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Modus Operandi of Covid-19–Does It Reflect Genetic Engineering?

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COMMENT: An inter­est­ing piece in “The Atlantic” describes how the SARS-CoV­‑2 virus that caus­es COVID-19 dif­fers from oth­er coro­n­avirus­es known to infect humans. We present this as sup­ple­men­tal to dis­cus­sion of DARPA research into bat-borne coro­n­avirus­es.

  1. The SARS-CoV­‑2 (Covid-19) virus is unusu­al in that it infects both the upper and low­er res­pi­ra­to­ry tracts. The ‘spike’ part of the SARS-CoV­‑2 virus is unusu­al­ly good at latch­ing into a pro­tein called ACE2 which is found on the exte­ri­or of the cells in human air­ways. This abil­i­ty appears to be fun­da­men­tal to the virus’s abil­i­ty to infect the upper res­pi­ra­to­ry tract. The virus appears to infect the upper air­ways first and then, as cells in them die and are sloughed off, it makes its way down to the low­er res­pi­ra­to­ry tract and lungs where the dead­ly infec­tions occur. This sequen­tial pat­tern of infect­ing the upper res­pi­ra­to­ry tract pri­or to mak­ing its way down to the lungs enables it to silent­ly spread asymp­to­mati­cal­ly before turn­ing more lethal in the low­er res­pi­ra­to­ry tract.
  2. We note that the ACE2 pro­tein appears to man­i­fest more heav­i­ly in the lung tis­sue of  East-Asians. As indi­cat­ed in the Whit­ney Webb arti­cle, genet­ic mod­i­fi­ca­tion has been envi­sioned as applic­a­ble to bio­log­i­cal war­fare to cre­ate “eth­no-spe­cif­ic” bio­log­i­cal weapons.
  3. Anoth­er key fea­ture of the virus’s abil­i­ty to infect humans con­cerns a pro­tein bridge con­nect­ing two halves of the virus’s spike. Acti­va­tion of this spike caus­es the virus injects its nucle­ic acid into the cell. Acti­vat­ing the spike requires the cleav­age of a pro­tein bridge con­nect­ing the two halves of the spike. That cleav­age is pre­cip­i­tat­ed by the enzyme furin which is ubiq­ui­tous in human cells. In con­trast, the coro­n­avirus which caused SARS had a pro­tein bridge that was less like­ly to be cleaved. SARS-CoV­‑2 first latch­es onto to human upper air­way cells and, once there, has the pro­tein bridge link­ing the halves of the spike sev­ered by the furin enzyme.
  4. Per­haps the most notable obser­va­tion made about this virus thus far: it doesn’t appear to be mutat­ing in evo­lu­tion­ar­i­ly sig­nif­i­cant ways. Of the 100-plus muta­tions observed in the virus so far, none has emerged as evo­lu­tion­ar­i­ly dominant–unusual for a virus that only recent­ly jumped to humans. and has spread pro­lif­i­cal­ly. It’s as though the virus is already evo­lu­tion­ar­i­ly opti­mized for spread­ing among humans and there are no ‘gain-of-fuc­tion’ muta­tions left for it acquire. As Lisa Gralin­s­ki, a coro­n­avirus expert at the Uni­ver­si­ty of North Car­oli­na Chapel Hill, described it, “The virus has been remark­ably sta­ble giv­en how much trans­mis­sion we’ve seen . . . . there’s no evo­lu­tion­ary pres­sure on the virus to trans­mit bet­ter. It’s doing a great job of spread­ing around the world right now.”
  5.  Gralin­sky works close­ly with Ralph Baric’s lab. Recall that Bar­ic is the researcher who con­struct­ed a chimeric virus out of a SARS virus and horse­shoe bat coro­n­avirus in 2015. When Gralin­s­ki observes that the virus wouldn’t feel any evo­lu­tion­ary pres­sure to spread because it’s already doing such a good job that is VERY sig­nif­i­cant. Evo­lu­tion doesn’t stop just because the sta­tus quo of an organ­ism is already effec­tive. A muta­tion allow­ing the virus to spread even more read­i­ly would be expect­ed. And nor­mal­ly such an event does hap­pen. But it hasn’t hap­pened so for SARS-CoV­‑2 because it is already at some­thing of a “coro­n­avirus evo­lu­tion­ary peak”.

In addi­tion, an arti­cle in Sci­ence Direct char­ac­ter­izes the advent of the furin-like cleav­age site as a “gain-of-func­tion” phe­nom­e­non. “Gain of Func­tion” is a mech­a­nism of action of an “Enhanced Poten­tial Pan­dem­ic Pathogen.” “. . . . Strik­ing­ly, the 2019-nCoV S‑protein sequence con­tains 12 addi­tion­al nucleotides upstream of the sin­gle Arg↓ cleav­age site 1 (Fig. 1, Fig. 2) lead­ing to a pre­dic­tive­ly sol­vent-exposed PRRAR↓SV sequence, which cor­re­sponds to a canon­i­cal furin-like cleav­age site (Braun and Sauter, 2019; Iza­guirre, 2019; Sei­dah and Prat, 2012). This furin-like cleav­age site, is sup­posed to be cleaved dur­ing virus egress (Mille and Whit­tak­er, 2014) for S‑protein “prim­ing” and may pro­vide a gain-of-func­tion to the 2019-nCoV for effi­cient spread­ing in the human pop­u­la­tion com­pared to oth­er lin­eage b beta­coro­n­avirus­es. This pos­si­bly illus­trates a con­ver­gent evo­lu­tion path­way between unre­lat­ed CoVs. Inter­est­ing­ly, if this site is not processed, the S‑protein is expect­ed to be cleaved at site 2 dur­ing virus endo­cy­to­sis, as observed for the SARS-CoV. . . .”

1.  “Why the Coro­n­avirus Has Been So Suc­cess­ful” Ed Yong; The Atlantic; 03/20/2020

One of the few mer­cies dur­ing this cri­sis is that, by their nature, indi­vid­ual coro­n­avirus­es are eas­i­ly destroyed. Each virus par­ti­cle con­sists of a small set of genes, enclosed by a sphere of fat­ty lipid mol­e­cules, and because lipid shells are eas­i­ly torn apart by soap, 20 sec­onds of thor­ough hand-wash­ing can take one down. Lipid shells are also vul­ner­a­ble to the ele­ments; a recent study shows that the new coro­n­avirus, SARS-CoV­‑2, sur­vives for no more than a day on card­board, and about two to three days on steel and plas­tic. These virus­es don’t endure in the world. They need bod­ies.

But much about coro­n­avirus­es is still unclear. Susan Weiss, of the Uni­ver­si­ty of Penn­syl­va­nia, has been study­ing them for about 40 years. She says that in the ear­ly days, only a few dozen sci­en­tists shared her interest—and those num­bers swelled only slight­ly after the SARS epi­dem­ic of 2002. “Until then peo­ple looked at us as a back­ward field with not a lot of impor­tance to human health,” she says. But with the emer­gence of SARS-CoV‑2—the cause of the COVID-19 disease—no one is like­ly to repeat that mis­take again.

To be clear, SARS-CoV­‑2 is not the flu. It caus­es a dis­ease with dif­fer­ent symp­tomsspreads and kills more read­i­ly, and belongs to a com­plete­ly dif­fer­ent fam­i­ly of virus­es. This fam­i­ly, the coro­n­avirus­es, includes just six oth­er mem­bers that infect humans. Four of them—OC43, HKU1, NL63, and 229E—have been gen­tly annoy­ing humans for more than a cen­tu­ry, caus­ing a third of com­mon colds. The oth­er two—MERS and SARS (or “SARS-clas­sic,” as some virol­o­gists have start­ed call­ing it)—both cause far more severe dis­ease. Why was this sev­enth coro­n­avirus the one to go pan­dem­ic? Sud­den­ly, what we do know about coro­n­avirus­es becomes a mat­ter of inter­na­tion­al con­cern.

The struc­ture of the virus pro­vides some clues about its suc­cess. In shape, it’s essen­tial­ly a spiky ball. Those spikes rec­og­nize and stick to a pro­tein called ACE2, which is found on the sur­face of our cells: This is the first step to an infec­tion. The exact con­tours of SARS-CoV‑2’s spikes allow it to stick far more strong­ly to ACE2 than SARS-clas­sic did, and “it’s like­ly that this is real­ly cru­cial for per­son-to-per­son trans­mis­sion,” says Angela Ras­mussen of Colum­bia Uni­ver­si­ty. In gen­er­al terms, the tighter the bond, the less virus required to start an infec­tion.

There’s anoth­er impor­tant fea­ture. Coro­n­avirus spikes con­sist of two con­nect­ed halves, and the spike acti­vates when those halves are sep­a­rat­ed; only then can the virus enter a host cell. In SARS-clas­sic, this sep­a­ra­tion hap­pens with some dif­fi­cul­ty. But in SARS-CoV­‑2, the bridge that con­nects the two halves can be eas­i­ly cut by an enzyme called furin, which is made by human cells and—crucially—is found across many tis­sues. “This is prob­a­bly impor­tant for some of the real­ly unusu­al things we see in this virus,” says Kris­t­ian Ander­sen of Scripps Research Trans­la­tion­al Insti­tute.

For exam­ple, most res­pi­ra­to­ry virus­es tend to infect either the upper or low­er air­ways. In gen­er­al, an upper-res­pi­ra­to­ry infec­tion spreads more eas­i­ly, but tends to be milder, while a low­er-res­pi­ra­to­ry infec­tion is hard­er to trans­mit, but is more severe. SARS-CoV­‑2 seems to infect both upper and low­er air­ways, per­haps because it can exploit the ubiq­ui­tous furin. This dou­ble wham­my could also con­ceiv­ably explain why the virus can spread between peo­ple before symp­toms show up—a trait that has made it so dif­fi­cult to con­trol. Per­haps it trans­mits while still con­fined to the upper air­ways, before mak­ing its way deep­er and caus­ing severe symp­toms. All of this is plau­si­ble but total­ly hypo­thet­i­cal; the virus was only dis­cov­ered in Jan­u­ary, and most of its biol­o­gy is still a mys­tery.

The new virus cer­tain­ly seems to be effec­tive at infect­ing humans, despite its ani­mal ori­gins. The clos­est wild rel­a­tive of SARS-CoV­‑2 is found in bats, which sug­gests it orig­i­nat­ed in a bat, then jumped to humans either direct­ly or through anoth­er species. (Anoth­er coro­n­avirus found in wild pan­golins also resem­bles SARS-CoV­‑2, but only in the small part of the spike that rec­og­nizes ACE2; the two virus­es are oth­er­wise dis­sim­i­lar, and pan­golins are unlike­ly to be the orig­i­nal reser­voir of the new virus.) When SARS-clas­sic first made this leap, a brief peri­od of muta­tion was nec­es­sary for it to rec­og­nize ACE2 well. But SARS-CoV­‑2 could do that from day one. “It had already found its best way of being a [human] virus,” says Matthew Frie­man of the Uni­ver­si­ty of Mary­land School of Med­i­cine.

This uncan­ny fit will doubtless­ly encour­age con­spir­a­cy the­o­rists: What are the odds that a ran­dom bat virus had exact­ly the right com­bi­na­tion of traits to effec­tive­ly infect human cells from the get-go, and then jump into an unsus­pect­ing per­son? “Very low,” Ander­sen says, “but there are mil­lions or bil­lions of these virus­es out there. These virus­es are so preva­lent that things that are real­ly unlike­ly to hap­pen some­times do.”

Since the start of the pan­dem­ic, the virus hasn’t changed in any obvi­ous­ly impor­tant ways. It’s mutat­ing in the way that all virus­es do. But of the 100-plus muta­tions that have been doc­u­ment­ed, none has risen to dom­i­nance, which sug­gests that none is espe­cial­ly impor­tant. “The virus has been remark­ably sta­ble giv­en how much trans­mis­sion we’ve seen,” says Lisa Gralin­s­ki of the Uni­ver­si­ty of North Car­oli­na. “That makes sense, because there’s no evo­lu­tion­ary pres­sure on the virus to trans­mit bet­ter. It’s doing a great job of spread­ing around the world right now.”

There’s one pos­si­ble excep­tion. A few SARS-CoV­‑2 virus­es that were iso­lat­ed from Sin­ga­pore­an COVID-19 patients are miss­ing a stretch of genes that also dis­ap­peared from SARS-clas­sic dur­ing the late stages of its epi­dem­ic. This change was thought to make the orig­i­nal virus less vir­u­lent, but it’s far too ear­ly to know whether the same applies to the new one. Indeed, why some coro­n­avirus­es are dead­ly and some are not is unclear. “There’s real­ly no under­stand­ing at all of why SARS or SARS-CoV­‑2 are so bad but OC43 just gives you a run­ny nose,” Frie­man says.

Researchers can, how­ev­er, offer a pre­lim­i­nary account of what the new coro­n­avirus does to the peo­ple it infects. Once in the body, it like­ly attacks the ACE2-bear­ing cells that line our air­ways. Dying cells slough away, fill­ing the air­ways with junk and car­ry­ing the virus deep­er into the body, down toward the lungs. As the infec­tion pro­gress­es, the lungs clog with dead cells and flu­id, mak­ing breath­ing more dif­fi­cult. (The virus might also be able to infect ACE2-bear­ing cells in oth­er organs, includ­ing the gut and blood ves­sels.)

The immune sys­tem fights back and attacks the virus; this is what caus­es inflam­ma­tion and fever. But in extreme cas­es, the immune sys­tem goes berserk, caus­ing more dam­age than the actu­al virus. For exam­ple, blood ves­sels might open up to allow defen­sive cells to reach the site of an infec­tion; that’s great, but if the ves­sels become too leaky, the lungs fill even more with flu­id. These dam­ag­ing over­re­ac­tions are called cytokine storms. They were his­tor­i­cal­ly respon­si­ble for many deaths dur­ing the 1918 flu pan­dem­ic, H5N1 bird flu out­breaks, and the 2003 SARS out­break. And they’re prob­a­bly behind the most severe cas­es of COVID-19. “These virus­es need time to adapt to a human host,” says Akiko Iwasa­ki of the Yale School of Med­i­cine. “When they’re first try­ing us out, they don’t know what they’re doing, and they tend to elic­it these respons­es.”

Dur­ing a cytokine storm, the immune sys­tem isn’t just going berserk but is also gen­er­al­ly off its game, attack­ing at will with­out hit­ting the right tar­gets. When this hap­pens, peo­ple become more sus­cep­ti­ble to infec­tious bac­te­ria. The storms can also affect oth­er organs besides the lungs, espe­cial­ly if peo­ple already have chron­ic dis­eases. This might explain why some COVID-19 patients end up with com­pli­ca­tions such as heart prob­lems and sec­ondary infec­tions.

But why do some peo­ple with COVID-19 get incred­i­bly sick, while oth­ers escape with mild or nonex­is­tent symp­toms? Age is a fac­tor. Elder­ly peo­ple are at risk of more severe infec­tions pos­si­bly because their immune sys­tem can’t mount an effec­tive ini­tial defense, while chil­dren are less affect­ed because their immune sys­tem is less like­ly to progress to a cytokine storm. But oth­er factors—a person’s genes, the vagaries of their immune sys­tem, the amount of virus they’re exposed to, the oth­er microbes in their bodies—might play a role too. In gen­er­al, “it’s a mys­tery why some peo­ple have mild dis­ease, even with­in the same age group,” Iwasa­ki says.

Coro­n­avirus­es, much like influen­za, tend to be win­ter virus­es. In cold and dry air, the thin lay­ers of liq­uid that coat our lungs and air­ways become even thin­ner, and the beat­ing hairs that rest in those lay­ers strug­gle to evict virus­es and oth­er for­eign par­ti­cles. Dry air also seems to damp­en some aspects of the immune response to those trapped virus­es. In the heat and humid­i­ty of sum­mer, both trends reverse, and res­pi­ra­to­ry virus­es strug­gle to get a foothold.

Unfor­tu­nate­ly, that might not mat­ter for the COVID-19 pan­dem­ic. At the moment, the virus is tear­ing through a world of immuno­log­i­cal­ly naive peo­ple, and that vul­ner­a­bil­i­ty is like­ly to swamp any sea­son­al vari­a­tions. After all, the new virus is trans­mit­ting read­i­ly in coun­tries like Sin­ga­pore (which is in the trop­ics) and Aus­tralia (which is still in sum­mer). And one recent mod­el­ing study con­clud­ed that “SARS-CoV­‑2 can pro­lif­er­ate at any time of year.” “I don’t have an immense amount of con­fi­dence that the weath­er is going to have the effect that peo­ple hope it will,” Gralin­s­ki says. “It may knock things down a lit­tle, but there’s so much per­son-to-per­son trans­mis­sion going on that it may take more than that.” Unless peo­ple can slow the spread of the virus by stick­ing to phys­i­cal-dis­tanc­ing rec­om­men­da­tions, the sum­mer alone won’t save us.

2. “The Spike Gly­co­pro­tein of the New Coro­n­avirus 2019-nCov Con­tains a Furin-Like Cleav­age Site Absent in CoV of the Same Clade” by B. Coutard, C. Valle, B. Canard, N.G. Sei­dah, E. Decroly et al.; Sci­ence Direct; Vol. 176: April 2020.

. . . . Based on its genome sequence, 2019-nCoV belongs to lin­eage b of Beta­coro­n­avirus (Fig. 1A), which also includes the SARS-CoV and bat CoV ZXC21, the lat­ter and CoV ZC45 being the clos­est to 2019-nCoV.  . . .

. . . . Since furin is high­ly expressed in lungs, an enveloped virus that infects the res­pi­ra­to­ry tract may suc­cess­ful­ly exploit this con­ver­tase to acti­vate its sur­face gly­co­pro­tein (Bassi et al., 2017Mbikay et al., 1997). Before the emer­gence of the 2019-nCoV, this impor­tant fea­ture was not observed in the lin­eage b of beta­coro­n­avirus­es. How­ev­er, it is shared by oth­er CoV (HCoV-OC43, MERS-CoV, MHV-A59) har­bour­ing furin-like cleav­age sites in their S‑protein (Fig. 2Table 1), which were shown to be processed by furin exper­i­men­tal­ly (Le Coupanec et al., 2015Mille and Whit­tak­er, 2014.

Strik­ing­ly, the 2019-nCoV S‑protein sequence con­tains 12 addi­tion­al nucleotides upstream of the sin­gle Arg↓ cleav­age site 1 (Fig. 1, Fig. 2) lead­ing to a pre­dic­tive­ly sol­vent-exposed PRRAR↓SV sequence, which cor­re­sponds to a canon­i­cal furin-like cleav­age site (Braun and Sauter, 2019; Iza­guirre, 2019; Sei­dah and Prat, 2012). This furin-like cleav­age site, is sup­posed to be cleaved dur­ing virus egress (Mille and Whit­tak­er, 2014) for S‑protein “prim­ing” and may pro­vide a gain-of-func­tion to the 2019-nCoV for effi­cient spread­ing in the human pop­u­la­tion com­pared to oth­er lin­eage b beta­coro­n­avirus­es. This pos­si­bly illus­trates a con­ver­gent evo­lu­tion path­way between unre­lat­ed CoVs. Inter­est­ing­ly, if this site is not processed, the S‑protein is expect­ed to be cleaved at site 2 dur­ing virus endo­cy­to­sis, as observed for the SARS-CoV. . . .

Discussion

One comment for “Modus Operandi of Covid-19–Does It Reflect Genetic Engineering?”

  1. Sure you’ve already seen these but on the off chance that you’ve not:

    Tiergartenstrasse4 for the 21st cen­tu­ry?:

    https://www.usatoday.com/story/news/nation/2020/03/26/coronavirus-crisis-people-with-disabilities-discriminate/5082197002/

    https://www.nytimes.com/2020/03/24/upshot/coronavirus-rationing-decisions-ethicists.html

    “Cap­i­tal­ist colony col­lapse”:

    https://www.cnbc.com/2020/03/18/bill-ackman-pleads-to-trump-to-increase-closures-to-save-the-economy-shut-it-down-now.html

    Investor Bill Ack­man urged Pres­i­dent Don­ald Trump and cor­po­rate Amer­i­ca in an impas­sioned plea on CNBC to shut down the coun­try for 30 days to con­tain the fast-spread­ing coro­n­avirus, call­ing it the only option to res­cue the econ­o­my.

    “What’s scar­ing the Amer­i­can peo­ple and cor­po­rate Amer­i­ca now is the grad­ual roll­out,” Ack­man told Scott Wap­n­er on “Half­time Report” on Wednes­day. “We need to shut it down now. ... This is the only answer.”

    Amer­i­ca will end as we know it. I’m sor­ry to say so, unless we take this option,” he said. Ack­man added that if Trump saves the coun­try from the coro­n­avirus, he will get reelect­ed in Novem­ber.

    Ack­man urged U.S. com­pa­nies to stop their buy­back pro­grams because “hell is com­ing.” The biggest U.S. banks have already halt­ed repur­chas­ing stocks to put their cap­i­tal to use help­ing con­sumers and busi­ness­es.

    Black swans and black eagles?

    https://www.forbes.com/sites/kenrapoza/2020/01/10/dont-discount-a-black-swan-event-for-china/

    https://www.cnn.com/2019/12/15/investing/stocks-week-ahead/index.html

    Posted by Peter Pandemic | March 27, 2020, 9:10 am

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