Can We Beat SARS-CoV-2? Lessons From Other Coronaviruses

When news broke that a novel coronavirus SARS-CoV-2 had emerged, scientists like myself were grimly aware of how difficult this novel coronavirus would be to control. For context, my research focuses on engineering bacteriophages for use as therapeutics, whereby bacterial viruses (phages) are used to infect and lyse bacteria as a replacement for traditional antibiotics.¹ We recently discovered a bacteriophage that hijacks a bacterial quorum sensing (QS) autoinducer (AI) and uses the information encoded in it to drive transitions between lysis and lysogeny.^2,3 This eavesdropping mechanism occurs in pandemic Vibrio cholerae, and it allows the phage to execute its lytic cycle exclusively at high host cell density, as well as drive the host biofilm dispersal program. So here we have evidence that viruses can naturally mutate to mimic host biology so as to ensure successful viral propagation. This knowledge of viral evolution and divergence rates parallels that of coronaviruses which precede pandemic SARS-CoV-2, and could provide guidance when predicting the virulence of SARS-CoV-2 variants in eukaryotic hosts, as well as the potential of prophylactics or treatments.

Could an effective vaccine for SARS-CoV-2 be in the horizon? Since the emergence of SARS-CoV-1 in 2003, scientists had been warning of the possibility for long-term affliction by coronaviruses, whereby the advice was to design broad-spectrum antiviral drugs and vaccines against this viral cluster. While such a therapeutic has not yet been discovered, due to the similarity in structure and cellular entry receptor, some drugs and pre-clinical vaccines against SARS-CoV-1 could theoretically be used to treat SARS-CoV-2.⁴ However, there are 2 caveats to this approach: SARS-CoV-2 can mutate into a strain that the vaccine would not protect against, and SARS-CoV-1 vaccine candidates exhibited adverse side effects and even exacerbated symptoms upon viral challenge.

Knowing that viral genomes are notoriously pliable, I am wary in regard to the efficacy of prophylactics against SARS-CoV-2. Just by comparing phage and bacterial genomes among mammalian hosts, one can already appreciate how rapidly phages and bacteria co-evolve and shape one another’s biology.^5,6 Coronaviruses have certainly been shown to exhibit high frequency recombination events,^7,8 and favored high frequency recombination sites have been documented.⁷ For instance, sustained human MERS-CoV infections are the result of several seasonal viral challenges from camels into humans, resulting in at least 3 different MERS-CoV genomes.⁹

Recent studies indeed demonstrate that the optimized binding site and polybasic cleavage site of SARS-CoV-2 is the product of accumulated mutations in the receptor-binding domain, most likely from natural selection on a human or human-like angiotensin converting enzyme II (ACE2),^10,11 during passage via repeated silent zoonotic transfer.¹² A host of high frequency mutations have resulted in at least 5 differentiated SARS-CoV-2 strains to date,¹³ whereby the mutations are predicted to enhance viral entry into host cells,¹⁴ virulence and viral transmission.^15,16 Thus, with enough time and patient samples, lineage tracing of SARS-CoV-2 must first identify relatively unchanging viral proteins as suitable targets for prophylactic development.

Efforts to develop a SARS-CoV-1 vaccine have been thwarted in the past by antibody-dependent enhancement (ADE)-mediated vaccine-induced infection aggravation.^17,18 In ferrets, rMVA-S vaccines were successful in inducing a rapid memory immune response, which is an essential feature of an effective prophylactic; but, when these ferrets were challenged with SARS-CoV-1, they developed enhanced liver damage.^19,20 Likewise, in mice, SARS-CoV-1 vaccines utilizing either live SARS-CoV-1 or DNA-based S-protein were able to induce antibody formation and protection against SARS-CoV-1;^21,22 however, challenged mice exhibited Th2-type immunopathology suggesting hypersensitivity to SARS-CoV-1 components.²³ These results suggest that comprehensive evaluation of target SARS-CoV-2 signatures is required before vaccine trials ensue in humans, so as to prevent organ damage upon viral challenge. Specifically, scientists must identify different viral proteins or anti-Spike sera concentrations which would not induce ADE.

While bleak, the literature regarding historical coronavirus outbreaks appear to provide ample guidance as to how to design an effective SARS-CoV-2 vaccine. Aside from developing prophylactics, there must also be a focus on screening for antiviral compounds from synthetic and/or natural chemical libraries to improve patient recovery rates. Finding such compounds is especially important if SARS-CoV-2 continues to mutate rapidly and/or infected individuals only develop short-term immunity, in which case individuals would be susceptible to reacquiring the infection.

Overall, as a scientist engaged in the SARS-CoV-2 volunteer task force, I am optimistic and firmly believe that our collective prowess in mathematical modeling and artificial intelligence will help to arrive at solutions for medical prevention and/or intervention.

Sun is a postdoctoral research associate in molecular biology at Princeton University. She received her PhD in molecular, cellular, and developmental biology from Yale University.

References:

1. Lin, D. M.; Koskella, B.; Lin, H. C. Phage Therapy: An Alternative to Antibiotics in the Age of Multi-Drug Resistance. World J. Gastrointest. Pharmacol. Ther. 2017, 8 (3), 162. https://doi.org/10.4292/wjgpt.v8.i3.162.

2. Silpe, J. E.; Bassler, B. L. A Host-Produced Quorum-Sensing Autoinducer Controls a Phage Lysis-Lysogeny Decision. Cell 2019, 176 (1—2), 268-280.e13. https://doi.org/10.1016/j.cell.2018.10.059.

3. Silpe, J. E.; Bassler, B. L. Phage-Encoded LuxR-Type Receptors Responsive to Host-Produced Bacterial Quorum-Sensing Autoinducers. mBio 2019, 10 (2). https://doi.org/10.1128/mBio.00638-19.

4. Zhou, P.; Yang, X.-L.; Wang, X.-G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H.-R.; Zhu, Y.; Li, B.; Huang, C.-L.; Chen, H.-D.; Chen, J.; Luo, Y.; Guo, H.; Jiang, R.-D.; Liu, M.-Q.; Chen, Y.; Shen, X.-R.; Wang, X.; Zheng, X.-S.; Zhao, K.; Chen, Q.-J.; Deng, F.; Liu, L.-L.; Yan, B.; Zhan, F.-X.; Wang, Y.-Y.; Xiao, G.-F.; Shi, Z.-L. A Pneumonia Outbreak Associated with a New Coronavirus of Probable Bat Origin. Nature 2020, 579 (7798), 270—273. https://doi.org/10.1038/s41586-020-2012-7.

5. Scanlan, P. D. Bacteria—Bacteriophage Coevolution in the Human Gut: Implications for Microbial Diversity and Functionality. Trends Microbiol. 2017, 25 (8), 614—623. https://doi.org/10.1016/j.tim.2017.02.012.

6. Koskella, B.; Brockhurst, M. A. Bacteria—Phage Coevolution as a Driver of Ecological and Evolutionary Processes in Microbial Communities. Fems Microbiol. Rev. 2014, 38 (5), 916—931. https://doi.org/10.1111/1574-6976.12072.

7. Makino, S.; Keck, J. G.; Stohlman, S. A.; Lai, M. M. High-Frequency RNA Recombination of Murine Coronaviruses. J. Virol. 1986, 57 (3), 729—737.

8. Kottier, S. A.; Cavanagh, D.; Britton, P. Experimental Evidence of Recombination in Coronavirus Infectious Bronchitis Virus. Virology 1995, 213 (2), 569—580. https://doi.org/10.1006/viro.1995.0029.

9. Dudas, G.; Carvalho, L. M.; Rambaut, A.; Bedford, T. MERS-CoV Spillover at the Camel-Human Interface. eLife 2018, 7, e31257. https://doi.org/10.7554/eLife.31257.

10. Andersen, K. G.; Rambaut, A.; Lipkin, W. I.; Holmes, E. C.; Garry, R. F. The Proximal Origin of SARS-CoV-2. Nat. Med. 2020, 1—3. https://doi.org/10.1038/s41591-020-0820-9.

11. Wan, Y.; Shang, J.; Graham, R.; Baric, R. S.; Li, F. Receptor Recognition by the Novel Coronavirus from Wuhan: An Analysis Based on Decade-Long Structural Studies of SARS Coronavirus. J. Virol. 2020, 94 (7). https://doi.org/10.1128/JVI.00127-20.

12. Sheahan, T.; Rockx, B.; Donaldson, E.; Sims, A.; Pickles, R.; Corti, D.; Baric, R. Mechanisms of Zoonotic Severe Acute Respiratory Syndrome Coronavirus Host Range Expansion in Human Airway Epithelium. J. Virol. 2008, 82 (5), 2274—2285. https://doi.org/10.1128/JVI.02041-07.

13. Wang, M.; Li, M.; Ren, R.; Brave, A.; Werf, S. van der; Chen, E.-Q.; Zong, Z.; Li, W.; Ying, B. International Expansion of a Novel SARS-CoV-2 Mutant; preprint; Infectious Diseases (except HIV/AIDS), 2020. https://doi.org/10.1101/2020.03.15.20035204.

14. Letko, M.; Marzi, A.; Munster, V. Functional Assessment of Cell Entry and Receptor Usage for SARS-CoV-2 and Other Lineage B Betacoronaviruses. Nat. Microbiol. 2020, 1—8. https://doi.org/10.1038/s41564-020-0688-y.

15. Hamming, I.; Timens, W.; Bulthuis, M. L. C.; Lely, A. T.; Navis, G. J.; Goor, H. van. Tissue Distribution of ACE2 Protein, the Functional Receptor for SARS Coronavirus. A First Step in Understanding SARS Pathogenesis. J. Pathol. 2004, 203 (2), 631—637. https://doi.org/10.1002/path.1570.

16. Lu, G.; Wang, Q.; Gao, G. F. Bat-to-Human: Spike Features Determining ‘Host Jump’ of Coronaviruses SARS-CoV, MERS-CoV, and Beyond. Trends Microbiol. 2015, 23 (8), 468—478. https://doi.org/10.1016/j.tim.2015.06.003.

17. Yip, M. S.; Leung, N. H. L.; Cheung, C. Y.; Li, P. H.; Lee, H. H. Y.; Daëron, M.; Peiris, J. S. M.; Bruzzone, R.; Jaume, M. Antibody-Dependent Infection of Human Macrophages by Severe Acute Respiratory Syndrome Coronavirus. Virol. J. 2014, 11, 82. https://doi.org/10.1186/1743-422X-11-82.

18. Luo, F.; Liao, F.-L.; Wang, H.; Tang, H.-B.; Yang, Z.-Q.; Hou, W. Evaluation of Antibody-Dependent Enhancement of SARS-CoV Infection in Rhesus Macaques Immunized with an Inactivated SARS-CoV Vaccine. Virol. Sin. 2018, 33 (2), 201—204. https://doi.org/10.1007/s12250-018-0009-2.

19. Weingartl, H.; Czub, M.; Czub, S.; Neufeld, J.; Marszal, P.; Gren, J.; Smith, G.; Jones, S.; Proulx, R.; Deschambault, Y.; Grudeski, E.; Andonov, A.; He, R.; Li, Y.; Copps, J.; Grolla, A.; Dick, D.; Berry, J.; Ganske, S.; Manning, L.; Cao, J. Immunization with Modified Vaccinia Virus Ankara-Based Recombinant Vaccine against Severe Acute Respiratory Syndrome Is Associated with Enhanced Hepatitis in Ferrets. J. Virol. 2004, 78 (22), 12672—12676. https://doi.org/10.1128/JVI.78.22.12672-12676.2004.

20. Marshall, E.; Enserink, M. Caution Urged on SARS Vaccines. Science 2004, 303 (5660), 944—946. https://doi.org/10.1126/science.303.5660.944.

21. Subbarao, K.; McAuliffe, J.; Vogel, L.; Fahle, G.; Fischer, S.; Tatti, K.; Packard, M.; Shieh, W.-J.; Zaki, S.; Murphy, B. Prior Infection and Passive Transfer of Neutralizing Antibody Prevent Replication of Severe Acute Respiratory Syndrome Coronavirus in the Respiratory Tract of Mice. J. Virol. 2004, 78 (7), 3572—3577. https://doi.org/10.1128/jvi.78.7.3572-3577.2004.

22. Yang, Z.; Kong, W.; Huang, Y.; Roberts, A.; Murphy, B. R.; Subbarao, K.; Nabel, G. J. A DNA Vaccine Induces SARS Coronavirus Neutralization and Protective Immunity in Mice. Nature 2004, 428 (6982), 561—564. https://doi.org/10.1038/nature02463.

23. Tseng, C.-T.; Sbrana, E.; Iwata-Yoshikawa, N.; Newman, P. C.; Garron, T.; Atmar, R. L.; Peters, C. J.; Couch, R. B. Immunization with SARS Coronavirus Vaccines Leads to Pulmonary Immunopathology on Challenge with the SARS Virus. PLOS ONE 2012, 7 (4), e35421. https://doi.org/10.1371/journal.pone.0035421.