The world of coronaviruses
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The world of coronaviruses
- 1. The world of coronaviruses John W. A. Rossen LMMI Isala, Zwolle, The Netherlands Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, Groningen, The Netherlands Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, USA
- 2. Disclosure of speaker’s interests (Potential) conflict of interest Expert advisor of IDbyDNA Potentially relevant company relationships in connection with event Expert advisor of IDbyDNA Sponsorship or research funding National and EU-grants (H2020, InterregVA)
- 3. Coronaviruses - history Fields Virology 6th edition; 1Wertheim JO, Chu DK, Peiris JS, Kosakovsky Pond SL, Poon LL (June 2013). "A case for the ancient origin of coronaviruses". Journal of Virology. 87 (12): 7039–45. doi:10.1128/JVI.03273-12. PMC 3676139. PMID 23596293. • enveloped RNA viruses • humans, other mammals, and birds • first described early 1930s as causative agent of: • infectious bronchitis in chickens, • transmissible gastroenteritis in pigs • severe hepatitis and neurologic diseases in mice • Named after their appearance: halo of spikes (solar corona) • The most recent common ancestor (MRCA) of all coronaviruses: 8000 BCE1 • Implying long term coevolution with bat and avian species
- 4. Coronaviridae - taxonomy Fields Virology 6th edition • coronaviruses studied because • causing economically significant respiratory and gastrointestinal diseases in domestic animals • providing unique models for viral pathogenesis • in humans: • two coronaviruses responsible for substantial fraction of common colds • expression of downstream genes via transcription of multiple 3’ nested subgenomic messenger RNAs (mRNAs) Latin nido = “nest”
- 5. Coronaviruses Fields Virology 6th edition • since the 2002 - 2004 SARS epidemic molecular surveillance • most members previously unknown coronaviruses • most identified in bats in Asia but also in Africa, Europe, and North and South America • include likely predecessors of SARS-CoV • birds also proven to be a rich source of new viruses • bats and birds ideally suited as reservoirs for incubation and evolution of coronaviruses fly, roost and flock
- 6. • serology: not circulated to a significant extent in humans prior to the outbreak in 2002– 2003 • some persons working in wild animal wet markets in China serologic evidence of a SARS-CoV–like infection before the 2003 outbreak no SARS-like respiratory illness • outbreak occurring only when a confluence of factors facilitated spread into larger populations • animals original source but global spread by human-to-human transmission SARS-CoV-1 Fields Virology 6th edition
- 7. SARS-CoV-1 Fields Virology 6th edition / WikiPedia
- 8. Coronaviruses - transmission Trends in Immunology 2020 411100-1115DOI: (10.1016/j.it.2020.10.004)
- 9. “New” human coronaviruses Fields Virology 6th edition • HCoV-NL63 and HCoV-HKU1 only discovered recently (post-SARS-CoV-1) • Worldwide prevalence and has been in circulation for a long time • HCoV-NL63 displays homology with HCoV-229E • Phylogenetic analyses: HCoV-NL63 and HCoV-229E diverged approximately 1,000 years ago • Unlike HCoV-229E, HCoV-NL63 does not use human aminopeptidase N as a receptor • Infection of cells is mediated by ACE2, the same molecule that is used by SARS- CoV, an unrelated betacoronavirus
- 10. IDbyDNA, Inc. Confidential. 2020 Microbiology of SARS-CoV-2 Zhou et al. Nature. 2020 Zhou et al. Nature. 2020 https://www.niaid.nih.gov/news- events/novel-coronavirus-sarscov2-images ■+sense RNA virus: 29,811bp ■distinctive spike (S) protein ■SARS-CoV-2: beta-coronavirus ■related to known bat CoV
- 11. Why is SARS-CoV-2 more infectious than SARS-CoV-1? • SARS-CoV-2 has a higher reproductive number (R0) than SARS-CoV-1, indicating much more efficient spread • R0 is defined as the average number of new cases of an infection caused by one typical infected individual, in a population consisting of susceptible individuals only • An R0 of less than 1 indicates the infection will die out “eventually.” An R0 of greater than 1 indicates the infection has the potential for sustained transmission
- 12. Why is SARS-CoV-2 more infectious than SARS-CoV-1? Fields Virology 6th edition • SARS-CoV-2 has a higher reproductive number (R0) than SARS-CoV-1, indicating much more efficient spread • R0 is defined as the average number of new cases of an infection caused by one typical infected individual, in a population consisting of susceptible individuals only • An R0 of less than 1 indicates the infection will die out “eventually.” An R0 of greater than 1 indicates the infection has the potential for sustained transmission • SARS-CoV-2 has structural differences in its surface proteins enabling stronger binding to the ACE 2 receptor • SARS-CoV-2 has greater efficiency at invading host cells • SARS-CoV-2 also has greater affinity (or bonding) for the upper respiratory tract and conjunctiva, thus can infect the upper respiratory tract and can conduct airways more easily
- 14. Coronaviruses – the S(pike) protein Fields Virology 6th edition In many beta- and gamma-coronaviruses the S protein is partially or completely cleaved by a furin-like host cell protease into two polypeptides, denoted S1 and S2 S1 domain is extremely variable, very low homology across the three genera and often diverging extensively among different isolates of a single coronavirus S2 domain is highly conserved considered a potential antiviral target Receptor SARS-CoV and SARS-CoV-2 is angiotensin-converting enzyme 2 (ACE2), structural features of SARS-CoV-2 receptor binding domain increase its ACE2-binding affinity The final jump of SARS-CoV from palm civets to human hosts was caused by only two mutations in the RBD of the civet SARS-CoV S protein to gain the ability to productively bind human ACE2 ACE2 is a cell-surface, zinc-binding carboxypeptidase involved in regulation of cardiac function and blood pressure ACE2 is expressed in epithelial cells of the lung and the small intestine, which are the primary targets of SARS-CoV, as well as in heart, kidney, and other tissues
- 16. Disease Fields Virology 6th edition Human coronaviruses (HCoVs), the alphacoronaviruses HCoV-229E and HCoV-NL63, and the betacoronaviruses HCoV-OC43, and HCoV-HKU1, typically cause common colds Can also cause lower respiratory tract infections and have more serious consequences in the young, the elderly, and immunocompromised HCoV-NL63 is strongly associated with childhood croup Most severe HCoV-HKU1, -OC43, and -229E infections are manifest in patients with other underlying illnesses
- 17. Trends in Immunology 2020 411100-1115DOI: (10.1016/j.it.2020.10.004) SARS-CoV-2 symptoms
- 18. Trends in Immunology 2020 411100-1115DOI: (10.1016/j.it.2020.10.004) SARS-CoV-2 incubation time BMJ2020;371:m3862, http://dx.doi.org/10.1136/bmj.m3862 A small study by the Centers for Disease Control: • omicron’s incubation 1 day shorter than delta’s (3 vs 4 days) • incubation of the original COVID-19 even longer (~5 days)
- 19. • SARS-CoV 1º infects epithelial cells • Mechanism of lung injury unknown • Viral titers ↓ as severe disease ↑ • Rodent adapted SARS-CoV strains show similar clinical features to the human disease • Increased levels proinflammatory cytokines and reduced T-cell responses • Possible immunopathological mechanism of disease Fehr Methods Mol Bio 2016; Hui Post Grad Med J 2004; Rodriguez-Morales AJ. Travel Med and Infect Dis. 2019 Pathogenesis SARS-CoV
- 21. Mechanisms underlying the diverse clinical outcomes • host factors such as older age, male sex, and underlying medical conditions • virus-related (viral load kinetics) • potential cross-reactive immune memory from previous exposure to seasonal coronaviruses • host-immune response • sex-related differences in immune response • men had higher plasma innate immune cytokines and chemokines at baseline than women • women had notably more robust T cell activation than men • among male participants T cell activation declined with age • adaptive immune response may be important in defining the clinical outcome • both the innate and adaptive arms of the immune response are required for successful virus clearance BMJ2020;371:m3862, http://dx.doi.org/10.1136/bmj.m3862
- 22. Immune evasion Fields Virology 6th edition Coronaviruses use several approaches, both active and passive, to evade the host IFN response and thereby establish a productive infection
- 24. • whole genome sequencing in 7,491 critically-ill cases compared with 48,400 controls • 16 new independent associations, including variants within genes involved in” • interferon signalling (IL10RB, PLSCR1) • leucocyte differentiation (BCL11A) • blood type antigen secretor status (FUT2) • using transcriptome-wide association to infer the effect of gene expression on disease severity: • evidence implicating multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease • at least two distinct mechanisms can predispose to life-threatening disease: • failure to control viral replication • an enhanced tendency towards pulmonary inflammation and intravascular coagulation Host factors
- 25. Anti-corona
- 26. Keeping in mind Fields Virology 6th edition • coronaviruses have the ability to cross species • coronaviruses readily undergo recombination • recombination events between canine (CCoV-I) and feline (FeCoV-I) coronaviruses and an unknown coronavirus resulted in the appearance of two novel viruses (CCoV-II and FeCoV-II) • this propensity for recombination has raised concerns about the use of live- attenuated coronavirus vaccines • in general, live attenuated vaccines are likely to be most effective in inducing protective immune responses against coronaviruses
- 27. Coronavirus and vaccines before 2020 Fields Virology 6th edition • development of live coronavirus vaccines is challenging • often natural infection does not prevent either subsequent infection or disease • an effective vaccine would need to be superior to immunity induced naturally • genetic and antigenic variability of coronaviruses and their ability to readily recombine hinder vaccine development • no equal protection from all antigenic variants, and subsequent recombination with vaccine strains could increase the number of different strains circulating in the wild • recombinants of IBV vaccine strains with virulent wild-type strains have caused disease outbreaks in chicken locks • immunization with an S protein–expressing FIPV vaccine led to more severe disease after subsequent natural infection • concern that other coronavirus vaccines might also enhance, rather than protect, from disease
- 28. Antibody dependent enhancement Nature Microbiology volume 5, pages1185–1191(2020)
- 29. Antibody dependent enhancement Fields Virology 6th edition • macrophage-tropic viruses (dengue virus and FIP), non-neutralizing or sub-neutralizing antibodies increased viral infection of monocytes or macrophages more severe disease • non-macrophage-tropic respiratory viruses (RSV and measles), non-neutralizing antibodies form immune complexes with viral antigens secretion of pro-inflammatory cytokines, immune cell recruitment and activation of the complement • human macrophage infection by SARS-CoV-2 is unproductive • currently no evidence for ADE in human COVID-19 pathology • reduce the risks of ADE induction or delivery of high doses of potent neutralizing antibodies, rather than lower concentrations of non-neutralizing antibodies that would be more likely to cause ADE
- 31. https://www.nytimes.com/interactive/2020/science/coronavirus-drugs-treatments.html Coronavirus Drugs
- 32. Why your GP advice aspirin against common cold
- 33. Why your GP advice aspirin against common cold
- 34. Coronaviruses variants https://www.nytimes.com/interactive/2021/health/coronavirus-variant-tracker.html • during replication errors are made during replication • often results in ”less fit” virus • sometimes beneficial (e.g., cross species barrier) • coronaviruses have a proofreading RNA-dependent RNA-polymerase • mutation rates lower than for other RNA viruses • not enough to prevent these mutations from accumulating • as the novel coronavirus ran amok around the world, it was inevitable that a range of variants would arise • for SARS-CoV-2, scientists estimate that one mutation becomes established in the population every 11 days or so https://www.nytimes.com/interactive/2021/health/coronavirus-variant-tracker.html
- 35. • Mutations that give rise to functional variants are further divided into higher order phylogenetic lineages and clades • Currently, three nomenclature systems are being used: • the GISAID (Global Initiative on Sharing All Influenza Data) • Nextstrain • Pango • Variants are also classified by the WHO and CDC into different categories based on their phenotype Coronaviruses variants
- 36. https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/ Variants of interest (VOI) • with genetic changes that are predicted or known to affect virus characteristics such as transmissibility, disease severity, immune escape, diagnostic or therapeutic escape; AND • Identified to cause significant community transmission or multiple COVID-19 clusters, in multiple countries with increasing relative prevalence alongside increasing number of cases over time, or other apparent epidemiological impacts to suggest an emerging risk to global public health.
- 37. https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/ Variants of Concern (VOC) A SARS-CoV-2 VOI and, through a comparative assessment, has been demonstrated to be associated with one or more of the following changes at a degree of global public health significance: •Increase in transmissibility or detrimental change in COVID-19 epidemiology; OR •Increase in virulence or change in clinical disease presentation; OR •Decrease in effectiveness of public health and social measures or available diagnostics, vaccines, therapeutics.
- 39. https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/ Coronaviruses variants Monday, 7th March 2022, 4:39 pm
- 41. 41 1. Evolution by Point Mutations (background mutation rate of 2.9–3.7 x 10-6/nt/replication cycle for SARS-CoV-2; 4–5 times higher for Spike gene) a. Point mutations increasing replication, transmissibility, and even lead to immune escape b. Feline CoV mutated to a lethal form named feline infectious peritonitis virus (FIPV) by a few point mutations in the C-terminal part of the Spike gene affect cell entry and cause a change in cell tropism, from enteric epithelia to macrophages 2. Evolution by Insertions/Deletions escape from neutralizing antibodies or even T-cell immunity 3. Evolution by Recombination a. Evolution by intratypic homologous recombination b. Evolution by intertypic homologous recombination c. Evolution by non-homologous recombination among CoVs and with other Taxa The future of SARS-CoV-2 Viruses 2022, 14, 78. https://doi.org/10.3390/v14010078
- 42. Viruses 2022, 14, 78. https://doi.org/10.3390/v14010078
- 43. Do we get rid of SARS-CoV-2? Fields Virology 6th edition • HCoV-OC43, HCoV-229E, HCoV-NL63, and HCoV-HKU1—are endemic in human populations • HCoV-OC43 and HCoV-229E cause up to 30% of all upper respiratory tract infections • The high rate of HCoV infections early in life and the pattern of infections during outbreaks demonstrate that HCoVs are efficiently transmitted in human populations • Serologic studies suggest that infection with HCoV-229E and HCoVOC43 frequently occurs in young children and then repeatedly throughout life • Neutralizing antibodies against HCoV-OC43 or HCoV-229E have been detected in about 50% of school-age children and up to 80% of adults • The SARS-CoV-1 outbreak was partly controlled using quarantining, and the lack of efficient spread contributed to the success of this approach
Notes de l'éditeur
- For SARS-CoV-2, various modes of transmission have been proposed, including aerosol, surface contamination, and the fecal–oral route, representing confounding factors in the current COVID-19 pandemic; thus, their relative importance is still being investigated (Figure 2) [57]. Aerosol transmission (spread >1 m) was implicated in the Amoy Gardens outbreak during the SARS epidemic, but the inconsistency of these findings in other settings suggested that SARS-CoV was an opportunistic airborne infection [43,58]. Similarly, no infectious SARS-CoV-2 virions have been isolated, although viral RNA was detectable in the air of COVID-19 hospital wards [59]. Generation of experimental aerosols carrying SARS-CoV-2 (comparable to those that might be generated by humans) have offered the plausibility of airborne transmission, but the aerodynamic characteristics of SARS-CoV-2 during a natural course of infection is still an area of intense inquiry [60]. Nonetheless, deposition of virus-laden aerosols might contaminate objects (e.g., fomites) and contribute to human transmission events [59,61]. Finally, fecal–oral transmission has also been considered as a potential route of human spread, but remains an enigma despite evidence of RNA-laden aerosols being found nearby toilet bowls, along with detectable SARS-CoV-2 RNA in rectal swabs during the precursor epidemic of COVID-19 in China [41,59,62].
- Remarkably, ACE2 also serves as the receptor for the alphacoronavirus HCoV-NL63,219 and the corresponding structural complex for that virus reveals that the HCoV-NL63 RBD and the SARS-CoV RBD bind to the same motifs. Because the SARS-CoV and HCoVNL63 RBDs have neither sequence nor structural homology, this finding strongly supports the notion that they have independently evolved to bind to the same hotspot on the ACE2 surface
- SARS-CoV primarily infects epithelial cells within the lung. The virus is capable of entering macrophages and dendritic cells but only leads to an abortive infection [87,88]. Despite this, infection of these cell types may be important in inducing pro-inflammatory cytokines that may contribute to disease [89]. In fact, many cytokines and chemokines are produced by these cell types and are elevated in the serum of SARS-CoV infected patients [90]. The exact mechanism of lung injury and cause of severe disease in humans remains undetermined. Viral titers seem to diminish when severe disease develops in both humans Fehr and Perlman Page 9 Methods Mol Biol. Author manuscript; available in PMC 2016 January 01. Author Manuscript Author Manuscript Author Manuscript Author Manuscript and in several animal models of the disease. Furthermore, animals infected with rodentadapted SARS-CoV strains show similar clinical features to the human disease, including an age-dependent increase in disease severity [91]. These animals also show increased levels proinflammatory cytokines and reduced T-cell responses, suggesting a possible immunopathological mechanism of disease [92,93].
- Following inhalation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the respiratory tract, the virus traverses deep into the lower lung, where it infects a range of cells, including alveolar airway epithelial cells, vascular endothelial cells, and alveolar macrophages. Upon entry, SARS-CoV-2 is likely detected by cytosolic innate immune sensors, as well as endosomal toll-like receptors (TLRs) that signal downstream to produce type-I/III interferons (IFNs) and proinflammatory mediators. The high concentration of inflammatory cytokines/chemokines amplifies the destructive tissue damage via endothelial dysfunction and vasodilation, allowing the recruitment of immune cells, in this case, macrophages and neutrophils. Vascular leakage and compromised barrier function promote endotheliitis and lung edema, limiting gas exchange that then facilitates a hypoxic environment, leading to respiratory/organ failure. The inflammatory milieu induces endothelial cells to upregulate leukocyte adhesion molecules, thereby promoting the accumulation of immune cells that may also contribute to the rapid progression of respiratory failure. Hyperinflammation in the lung further induces transcriptional changes in macrophages and neutrophils that perpetuate tissue damage that ultimately leads to irreversible lung damage. Recent evidence suggests that systemic inflammation induces long-term sequela in heart tissues Abbreviations: BALF, bronchoalveolar lavage fluid; IRF3, interferon regulatory factor 3; NF-κB, nuclear factor-κB; RIG-I, retinoic acid-inducible gene I; STAT1/2, signal transducer and activator of transcription 1/2; STING, Stimulator of interferon genes. Figure generated with BioRender.
- a, For macrophage-tropic viruses such as dengue virus and FIPV, non-neutralizing or sub-neutralizing antibodies cause increased viral infection of monocytes or macrophages via FcγRIIa-mediated endocytosis, resulting in more severe disease. b, For non-macrophage-tropic respiratory viruses such as RSV and measles, non-neutralizing antibodies can form immune complexes with viral antigens inside airway tissues, resulting in the secretion of pro-inflammatory cytokines, immune cell recruitment and activation of the complement cascade within lung tissue. The ensuing inflammation can lead to airway obstruction and can cause acute respiratory distress syndrome in severe cases. COVID-19 immunopathology studies are still ongoing and the latest available data suggest that human macrophage infection by SARS-CoV-2 is unproductive. Existing evidence suggests that immune complex formation, complement deposition and local immune activation present the most likely ADE mechanisms in COVID-19 immunopathology. Figure created using
- Figure 1. Five scenarios for the future evolutionary trajectory of SARS-CoV-2. (A) Scenario 1: structural constraints limit any further evolution of the SARS-CoV-2 spike; Scenario 2a: point mutations, insertions/deletions, and/or intra-SARS-CoV-2 recombination events lead to the evolution of novel SARS-CoV-2 strains. (B) Scenario 2b: intra-SARS-CoV-2 recombination events lead to the evolution of novel SARS-CoV-2 strains. (C) Scenario 3a: intratypic recombinations between SARS-CoV-2 and closely related sarbecoviruses. (D) Scenario 3b: intratypic recombinations between SARS-CoV-2 and other related sarbecoviruses. (E) Scenario 4: intertypic recombination between SARS-CoV-2 and viruses from other Beta-CoV subgenera. (F) Scenario 5: non-homologous recombination of SARS-CoV-2 with other coronaviruses or even other viruses/hosts.