6COVID19 Virus h What are zoonotic viral diseases

6_COVID-19 Virus h. What are zoonotic viral diseases? What is “Spillover”, and how often and when has this happened? How can viruses jump species barriers and cause diseases in humans? i. What is a coronavirus? What is SARS-Co. V-19, and how is this virus different from other coronaviruses that cause disease in humans? 1

COVID-19 VIRUS A virus is not a disease; a disease is not a virus Virus Disease Rubeola Enveloped Measles Rubella virus (togavirus) Enveloped Rubella Varicella-zoster Enveloped Chickenpox Parvovirus B-19 Naked Fifth disease Noroviruses Naked Gastrointestinal disease HIV Enveloped AIDS SARS-Co. V-2 Enveloped COVID-19 Answer: no time! 2

SARS-Co. V-2 ORIGIN? MYTHS! SARS-Co. V-2 was engineered in a lab in China. Compared genome of different coronaviruses to SARS-Co. V-2 https: //www. nature. com/articles/s 41591 -020 -0820 -9 3

SARS-Co. V-2 ORIGIN? MYTHS! Mutations in the receptor binding area of the spike protein that binds ACE 2 receptor • The gene that builds the area of the spike protein is the most variable part of coronaviruses genomes • Key areas within the gene that make contact with the ACE 2 receptor on host cells varied • Computer simulations of these changes show that SAR-Co. V-2 do not allow the spike to bind to human cells very well • If the virus was deliberately engineered, changes would have been chosen to do the opposite Mutations in the area of spike that allows the virus to open and enter cells • Overall structure does not look like known coronaviruses but does look like viruses found in bats. These bat viruses cause no harm. • If the virus was deliberately engineered, it would have been constructed from a virus known to cause disease. https: //www. nature. com/articles/s 41591 -020 -0820 -9 4

SARS-Co. V-2 ORIGIN? MYTHS! SARS-Co. V-2 is the seventh coronavirus known to infect humans; SARS-Co. V, MERS-Co. V and SARS-Co. V-2 can cause severe disease, whereas HKU 1, NL 63, OC 43 and 229 E are associated with mild symptoms 6. Here we review what can be deduced about the origin of SARS-Co. V-2 from comparative analysis of genomic data. We offer a perspective on the notable features of the SARS-Co. V-2 genome and discuss scenarios by which they could have arisen. Our analyses clearly show that SARS-Co. V-2 is not a laboratory construct or a purposefully manipulated virus. https: //www. nature. com/articles/s 41591 -020 -0820 -9 5

SARS-Co. V-2 Natural origin! 1. Natural selection in an animal host before zoonotic transfer: Given the similarity of SARS-Co. V-2 to bat SARS-Co. V-like coronaviruses, it is likely that bats serve as reservoir hosts for its progenitor. 2. Natural selection in humans following zoonotic transfer: It is possible that a progenitor of SARS-Co. V-2 jumped into humans, acquiring the genomic features described above through adaptation during undetected human-to-human transmission. Once acquired, these adaptations would enable the pandemic to take off and produce a sufficiently large cluster of cases to trigger the surveillance system that detected it. https: //www. nature. com/articles/s 41591 -020 -0820 -9 6

SARS-Co. V-2 Natural Origin! SARS-Co. V-2 escaped from a lab in China. 7

SARS-Co. V-2 ORIGIN? ZOONOTIC VIRAL DISEASES AND SPILLOVER? 8

SARS-Co. V-2 ORIGIN? ZOONOTIC VIRAL DISEASES AND SPILLOVER? Coronaviruses are notoriously promiscuous. Bats host thousands of types without succumbing to illness, and the viruses have the potential to leap to new species. Sometimes they mutate along the way to adapt to their new host; sometimes they can make the leap without changing. 9

SARS-Co. V-2 ORIGIN? ZOONOTIC VIRAL DISEASES AND SPILLOVER? • • Science titled “Bats Are Natural Reservoirs of SARS-like Coronaviruses” “Hordes of deadly diseases are lurking in bats and sometimes jumping to people, ” New Scientist “Why Bats Are Such Good Hosts for Ebola and Other Deadly Diseases, ” Wired National Public Radio report called “Why Killer Viruses Are On The Rise” portrays bats as “arguably one of the most dangerous animals in the world, ” 10

SARS-Co. V-2 ORIGIN? ZOONOTIC VIRAL DISEASES AND SPILLOVER? a social media game of broken telephone ensued. People grabbed the video and reposted it with their own captions, draining it of context and—perhaps inadvertently—twisting the message. The story transformed: Sandra started washing her hands, it was said, because she saw her keepers doing so repeatedly during the COVID-19 crisis. 11

SARS-Co. V-2 ORIGIN? ZOONOTIC VIRAL DISEASES AND SPILLOVER? What is the harm from fake stories like these? 12

SARS-Co. V-2 ORIGIN? ZOONOTIC VIRAL DISEASES AND SPILLOVER? In total, the evidence that bats are the source of emerging viral diseases is weak. The human toll of those diseases is minor relative to other infectious diseases, and public health measures to protect against any limited health threat from bats are simple, cheap, and proven. At the same time, there is rapidly growing documentation that bats are worth billions of dollars annually to human economies and that their loss can threaten the health of whole ecosystems upon which we depend. 13

Coronaviruses 4 groups: Alphacoronavirus: 229 E, NL 63, OC 43 Betacoronavirus: HKU 1, SARS-Co. V, MERS-Co. V, SARS-Co. V-2 Gammacoronavirus: no human infections Deltacoronavirus: no human infections 14 https: //www. nature. com/articles/s 41433 -020 -0790 -7/figures/1

Common human coronaviruses Mild to moderate upper-respiratory tract illness • Alphacoronavirus: 229 E, NL 63, OC 43 • Betacoronavirus: HKU 1 15

Coronovirus Transmission Respiratory droplets 16

Coronovirus Transmission Respiratory droplets Fomite Transmission 17

Virion Structure Why are envelopes important? Enveloped viruses are more “fragile” than naked viruses Respiratory Transmission Fomite transmission 18

Coronovirus Transmission Why does soap work so well on enveloped viruses? Polar: have a charge, bind to other things with a charge like water Nonpolar: no charge, bind to other things without a charge like lipids (Fats) 19

Coronovirus Transmission Why does soap work so well on enveloped viruses? Polar: have a charge, bind to other things with a charge like water Nonpolar: no charge, bind to other things without a charge like lipids (Fats) 20

Coronovirus Transmission Why does soap work better than hand sanitizers? https: //www. businessinsider. com/coronavirus-photos-why-you-should-wash-hands-with-soap-water-2020 -3 21

Coronaviruses 22 https: //www. nature. com/articles/s 41433 -020 -0790 -7/figures/1

Receptor recognition pattern of coronaviruses. Angiotensin Converting Enzyme Receptor 2 Fang Li J. Virol. 2015; doi: 10. 1128/JVI. 02615 -14 23

SARS Co. V-2 Entry into host cell depends on ACE-2 receptor and TMPRSS 2 1. 2. 3. 4. 5. 6. Spike protein recognizes and binds to ACE-2 receptor This associates with TMPRSS 2 (Transmembrane protease, serine 2 enzyme that cuts proteins TMPRSS 2 binds to complex of spike protein and ACE-2 receptor Activates spike protein Viral envelope fuses to host cell membrane Virus enters cell 24 https: //www. mdpi. com/2076 -0817/9/3/231/htm#

SARS Co. V-2 Why are we discussing this? • What if you could block the spike to ACE-2 R binding? • What if you could block the activity of TMPRSS 2? 25 https: //www. mdpi. com/2076 -0817/9/3/231/htm#

SARS Co. V-2 Why are we discussing this? https: //www. nejm. org/doi/full/10. 1056/NEJMsr 2005760 • What if you could block the spike to ACE-2 R binding? • ACE-2 R does more then just serve as ligand for spike protein! After virus enters cell, ACE 2 R decreases ACE 2 R normal role is to stop formation of Angiotensin II which does all of this 26

SARS Co. V-2 Why are we discussing this? • What if you could block the activity of TMPRSS 2? SARS-Co. V-2 Cell Entry Depends on ACE 2 and TMPRSS 2 and Is Blocked by a Clinically Proven Protease Inhibitor Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder, Nadine Krüger, Tanja Herrler, Sandra Erichsen, Tobias S. Schiergens, Georg Herrler, Nai-Huei Wu, Andreas Nitsche, Marcel A. Müller, Christian Drosten, Stefan Pöhlmann Cell Volume 181 Issue 2 Pages 271 -280. e 8 (April 2020) DOI: 10. 1016/j. cell. 2020. 02. 052 Done in human cells, not in humans!!!! 27

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SARS Co. V-2 Evolution 29

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