Fig. 6e).

We detected higher mRNA expression of ACE2-L, but not TMPRSS2, in the intestinal enteroids than Caco-2 cells (Extended Data Fig. 1a). Through direct comparison of the cellular markers, the intestinal enteroids were characterized by elevated intestinal cell markers expression of lysozyme (LYZ), villin 1 (VIL1) and GATA binding protein 4 (GATA4) while Caco-2 cells had upregulated GATA binding protein 6 (GATA 6), which is expressed in colorectal epithelium (Extended Data Fig. 1b and 1c).

Vaccination and XBB breakthrough infection sera have lower neutralization titres against BA.2.86 than EG.5.1^11,12, while JN.1 has an even higher immune evasion ability than BA.2.86^10,13. The immune evasion properties may mask the intrinsic virological characteristics of EG.5.1, BA2.86 and JN.1 during human infection. Here in human respiratory explant cultures, the replication competence of EG.5.1 is much higher than that of BA.2.86 and JN.1 in human bronchus and lung tissues. This may be attributed by the ability of EG.5.1 but not BA.2.86 to enter cell via both plasma membrane and endocytosis pathways which were observed in our airway organoid (AO) experiments. BA.2.86, but not EG.5.1, is more sensitive to TMPRSS2 inhibitor treatment implying that cell entry of BA.2.86 is TMPRSS2-dependent in airway epithelium which is consistent with others report on TMPRSS2-dependent pathway of BA.2.86 in lung cells^7,20. In contrast, EG.5.1 enters airway cells via both plasma membrane and endocytosis pathways, and they compensate each other. The dual entry pathways suggest that EG.5.1 probably causes more severe infections and hence more severe diseases than BA.2.86. The elevated lung tropism of EG.5.1 was demonstrated by our ex vivo lung infection implying that this virus may cause more severe disease than BA.2.86 and JN.1. This finding is confirmed by a hamster study showing the lower pathogenicity of BA.2.86 and lower ability to breach the barriers between airway epithelium and endothelium than EG.5.1¹². Another important point is that there are discrepancies in the results performed in Vero E6-T2 cells and AO, which is a more physiologically relevant in vitro model, and our findings suggest that cell entry experiments of SARS-CoV-2 should not be done Vero E6-T2 cells, otherwise, interpretations may not reflect the situation in the human body. Since JN.1 is a close descendant virus of BA.2.86 and has only one additional mutation of spike protein Leu455Ser¹³, we speculate from our observations from inhibitor experiments in AO that JN.1 similar to BA.2.86 may use TMPRSS2-dependent route of cell entry and hence this may lead to less infection and severe diseases caused by JN.1 when compared to EG.5.1, which is consistent with our lung tropism findings.

A study found that the replication efficiency of BA.2.86 was similar to EG.5.1 in colon organoids¹². However, we observed a higher replication competence of EG.5.1 over BA.2.86 and JN.1 in human Caco-2 cells, which are colon epithelial cells. The discrepancies may lie in the differences of cell populations in the colon organoids and Caco-2 cells. While the colon organoids have more goblet cells, non-differentiated Caco-2 cells mainly comprise of colonocytes. Interestingly, BA.2.86 and JN.1, two BA.2 subvariants, replicated to significantly higher titres than EG.5.1 in intestinal enteroids. Clinical evidence showing that BA.2.86 and JN.1 have higher viral shedding in faecal samples when compared with EG.5.1 and XBB.1.5²¹ and BA.2.86 and JN.1 were detected in wastewater²², taken together with our enteroid findings suggest that the tropism and replication competence of SARS-CoV-2 in intestinal enteroids but not colon cells or colon organoids is associated with faecal viral shedding. Furthermore, our analysis of pro-inflammatory cytokines shows that JN.1 induced relatively lower levels than BA.2.86 and EG.5.1 in intestinal enteroids and colon epithelial cells (Caco-2 cells), respectively. These findings imply that there may not be severe digestive symptoms in the JN.1 infected patients and this probably promotes the spreading of virus via the faecal route. These observations are in concordance with the study that there was no observation of severe digestive illnesses from patients with JN.1 infection²¹.

Moreover, compared to EG.5.1, BA.2.86 and JN.1 replicated to higher titres in intestinal enteroids but lower titres in colon epithelial cells, bronchial and lung explant cultures. From the immunofluorescence staining, the cellular tropism between these BA.2 subvariants and EG.5.1 is comparable suggesting that their differential replication competence is not attributed by the cellular tropism. We found that the ACE2 long form, SARS-CoV-2 receptor, but not TMPRSS2 has a higher expression level in intestine enteroids than colon epithelial cells. BA.2.86 and JN.1 have a higher ACE2 binding affinity than EG.5.1 despite that JN.1 has a relatively lower ACE2 binding affinity than BA.2.86^1,13,23. These findings indicate that high ACE2 binding affinity may contribute to the intestine tropism rather than bronchial or lung tropism. More importantly, the higher transmission efficiency of BA.2.86 and JN.1 over EG.5.1, at least partly, is attributed by the higher replication competence in the human intestine but not in the colon, bronchial or lung tissues. Taken together, both clinical findings and our experimental evidence suggest that faecal shedding may play an important role for the spread of BA.2.86 and JN.1 and explain why BA.2.86 and JN.1 become predominant over EG.5.1 infection and subsequently JN.1 has a higher transmission rate than BA.2.86.

EG.5.1 exhibits a higher effective reproduction number compared with XBB.1.5, XBB.1.16, and its parental lineage (XBB.1.9.2)¹³. This may be partly attributed to the higher immune evading ability of EG.5.1 than XBB.1.5 and XBB.1.9.2²⁴, and EG.5.1 is more resistant to serum neutralization from BQ or XBB breakthrough infection than XBB.1.16³. We also compared a number of BA.1 to BA.5 variants and XBB subvariants side-by-side with BA.5 in human bronchi and lung tissues. Apart from the immune evasion, we found that like XBB.1.5, EG.5.1 replicated to higher titres in human bronchial and lung tissues than XBB.1.16 and XBB.1.9.1 indicating that EG.5.1 has growth advantage in the human respiratory tract, which contributes at least partially to the high prevalence over other XBB subvariants. Besides, EG.5.1 has similar lung tropism to BA.5 which is higher than that of BA.1 and BA.2 indicating that EG.5.1 gains replication fitness over BA.1 and BA.2. Reports showing that EG.5.1 and XBB.1.5 have similar growth kinetics and pathogenicity in hamsters and EG.5.1 is transmitted more efficiently between hamsters than BA.2²⁵ which are in line with our findings on their bronchial and lung tropism.

The upsurge of BA.5 over BA.1 and BA.2 may be partly due to the reduced neutralization titres against BA.5^26,27. However, we provide additional information of their infection in lung explants. BA.5 replicating to higher titres than BA.2-lineage (BA.2.12.1, CH.1.1, BA.2.86 and JN.1) indicating that BA.5 may cause more severe disease than BA.2 and its subvariants, which is in concordance to the higher hospitalization rates of BA.5 infected patients than that of BA.2 infected individuals¹². This may be attributed to the higher fusogenicity and enhanced ability to disrupt the respiratory epithelial and endothelial barriers leading to the observed higher in-vivo pathogenicity of BA.5 than BA.1 and BA.2^26,28.

In summary, taken all together our findings, BA.1 to BA.5 and BA.5.2.1 have similar and higher replication competences in the bronchial tissues than WT while BA.5-lineage (BA.5 and BA.5.2.1) has a higher replication efficiency than BA.1 and BA.2.12.1 but a lower replication than WT in lung tissues. BA.2 descendants (CH.1.1, BA.2.86 and JN.1) have a lower replication competence in bronchus and lung parenchyma than BA.5- and XBB-lineages while BA.5 descendants (BQ.1.22 and BA.5.2.1) maintain replication efficiency as the parental BA.5 virus. Certain XBB sub-variants (XBB.1.5 and EG.5.1) replicated to higher titres as BA.5 in bronchial tissues than BA.2-lineage except XBB.1.9.1, while XBB.1.5, XBB.1.16 and EG.5.1 have a higher replication competence than BA.2-lineage (CH.1.1, BA.2.86 and JN.1) in lung tissues.

Our findings indicate that BA.5 (BA.5 and BA.5.2.1) and certain XBB sub-variants (XBB.1.5 and EG.5.1) maintain the replication competence in human bronchial and lung tissues, which can promote virus spreading and may lead to more severe lung diseases. Furthermore, BA.2.86 and JN.1 (from the BA.2-lineage) although replicated to lower titres than BA.5 and EG.5.1 in respiratory tissues, they have a higher replication competence in human intestinal enteroids than EG.5.1 implying that these two viruses could transmit not only via respiratory tract but also via faecal-oral route.

Furthermore, we provide evidence demonstrating the ACE2 binding affinity of BA.2.86 and JN.1 is probably associated with the intestine tropism rather than bronchial or lung tropism. Airway organoid is a more appropriate model than Vero E6-T2 cells for SARS-CoV-2 host cell entry assay and intestine tropism is more physiologically relevant than colon tropism for studying the faecal route of virus dissemination.

SARS-CoV-2 variants can emerge from any previous lineages—BA.2.86 and JN.1 are derived from the BA.2-lineage which is a far variant of XBB-lineage. Since immune protection in the community wanes quickly after vaccination or infection, characterization and surveillance of emerging SARS-CoV-2 variants are essential to safeguard public health and help better prepare for the epidemic or pandemic especially for those variants that can cause severe lung diseases and transmit efficiently between humans.

Acknowledgements

The authors would like to thank Rachel Ching (School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China), Kevin Fung (Department of Pathology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China) and Martin CW Chan for technical support. The authors want to thank Ko-Yung Sit, Michael KY Hsin and Timmy WK Au for the provision of human tissues. This work was supported by grants from InnoHK, an initiative of the Innovation and Technology Commission, the Government of Hong Kong Special Administrative Region; Theme-Based Research Scheme (T11-705/21-N), University Grants Committee of Hong Kong Special Administrative Region and the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services (contract no. 75N93021C00016).

Authors’ contributions

KPYH: study design, coordination, analysis, interpretation of results and writing of the manuscript; JCWH, KCN, JCMC: perform experiments, analysis and interpretation of results; LLMP, MP: interpretation of results and critical review of the manuscript; JMN: analysis and interpretation of results, co-ordination of sample collection and critical review of the manuscript; MCWC: study design, overall coordination, interpretation of results and writing of the manuscript.

Conflict of interest

There is no conflict of interest for all authors.

Role of the funding source

The funders had no role in study design, data collection, analysis, or interpretation of the data, or in the writing of the report. The corresponding authors had full access to all the data and the final responsibility for the decision to submit for publication.

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

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Abstract

Figures

Introduction

Results

BA.5, XBB.1.5 and EG.5.1 replicate efficiently than BA.2.86 and JN.1 in human bronchial tissues

BA.5, XBB.1.5 and EG.5.1 replicate efficiently than BA.2.86 and JN.1 in human lung tissues

Cellular tropism of Omicron variants in human bronchial and lung tissues

BA.2.86 but not EG.5.1 enters cell via TMPRSS2-dependent pathways in airway organoids

BA.2.86 and JN.1 replicated efficiently in intestinal enteroids

Discussion

Declarations

References

Additional Declarations

Supplementary Files

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