Coronaviris Pandemic - an inflection point in human history?

[Peter Lemkin]

USA is #1.....but in what exactly? Perhaps mendacity and lack of care for those without money.....

A 17-year-old U.S. citizen with symptoms of coronavirus did not receive medical attention at an emergency clinic because he did not have health insurance, Lancaster Mayor Rex Parris said on March 25 in a video posted on YouTube.
"He did not have insurance, so he was not treated," Parris said, adding that medical personnel at this emergency center, whose name was not released by authorities, advised the teen to go to the Antelope Valley Hospital emergency department, the public hospital in the area.
"On the way to Antelope Valley Hospital, he suffered cardiac arrest, the mayor said, adding: "They were able to revive him and keep him alive for about six hours. But when he got there, it was too late."
Parris emphasize that the patient was healthy until he began to experience problems in his respiratory system: "On the Friday before he died, he was healthy. On Wednesday he was already dead."
The teenager's death was reported on March 24. The Los Angeles County Department of Public Health initially reported the cause as coronavirus, but then rejected the comment, reporting that further testing by the Centers for Disease Control and Prevention was necessary to confirm the cause of death, according to The Hill.
"Although the first tests indicated a positive result for COVID-19 (coronavirus), the case is complex and there may be an alternative explanation for this death," the authorities said.
On Friday, the USA It has become  the first country in the world to exceed 100,000 diagnosed cases of coronavirus.

[Marlene Zenker]

That guy is a GREAT Trump immitator!! I hope that goes 'viral'. I think the ONLY good thing to come out of the current pandemic is it will put the last nail in Trump's political coffin. What wories me is how one will have an election in November, as this will sadly not be over by then and voting by mail would both be oppossed by the Republicans, and nearly impossible to set up in time. Voting by some electronic means would also not be possible in the time available, and some do not have connection to the internet. Both means would also be subject to manipulation without being very carefully constructed and thought out by neutral experts. Best I can think of is an extended voting period, with wide distribution of the ballots before and drive up, drop-off of ballots and individual walk up, drop-off for those without cars. It will make a mess of the election, if one can even be arranged! Trump will surely try to declare some kind of emergency situation and try to cancel the election.

Constitutionally, Trump/Pence cannot remain in office as of January 20, 2021 even if there is no election - which of course would mean Nancy Pelosi becomes the first woman president of the USA - I would pay to see the republican's faces if that happens.

[Peter Lemkin]

Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1
To the Editor:
A novel human coronavirus that is now named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (formerly called HCoV-19) emerged in Wuhan, China, in late 2019 and is now causing a pandemic.1 We analyzed the aerosol and surface stability of SARS-CoV-2 and compared it with SARS-CoV-1, the most closely related human coronavirus.2
We evaluated the stability of SARS-CoV-2 and SARS-CoV-1 in aerosols and on various surfaces and estimated their decay rates using a Bayesian regression model (see the Methods section in the Supplementary Appendix, available with the full text of this letter at NEJM.org). SARS-CoV-2 nCoV-WA1-2020 (MN985325.1) and SARS-CoV-1 Tor2 (AY274119.3) were the strains used. Aerosols (<5 μm) containing SARS-CoV-2 (105.25 50% tissue-culture infectious dose [TCID50] per milliliter) or SARS-CoV-1 (106.75-7.00 TCID50 per milliliter) were generated with the use of a three-jet Collison nebulizer and fed into a Goldberg drum to create an aerosolized environment. The inoculum resulted in cycle-threshold values between 20 and 22, similar to those observed in samples obtained from the upper and lower respiratory tract in humans.
Our data consisted of 10 experimental conditions involving two viruses (SARS-CoV-2 and SARS-CoV-1) in five environmental conditions (aerosols, plastic, stainless steel, copper, and cardboard). All experimental measurements are reported as means across three replicates.
Figure 1. Viability of SARS-CoV-1 and SARS-CoV-2 in Aerosols and on Various Surfaces.
SARS-CoV-2 remained viable in aerosols throughout the duration of our experiment (3 hours), with a reduction in infectious titer from 103.5 to 102.7 TCID50 per liter of air. This reduction was similar to that observed with SARS-CoV-1, from 104.3 to 103.5 TCID50 per milliliter (Figure 1A).
SARS-CoV-2 was more stable on plastic and stainless steel than on copper and cardboard, and viable virus was detected up to 72 hours after application to these surfaces (Figure 1A), although the virus titer was greatly reduced (from 103.7 to 100.6 TCID50 per milliliter of medium after 72 hours on plastic and from 103.7 to 100.6 TCID50 per milliliter after 48 hours on stainless steel). The stability kinetics of SARS-CoV-1 were similar (from 103.4 to 100.7 TCID50 per milliliter after 72 hours on plastic and from 103.6 to 100.6 TCID50 per milliliter after 48 hours on stainless steel). On copper, no viable SARS-CoV-2 was measured after 4 hours and no viable SARS-CoV-1 was measured after 8 hours. On cardboard, no viable SARS-CoV-2 was measured after 24 hours and no viable SARS-CoV-1 was measured after 8 hours (Figure 1A).
Both viruses had an exponential decay in virus titer across all experimental conditions, as indicated by a linear decrease in the log10TCID50 per liter of air or milliliter of medium over time (Figure 1B). The half-lives of SARS-CoV-2 and SARS-CoV-1 were similar in aerosols, with median estimates of approximately 1.1 to 1.2 hours and 95% credible intervals of 0.64 to 2.64 for SARS-CoV-2 and 0.78 to 2.43 for SARS-CoV-1 (Figure 1C, and Table S1 in the Supplementary Appendix). The half-lives of the two viruses were also similar on copper. On cardboard, the half-life of SARS-CoV-2 was longer than that of SARS-CoV-1. The longest viability of both viruses was on stainless steel and plastic; the estimated median half-life of SARS-CoV-2 was approximately 5.6 hours on stainless steel and 6.8 hours on plastic (Figure 1C). Estimated differences in the half-lives of the two viruses were small except for those on cardboard (Figure 1C). Individual replicate data were noticeably “noisier” (i.e., there was more variation in the experiment, resulting in a larger standard error) for cardboard than for other surfaces (Fig. S1 through S5), so we advise caution in interpreting this result.
We found that the stability of SARS-CoV-2 was similar to that of SARS-CoV-1 under the experimental circumstances tested. This indicates that differences in the epidemiologic characteristics of these viruses probably arise from other factors, including high viral loads in the upper respiratory tract and the potential for persons infected with SARS-CoV-2 to shed and transmit the virus while asymptomatic.3,4 Our results indicate that aerosol and fomite transmission of SARS-CoV-2 is plausible, since the virus can remain viable and infectious in aerosols for hours and on surfaces up to days (depending on the inoculum shed). These findings echo those with SARS-CoV-1, in which these forms of transmission were associated with nosocomial spread and super-spreading events,5 and they provide information for pandemic mitigation efforts.
Neeltje van Doremalen, Ph.D.
Trenton Bushmaker, B.Sc.
National Institute of Allergy and Infectious Diseases, Hamilton, MT
Dylan H. Morris, M.Phil.
Princeton University, Princeton, NJ
Myndi G. Holbrook, B.Sc.
National Institute of Allergy and Infectious Diseases, Hamilton, MT
Amandine Gamble, Ph.D.
University of California, Los Angeles, Los Angeles, CA
Brandi N. Williamson, M.P.H.
National Institute of Allergy and Infectious Diseases, Hamilton, MT
Azaibi Tamin, Ph.D.
Jennifer L. Harcourt, Ph.D.
Natalie J. Thornburg, Ph.D.
Susan I. Gerber, M.D.
Centers for Disease Control and Prevention, Atlanta, GA
James O. Lloyd-Smith, Ph.D.
University of California, Los Angeles, Los Angeles, CA, Bethesda, MD
Emmie de Wit, Ph.D.
Vincent J. Munster, Ph.D.
National Institute of Allergy and Infectious Diseases, Hamilton, MT
vincent.munster@nih.gov

[Lauren Johnson]

That guy is a GREAT Trump immitator!! I hope that goes 'viral'. I think the ONLY good thing to come out of the current pandemic is it will put the last nail in Trump's political coffin. What wories me is how one will have an election in November, as this will sadly not be over by then and voting by mail would both be oppossed by the Republicans, and nearly impossible to set up in time. Voting by some electronic means would also not be possible in the time available, and some do not have connection to the internet. Both means would also be subject to manipulation without being very carefully constructed and thought out by neutral experts. Best I can think of is an extended voting period, with wide distribution of the ballots before and drive up, drop-off of ballots and individual walk up, drop-off for those without cars. It will make a mess of the election, if one can even be arranged! Trump will surely try to declare some kind of emergency situation and try to cancel the election.

Constitutionally, Trump/Pence cannot remain in office as of January 20, 2021 even if there is no election - which of course would mean Nancy Pelosi becomes the first woman president of the USA - I would pay to see the republican's faces if that happens.

We are now in an emergency.  Trump can claim that he won't be run out of office by a bunch of traitors.

[Peter Lemkin]

If there is a cancelled, postponed or 'emergency - delayed' election chaos will occur, as I think there is no clear answer to how it should be handled and the Supreme Court is the worst place to decide, the Electoral College next worst. We have long been loosing our democracy [what little we ever had], and this could be the death knell. I would not trust Congress, especially the Senate to pass any new legislation to get us through what now looks like an inevitable crisis over the election. EVEN if [and that is unlikely] the virus is gone or  dormant in November, a normal election is hardly going to be possible without re-infecting most who come to vote - and the voter repression techniques of the Republicans will be GREATLY helped by the virus.

[Peter Lemkin]

Why so many novel and dangerous virus come from bats.....

Jeff Schechtman:
Welcome to the WhoWhatWhy podcast. I’m your host, Jeff Schechtman. It’s amazing how many times in the past few weeks I’ve read, “How did we get here?” Sometimes that refers to the public health and political response to the Coronavirus, but it also sometimes refers to how it all began. 90 days ago we were with friends and family celebrating the holiday season. Today, a global pandemic has shaken the world to its very core. The answer simply stated is that it all started with bats. Before pigs, before the wet markets in Wuhan, the evolution of bats might be referred to as patient zero.
Jeff Schechtman:
If this seems hard to believe or to understand, my guest, UC Berkeley researcher Cara Brook is here to explain. Cara Brook is a postdoctoral fellow with UC Berkeley’s Miller Institute for Basic Research. Her research focuses on understanding the role that bats play as reservoirs for highly virulent emerging diseases, including rabies and viruses. Cara is a graduate of Stanford and Princeton, and it is my pleasure to welcome Dr. Cara Brook to the WhoWhatWhy podcast. Cara, thanks so much for joining us.
Cara Brook:
Oh, thanks. It’s a pleasure to be here.
Jeff Schechtman:
As we look at this and past pandemics, things like SARS and Ebola, so much of it could be traced back to bats. Talk about that first.
Cara Brook:
Yeah, so bats as reservoirs for virulent viruses is, as you said, the focus of my research, and we, a graduate student and I and my group last year published a paper where we actually were able to demonstrate that bat borne zoonotic viruses, zoonotic means passing from an animal reservoir to a human host, and that bat borne zoonoses are the most virulent of all mammalian zoonoses. So meaning they cause the highest base fatality rates upon emergence into the human population.
Cara Brook:
We think that the reason for this is related to the evolution of flight. So, bats are the only flying mammal and flight as a physiological process is more metabolically expensive than any form of terrestrial locomotion, so a human at full speed running will raise their baseline metabolic rate two or threefold. A rodent will raise their metabolic rate up to seven fold, but a bat in flight will elevate its BMR, basal metabolic rate up to 15 fold when flying. And typically we expect the bat metabolic activity trades off with longevity. So species that have really high metabolic rates tend to be much shorter lived. Rodents are a perfect example of that.
Cara Brook:
But sort of flying in the face of that prediction, bats are the longest lived for their body size of any mammalian taxon. So the longest living bat that’s ever been recorded, the Brant bat, has been found to live up to 40 years in the wild, and a rodent of the same size, it’s only a couple of grams, would live up to two years at most. So what we think is going on is that bats, in order for flight to even have become evolutionarily possible to begin with, bats needed to evolve hyper-efficient cellular mechanisms by which to reduce the oxidative stress that’s encouraged from the general process of metabolism.
Cara Brook:
So metabolism accrues oxygen free radicals as a byproduct, which then get oxidized and the damage gets mitigated and repaired by cellular functioning. But when that damage accumulates and outpaces the body’s ability to reduce it, that’s what we call oxidative stress. And generally over time, the accumulation of oxidative stressors leads to senescence. So, leads to the inability of our tissues and organs to continue functioning, and that’s what we now think of as aging. So bats it seems as a mechanism to support their ability to fly, which is so metabolically expensive, have evolved these really efficient DNA damage and repair pathways and oxidative stress mitigation pathways at the cellular level that enable them to withstand this highly physiologically expensive activity. Then as a consequence of that, bats have evolved this extraordinary longevity because their cells are so resilient to these stressors.
Cara Brook:
More recently we’ve started to think that this also might play a role in their resilience to viral infection. So viruses in a cell will cause oxidative damage directly to that cell. And then in addition, a viral infection will lead to the recruitment of immune cells to the site of that infection causing widespread inflammation, and that is also an oxidative stressor. So it seems that because of flight bats have evolved these efficient pathways to mitigate that damage, but then that’s also allowed them to be long lived and to be really resilient to virus so they can host these viruses, such as Ebola, or Marburg, or SARS, or MERS without actually experiencing disease, without getting sick.
Jeff Schechtman:
If we can, let’s back up a little bit and talk about how the bats could infect other mammals even before they get to humans, and how that transfer then to humans takes place.
Cara Brook:
Yeah, so typically in disease ecology, which is my field, we do a lot of epidemiological modeling, and when we model the process of transmission, so passing a pathogen such as a virus from one host to another, we estimate this transmission rate, which we usually use the Greek letter beta to describe. Encapsulated in that transmission rate, beta is both the infectiousness of the first host that’s passing the infection, the susceptibility of the host that’s receiving the infection, then the contact rates between them. So any of those three components of beta modulating any of those three is going to affect the probability of transmission taking place.
Cara Brook:
So with respect to infectiousness, research is suggesting that there’s a certain seasonality to that infectiousness. They appear to shed more virus during periods in which they are immunocompromised or otherwise physiologically stressed. So during the reproductive period and then also during nutritionally dry periods, many of these infections come from fruit bats. So there’s a distinctive seasonality to the fruit availability in the country that these bats … whichever viral emergence you happen to be focusing on. So, that’s infectiousness.
Cara Brook:
Susceptibility is going to vary by host to host. There might be seasonal factors related to that as well. There might also be certain individuals are more immune-compromised. Then also we’ve discovered that there’s an inverse correlation between biogenetic distance between two hosts and the probability of zoonosis. So it seems that viruses that have evolved for a long time in a bat are more likely to transmit to an organism that is closely related to a bat. So bats and humans are quite phylogenetically distant from one another, so they are both still mammals, but they’re about as far apart mammalian orders as you could find. So often what we see in this transmission process is that viruses will first spill over from bats to what we call an intermediate host or a secondary host.
Cara Brook:
In the case of SARS, that was a civet cat. In the case of MERS, that was a camel. In the case of Ebola and Marburg, we sometimes see nonhuman primates. In the case of Hendra and Nipah, Henipaviruses, Hendra is horses, Nipah it’s pigs, and then from that organism to a human. So that acts as sort of a secondary bridge host that bridges that phylogenetic distance between the bat and the human.
Cara Brook:
There are some bat borne pathogens that can spill over directly, Nipah virus for instance in Bangladesh will spill over directly every year from bat to human. But they’re sort of interesting, unique transmission pathways that enable that bat could host jump. So in the case of Nipah virus in Bangladesh, the viruses shed in bat urine. And in Malaysia we saw Nipah emerge first through a pig host. So it went from a bat where they shed virus in their urine, it landed in pig paddocks, pigs obtain the virus, and then [inaudible] workers became infected from handling the pigs.
Cara Brook:
But in the case of Bangladesh, people actually consume date palm sap, there and bats roost in these date palms. So when viruses shed in that urine into the sap and collected in these vessels that people use to collect sap for drinking, that can be infected with virus and get this very high dose that is able to make that evolutionary jump. So a place like the wet markets that we see in southern and central China bring together a lot of these organisms that are not typically found in close proximity. That brings us to that third component of beta, the transmission term, that contact rate.
Cara Brook:
So, something like a wet market is going to really increase the contact rates between distantly related hosts and make the probability of emergence between them much more likely. So in the case of SARS-Covid-2, which is the virus that causes Covid-19, we’ve not yet categorically demonstrated a clear secondary host. There’s been some discussion of pangolins, some discussion of pigs, but no clear evidence whether there was a secondary host, and if so, what that host might’ve been. But you can imagine that bringing live bats in captivity in close proximity to something like a pig, or something like a pangolin that they might otherwise not encounter in the wild, is going to greatly facilitate the probability of a virus transmitting from one host to another and then onto the human.
Jeff Schechtman:
Once it transfers to humans, talk a little bit about how those characteristics of the bat relate to humans and the way the human immune system responds to it almost in overdrive, which is part of what’s killing people right now.
Cara Brook:
Yeah, so because bats are so resilient to viral infection, this hypothesis related to flight, I’ve done some work both in cell culture and also some theoretical modeling work that suggests that viruses evolved different evolutionary optimums. So typically we think that viruses will evolve to balance their rates of transmission and the virulence incurred on their host, virulence being damage to the host, so what we think of as disease. So typically a virus is not going to want to hurt its host, because a virus’s evolutionary goal is to transmit to as many new hosts as possible to maximize its rate of between host transmission. We refer to that as R Naught, that basic reproduction number for a pathogen, and R0 is both the compilation of the number of new transmissions divided by the loss of transmissions through the loss of infected hosts.
Cara Brook:
That can take place through a host recovering from infection or also from dying. So if the virus replicates very fast, it might improve its ability to transmit to new hosts, but at the same time it might be killing its first host much more quickly, and there’s a trade-off between those two where at some point, even though it’s replicating fast, reaching high viral loads that are likely to infect others, that host is going to be dying too quickly for the pathogen to be able to spread any more quickly than it was before, so we call that its optimal virulence when it’s balanced, that equation, and maximized its R0. And in the case of bats, since they are so resilient to these viral infections, we think that essentially the optimal R0 for this pathogen involves a very high within host rate of virus spread, because that viral replication in the bat host is not actually damaging the bat.
Cara Brook:
So the virus, this sort of evolutionary ceiling on that trade-off is lifted, and a virus can evolve to either replicate or overcome host defenses much more quickly to enable it to reach higher viral loads in its host, and when that emerges into a host that is not a bat, we expect that that would cause extreme pathology because our immune systems are not as equipped to deal with those infections as others.
Cara Brook:
So one good example of that is that several species of Old World fruit bat have been demonstrated to have constitutively expressed interferon alpha. Interferon is an antiviral cytokine, which is a signaling protein. And typically what happens when a virus invades a cell, the viral RNA in that cell, the cell perceives that the virus has infected it and secretes interferon to initiate this downstream signaling cascade that alerts neighboring cells to the presence of infection and induces this antiviral state where those neighboring cells secrete a series of host factors and basically go into lock down and trap the infection from spreading any more quickly.
Cara Brook:
So in a human host, we couldn’t have a conclusively expressed antiviral response because it would induce widespread inflammation, but we think that bats, due to their evolutionary adaptations related to flight, are able to sustain these otherwise inflammatory pathways. So we can imagine that if the virus co-evolved with a bat host that has these really robust antiviral immune defenses, it’s going to evolve ways to circumvent those processes and still maintain infection within that host. But then when it emerges into something like a human that lacks those pathways, it ends up being too virulent and showing maladaptive virulence and killing that host much faster.
Cara Brook:
What I should say is that in the case of this SARS-CoV-2 that causes Covid-19, this virus actually is very well adapted to its human host. It’s not as virulent as SARS or MERS for example, both of which had higher case fatality rates than the human host but were much less transmissible. So in the case of this virus, we think that we’ve seen a bit of evolution in the human host that now means that this virus is well equipped to spread from human to human without killing those people too quickly before it achieves a new infection.
Jeff Schechtman:
To what extent can understanding all of this help us in the treatment of the virus?
Cara Brook:
Yeah, it would be difficult to try to induce the same sort of immune responses that we see in bats in human hosts. As I mentioned, we’re not equipped to sustain that kind of inflammation, so it’s not really an effective pathway for therapeutics. But understanding the transmission dynamics and the reservoir host is absolutely essential to avoiding these spillover events in the future.
Jeff Schechtman:
One of the things that also goes on is what’s going on with bats today and the loss of habitat throughout the world and the impact that that’s having.
Cara Brook:
Yeah, so as I mentioned, transmission from a bat host to a human or to a secondary host is dependent on this term beta that involves both infectiousness, susceptibility, and these rates of contact. When we encroach on wild habitat where these animals live, we’re overburdening that contact rate and making it much more likely that we are going to encounter pathogens that we would not otherwise. The same goes for our domestic wildlife, such as pigs that are often these secondary amplifying hosts.
Cara Brook:
At the same time, our work … I’m part of a collaborative network called BatOneHealth. We work in Australia studying Hendra virus, in Bangladesh studying Nipah virus, and then in Madagascar and Ghana studying bat borne Henipaviruses in the same family. What we’ve been able to demonstrate is that bats in intact habitats under good nutritional condition actually shed less virus in their urine during these annual pulses that take place during the nutritionally poor periods of the year. So bats that are in better conditions pose less of a zoonotic threat. So increased anthropogenic impacts on wild animal habitat elevate the stress levels in these wild organisms, and then also compromise their immunity, which can lead both to heightened contact rates between bats and human hosts and to heightened infectiousness in the bat host through the process of viral shedding.
Jeff Schechtman:
Tell us a little bit about where this research is going on right now, and who are the people that are funding and responsible for it.
Cara Brook:
So as I mentioned, our BatOneHealth team works in four global field sites. My work is focused in Madagascar. I studied three species of endemic Old World fruit bat on the Island of Madagascar and worked very closely with Institut Pasteur of Madagascar, and in particular a Malagasy biologist, [inaudible 00:19:09]. The field team in Australia is led by Dr. Raina Plowright of Montana State University, Dr. Ali Peel of Griffith University in Australia, and a number of hardworking graduate students and post docs who work with them. There’s a team that is joined with John Hopkins University and led by Dr Emily [inaudible] that works in Bangladesh. Then our team in Ghana involves a number of Ghanaian scientists joint with the team at Cambridge University as well.
Jeff Schechtman:
To what extent can all of this be anticipated looking forward that we are going to see future pandemics, not unlike this, also emanating from bat.
Cara Brook:
I think that bats certainly serve as a source of highly virulent, dangerous pathogens and the more impacts on wild fruit bats and insectivorous bat habitat that we’re going to see into the future are going to be paired with future zoonosis. I mean, already in the past 20 years, we’ve seen outbreaks of SARS and MERS and now SARS-CoV-2 Coronaviruses. In addition, Ebola and Marburg, filoviruses, Hendra and Nipah Henipaviruses, where we see human cases every year.
Cara Brook:
So this is a recurring problem and zoonotic pathogens pose some of the greatest threats because we are not able to control the infection through human public health. The Black Death was so globally destructive because a lot of the public health measures that were taking to combat Covid-19 were ineffective because there was a rodent reservoir for that pathogen. So regardless of how we vaccinate or control a pathogen within the human population, if it has a zoonotic source, it’s going to become a recurring threat.
Cara Brook:
And in the case of Coronaviruses, they’re highly, highly diverse in bat populations globally and several have demonstrated their ability to enter human cells, to bind this human cell receptor ACE2 and become infectious in the human population. So I think that it’s really important that we be aware of the potential threats posed by these bat populations, but also understand that processes and patterns of exploitation actually exacerbate this problem, and that by working together with conservation biologists and public health practitioners, we can achieve win-wins for both wildlife conservation and human public health.
Jeff Schechtman:
What is the cutting edge of the research right now? What is it that you and your colleagues are still trying to uncover and understand about these processes that we’ve been talking about?
Cara Brook:
Bat immunology is a very young and up and coming field. I mentioned some of the pathways, interferon was one, but there’s a number of unique host virus specific evolutionary adaptations taken by different bat species with respect to different viruses. Also, to an extent, we sort of off the cuff tend to say that bats don’t get sick from these viral infections, but in most cases of reservoir hosts we’ve eventually been able to demonstrate that there is some sort of pathology.
Cara Brook:
So, a great example is SIV, simian immunodeficiency virus, which infects chimpanzees for a number of years, it was cited in the scientific literature that SIV was totally non-pathogenic but took a 40 year dataset coming out of Jane Goodall’s work to demonstrate that there actually are more survival effects on the offspring of infected mothers. So demonstrating fitness affects of these pathogens on the bat hosts, understanding exactly how they cope with them and what the sort of trade-offs are might give us an opportunity to understand if any of these unique bat defenses are something that could be leveraged for something like immunotherapy in a human.
Jeff Schechtman:
Cara Brook, I thank you much for spending time with us today.
Cara Brook:
Yeah. Thanks, it was a pleasure.

[Peter Lemkin]

The findings, published today in Cell, hold promise as a treatment capable of stopping early infection of the novel coronavirus that, as of April 2, has affected more than 981,000 people and claimed the lives of 50,000 people worldwide.
The study provides new insights into key aspects of SARS-CoV-2, the virus that causes COVID-19, and its interactions on a cellular level, as well as how the virus can infect blood vessels and kidneys.
"We are hopeful our results have implications for the development of a novel drug for the treatment of this unprecedented pandemic," says Penninger, professor in UBC's faculty of medicine, director of the Life Sciences Institute and the Canada 150 Research Chair in Functional Genetics at UBC.
"This work stems from an amazing collaboration among academic researchers and companies, including Dr. Ryan Conder's gastrointestinal group at STEMCELL Technologies in Vancouver, Nuria Montserrat in Spain, Drs. Haibo Zhang and Art Slutsky from Toronto and especially Ali Mirazimi's infectious biology team in Sweden, who have been working tirelessly day and night for weeks to better understand the pathology of this disease and to provide breakthrough therapeutic options."
ACE2 -- a protein on the surface of the cell membrane -- is now at centre-stage in this outbreak as the key receptor for the spike glycoprotein of SARS-CoV-2. In earlier work, Penninger and colleagues at the University of Toronto and the Institute of Molecular Biology in Vienna first identified ACE2, and found that in living organisms, ACE2 is the key receptor for SARS, the viral respiratory illness recognized as a global threat in 2003. His laboratory also went on to link the protein to both cardiovascular disease and lung failure.
While the COVID-19 outbreak continues to spread around the globe, the absence of a clinically proven antiviral therapy or a treatment specifically targeting the critical SARS-CoV-2 receptor ACE2 on a molecular level has meant an empty arsenal for health care providers struggling to treat severe cases of COVID-19.
"Our new study provides very much needed direct evidence that a drug -- called APN01 (human recombinant soluble angiotensin-converting enzyme 2 -- hrsACE2) -- soon to be tested in clinical trials by the European biotech company Apeiron Biologics, is useful as an antiviral therapy for COVID-19," says Dr. Art Slutsky, a scientist at the Keenan Research Centre for Biomedical Science of St. Michael's Hospital and professor at the University of Toronto who is a collaborator on the study.
In cell cultures analyzed in the current study, hrsACE2 inhibited the coronavirus load by a factor of 1,000-5,000. In engineered replicas of human blood vessel and kidneys -- organoids grown from human stem cells -- the researchers demonstrated that the virus can directly infect and duplicate itself in these tissues. This provides important information on the development of the disease and the fact that severe cases of COVID-19 present with multi-organ failure and evidence of cardiovascular damage. Clinical grade hrsACE2 also reduced the SARS-CoV-2 infection in these engineered human tissues.
"Using organoids allows us to test in a very agile way treatments that are already being used for other diseases, or that are close to being validated. In these moments in which time is short, human organoids save the time that we would spend to test a new drug in the human setting," says Núria Montserrat, ICREA professor at the Institute for Bioengineering of Catalonia in Spain.
"The virus causing COVID-19 is a close sibling to the first SARS virus," adds Penninger. "Our previous work has helped to rapidly identify ACE2 as the entry gate for SARS-CoV-2, which explains a lot about the disease. Now we know that a soluble form of ACE2 that catches the virus away, could be indeed a very rational therapy that specifically targets the gate the virus must take to infect us. There is hope for this horrible pandemic."
This research was supported in part by the Canadian federal government through emergency funding focused on accelerating the development, testing, and implementation of measures to deal with the COVID-19 outbreak.

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Journal Reference:

1. Vanessa Monteil, Hyesoo Kwon, Patricia Prado, Astrid Hagelkrüys, Reiner A. Wimmer, Martin Stahl, Alexandra Leopoldi, Elena Garreta, Carmen Hurtado Del Pozo, Felipe Prosper, J.p. Romero, Gerald Wirnsberger, Haibo Zhang, Arthur S. Slutsky, Ryan Conder, Nuria Montserrat, Ali Mirazimi, Josef M. Penninger. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Submitted to Cell, 2020 DOI: 10.1016/j.cell.2020.04.004
   

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The paper appeared today in EBioMedicine, which is published by The Lancet, and is the first study to be published after critique from fellow scientists at outside institutions that describes a candidate vaccine for COVID-19. The researchers were able to act quickly because they had already laid the groundwork during earlier coronavirus epidemics.
"We had previous experience on SARS-CoV in 2003 and MERS-CoV in 2014. These two viruses, which are closely related to SARS-CoV-2, teach us that a particular protein, called a spike protein, is important for inducing immunity against the virus. We knew exactly where to fight this new virus," said co-senior author Andrea Gambotto, M.D., associate professor of surgery at the Pitt School of Medicine. "That's why it's important to fund vaccine research. You never know where the next pandemic will come from."
"Our ability to rapidly develop this vaccine was a result of scientists with expertise in diverse areas of research working together with a common goal," said co-senior author Louis Falo, M.D., Ph.D., professor and chair of dermatology at Pitt's School of Medicine and UPMC.
Compared to the experimental mRNA vaccine candidate that just entered clinical trials, the vaccine described in this paper -- which the authors are calling PittCoVacc, short for Pittsburgh Coronavirus Vaccine -- follows a more established approach, using lab-made pieces of viral protein to build immunity. It's the same way the current flu shots work.
The researchers also used a novel approach to deliver the drug, called a microneedle array, to increase potency. This array is a fingertip-sized patch of 400 tiny needles that delivers the spike protein pieces into the skin, where the immune reaction is strongest. The patch goes on like a Band-Aid and then the needles -- which are made entirely of sugar and the protein pieces -- simply dissolve into the skin.
"We developed this to build on the original scratch method used to deliver the smallpox vaccine to the skin, but as a high-tech version that is more efficient and reproducible patient to patient," Falo said. "And it's actually pretty painless -- it feels kind of like Velcro."
The system also is highly scalable. The protein pieces are manufactured by a "cell factory" -- layers upon layers of cultured cells engineered to express the SARS-CoV-2 spike protein -- that can be stacked further to multiply yield. Purifying the protein also can be done at industrial scale. Mass-producing the microneedle array involves spinning down the protein-sugar mixture into a mold using a centrifuge. Once manufactured, the vaccine can sit at room temperature until it's needed, eliminating the need for refrigeration during transport or storage.
"For most vaccines, you don't need to address scalability to begin with," Gambotto said. "But when you try to develop a vaccine quickly against a pandemic that's the first requirement."
When tested in mice, PittCoVacc generated a surge of antibodies against SARS-CoV-2 within two weeks of the microneedle prick.
Those animals haven't been tracked long term yet, but the researchers point out that mice who got their MERS-CoV vaccine produced a sufficient level of antibodies to neutralize the virus for at least a year, and so far the antibody levels of the SARS-CoV-2 vaccinated animals seem to be following the same trend.
Importantly, the SARS-CoV-2 microneedle vaccine maintains its potency even after being thoroughly sterilized with gamma radiation -- a key step toward making a product that's suitable for use in humans.
The authors are now in the process of applying for an investigational new drug approval from the U.S. Food and Drug Administration in anticipation of starting a phase I human clinical trial in the next few months.
"Testing in patients would typically require at least a year and probably longer," Falo said. "This particular situation is different from anything we've ever seen, so we don't know how long the clinical development process will take. Recently announced revisions to the normal processes suggest we may be able to advance this faster."
Additional authors on the study are Eun Kim, Geza Erdos, Ph.D., Shaohua Huang, Thomas Kenniston, Stephen Balmert, Ph.D., Cara Donahue Carey, Michael Epperly, Ph.D., William Klimstra, Ph.D., and Emrullah Korkmaz, Ph.D., all of Pitt; and Bart Haagmans, of Erasmus Medical Center.
Funding for this study was provided by National Institute of Allergy and Infectious Diseases grant R21-AI114264, National Institute of Arthritis and Musculoskeletal and Skin Diseases grants R01-AR074285, R01-AR071277 and R01-AR068249, and National Cancer Institute grant T32-CA175294.

[Lauren Johnson]

[Peter Lemkin]

Pffft! Not good news to report! I've read a few technical papers on this virus [they have begun to be published], although a LOT about this virus is NOT yet known!!! The picture that emerges is of a virus that is quite different and a lot more nasty than most! In low humidity the virus can stay floating in the air for many minutes from a person shedding the virus. It eventually settles on the ground unless there is a high wind and can stay pathogenic for quite a long time on the ground. Large amounts have been found on shoes in urban locations. So, maybe the habit of some and taking off shoes just outside the door [or just inside] and then washing one's hands well might not be a bad idea. There are also reports of persons who had gotten the virus and then recovered apparently getting re-infected [either that, or they never really were rid of the virus the first time and it lay dormant in some tissues]. It is about  10x more deadly than most other pulmanary viruses - although the exact number is not known. As would be expected, sadly, the poor, those of non-dominant groups, and those with comormid diseases suffer and die most. i.e.,  non-whites and the poor are dying at rates 2-5x the rate of whites and wealthy persons for a number of understood reasons [the effects of societal racism and classism]. When one person in a household gets a full case of the disease, it often is the case that others they live with will, as well. Many of those who died, died of cardiac arrest [it seems to have some negative effects on heart tissue], but more died of lung problems and often had both viral and microbial infection in the lungs [the latter taking advantage of the damage done by the former]. In effect, they drown. There is a very characteristic and unusual pattern seen on CT scans of the lungs - almost a signature for this virus. the lungs heal from the damage very slowly and it is not known if some of the damge may even be permanent. So, the two yard/meter distance rule is not as good as first thought - and double that, when possible is better. Those who have a temperature, feel unwell OR have been in contact [even briefly] with someone who had or within two weeks developed this viral disease should self-quarentine themselves for at least two weeks from that contact OR the end of all symtoms in themselves. Everyone wants this to be over, and eventually it will be - but it will not be over as quickly as most think or most political leaders even dare tell you. It will likely be another 18 months [under optimum conditions] until there is a vaccine and the innoculation of everyone on the Planet is begun [taking another few months]. Between now and then it will vary from location to location dependant on many factors. In most developed countries there will likely continue throughout that entire period some restrictions against large gatherings, handshakes and some other restrictions, although some businesses may be allowed to re-open for periods and be closed for periods. When this is over, we will all be exhausted and damaged financially [except the rich, of course]. Nature lovers will do better than those who are used to doing things in urban areas at least until this is all over. The WHO is suggesting that no local resume anthing approaching normal activities and opening of stores and activities unless and until everyone is tested and those who test positive are kept at home or somewhere for two weeks. People will likely need to be re-tested often [these tests are rather non-invasive and there are attempts at constructing do-it-yourself home tests]...but this means someone has to develop, make and pay for several tens of BILLIONS of such tests!

[Lauren Johnson]

Watch this video @8:40.  A new study would indicate other points of attack.  

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DO THE MEDICAL PROFESSIONALS UNDERSTAND THE VIRUS AND THE DISEASE?  BIG DEBATE.

https://www.nytimes.com/2020/04/14/nyreg...virus.html

Is the disease actually a blood disease that strips the iron from hemoglobin leaving reactive Fe++ free radicals loose in the blood and therefore every organ.  Link: https://medium.com/@agaiziunas/covid-19-...182386efcb

[color=rgba(0, 0, 0, 0.84)]In the last 3–5 days, a mountain of anecdotal evidence has come out of NYC, Italy, Spain, etc. about COVID-19 and characteristics of patients who get seriously ill. It’s not only piling up but now leading to a general field-level consensus backed up by a few previously little-known studies that we’ve had it all wrong the whole time. Well, a few had some things eerily correct (cough Trump cough), especially with Hydroxychloroquine with Azithromicin, but we’ll get to that in a minute.[/color]
[color=rgba(0, 0, 0, 0.84)]There is no ‘pneumonia’ nor ARDS. At least not the ARDS with established treatment protocols and procedures we’re familiar with. Ventilators are not only the wrong solution, but high pressure intubation can actually wind up causing more damage than without, not to mention complications from tracheal scarring and ulcers given the duration of intubation often required… They may still have a use in the immediate future for patients too far to bring back with this newfound knowledge, but moving forward a new treatment protocol needs to be established so we stop treating patients for the wrong disease.[/color]

[color=rgba(0, 0, 0, 0.8)][color=rgba(0, 0, 0, 0.84)]The past 48 hours or so have seen a huge revelation: COVID-19 causes prolonged and progressive hypoxia (starving your body of oxygen) by binding to the heme groups in hemoglobin in your red blood cells. People are simply desaturating (losing o2 in their blood), and that’s what eventually leads to organ failures that kill them, not any form of ARDS or pneumonia. All the damage to the lungs you see in CT scans are from the release of oxidative iron from the hemes, this overwhelms the natural defenses against pulmonary oxidative stress and causes that nice, always-bilateral ground glass opacity in the lungs. Patients returning for re-hospitalization days or weeks after recovery suffering from apparent delayed post-hypoxic leukoencephalopathy strengthen the notion COVID-19 patients are suffering from hypoxia despite no signs of respiratory ‘tire out’ or fatigue.[/color][/color]

[color=rgba(0, 0, 0, 0.84)]Here’s the breakdown of the whole process, including some ELI5-level cliff notes. Much has been simplified just to keep it digestible and layman-friendly.[/color]
[color=rgba(0, 0, 0, 0.84)]Your red blood cells carry oxygen from your lungs to all your organs and the rest of your body. Red blood cells can do this thanks to hemoglobin, which is a protein consisting of four “hemes”. Hemes have a special kind of iron ion, which is normally quite toxic in its free form, locked away in its center with a porphyrin acting as it’s ‘container’. In this way, the iron ion can be ‘caged’ and carried around safely by the hemoglobin, but used to bind to oxygen when it gets to your lungs.[/color]
[color=rgba(0, 0, 0, 0.84)]When the red blood cell gets to the alveoli, or the little sacs in your lungs where all the gas exchange happens, that special little iron ion can flip between FE2+ and FE3+ states with electron exchange and bond to some oxygen, then it goes off on its little merry way to deliver o2 elsewhere.[/color]
[color=rgba(0, 0, 0, 0.84)]Here’s where COVID-19 comes in. Its glycoproteins bond to the heme, and in doing so that special and toxic oxidative iron ion is “disassociated” (released). It’s basically let out of the cage and now freely roaming around on its own. This is bad for two reasons:[/color]
[color=rgba(0, 0, 0, 0.84)][b]1)[/b] Without the iron ion, hemoglobin can no longer bind to oxygen. Once all the hemoglobin is impaired, the red blood cell is essentially turned into a Freightliner truck cab with no trailer and no ability to store its cargo.. it is useless and just running around with COVID-19 virus attached to its porphyrin. All these useless trucks running around not delivering oxygen is what starts to lead to desaturation, or watching the patient’s spo2 levels drop. It is INCORRECT to assume traditional ARDS and in doing so, you’re treating the WRONG DISEASE. Think of it a lot like carbon monoxide poisoning, in which CO is bound to the hemoglobin, making it unable to carry oxygen. In those cases, ventilators aren’t treating the root cause; the patient’s lungs aren’t ‘tiring out’, they’re pumping just fine. The red blood cells just can’t carry o2, end of story. Only in this case, unlike CO poisoning in which eventually the CO can break off, the affected hemoglobin is permanently stripped of its ability to carry o2 because it has lost its iron ion. The body compensates for this lack of o2 carrying capacity and deliveries by having your kidneys release hormones like erythropoietin, which tell your bone marrow factories to ramp up production on new red blood cells with freshly made and fully functioning hemoglobin. This is the reason you find elevated hemoglobin and decreased blood oxygen saturation as one of the 3 primary indicators of whether the shit is about to hit the fan for a particular patient or not.[/color]
[color=rgba(0, 0, 0, 0.84)][b]2)[/b] That little iron ion, along with millions of its friends released from other hemes, are now floating through your blood freely. As I mentioned before, this type of iron ion is highly reactive and causes oxidative damage. It turns out that this happens to a limited extent naturally in our bodies and we have cleanup & defense mechanisms to keep the balance. The lungs, in particular, have 3 primary defenses to maintain “iron homeostasis”, 2 of which are in the alveoli, those little sacs in your lungs we talked about earlier. The first of the two are little macrophages that roam around and scavenge up any free radicals like this oxidative iron. The second is a lining on the walls (called the epithelial surface) which has a thin layer of fluid packed with high levels of antioxidant molecules.. things like abscorbic acid (AKA Vitamin C) among others. Well, this is usually good enough for naturally occurring rogue iron ions but with COVID-19 running rampant your body is now basically like a progressive state letting out all the prisoners out of the prisons… it’s just too much iron and it begins to overwhelm your lungs’ countermeasures, and thus begins the process of pulmonary oxidative stress. This leads to damage and inflammation, which leads to all that nasty stuff and damage you see in CT scans of COVID-19 patient lungs. Ever noticed how it’s always bilateral? (both lungs at the same time) Pneumonia rarely ever does that, but COVID-19 does… EVERY. SINGLE. TIME.[/color]
[color=rgba(0, 0, 0, 0.84)]— — — — — — — — — — — — -[/color]
[color=rgba(0, 0, 0, 0.84)]Once your body is now running out of control, with all your oxygen trucks running around without any freight, and tons of this toxic form of iron floating around in your bloodstream, other defenses kick in. While your lungs are busy with all this oxidative stress they can’t handle, and your organs are being starved of o2 without their constant stream of deliveries from red blood cell’s hemoglobin, and your liver is attempting to do its best to remove the iron and store it in its ‘iron vault’. Only its getting overwhelmed too. It’s starved for oxygen and fighting a losing battle from all your hemoglobin letting its iron free, and starts crying out “help, I’m taking damage!” by releasing an enzyme called alanine aminotransferase (ALT). BOOM, there is your second of 3 primary indicators of whether the shit is about to hit the fan for a particular patient or not.[/color]
[color=rgba(0, 0, 0, 0.84)]Eventually, if the patient’s immune system doesn’t fight off the virus in time before their blood oxygen saturation drops too low, ventilator or no ventilator, organs start shutting down. No fuel, no work. The only way to even try to keep them going is max oxygen, even a hyperbaric chamber if one is available on 100% oxygen at multiple atmospheres of pressure, just to give what’s left of their functioning hemoglobin a chance to carry enough o2 to the organs and keep them alive. Yeah we don’t have nearly enough of those chambers, so some fresh red blood cells with normal hemoglobin in the form of a transfusion will have to do.[/color]
[color=rgba(0, 0, 0, 0.84)]The core point being, treating patients with the iron ions stripped from their hemoglobin (rendering it abnormally nonfunctional) with ventilator intubation is futile, unless you’re just hoping the patient’s immune system will work its magic in time. The root of the illness needs to be addressed.[/color]
[color=rgba(0, 0, 0, 0.84)]Best case scenario? Treatment regimen early, before symptoms progress too far. Hydroxychloroquine (more on that in a minute, I promise) with Azithromicin has shown fantastic, albeit critics keep mentioning ‘anecdotal’ to describe the mountain, promise and I’ll explain why it does so well next. But forget straight-up plasma with antibodies, that might work early but if the patient is too far gone they’ll need more. They’ll need all the blood: antibodies and red blood cells. No help in sending over a detachment of ammunition to a soldier already unconscious and bleeding out on the battlefield, you need to send that ammo along with some hemoglobin-stimulant-magic so that he can wake up and fire those shots at the enemy.[/color]
[color=rgba(0, 0, 0, 0.84)]The story with Hydroxychloroquine[/color]
[color=rgba(0, 0, 0, 0.84)]All that hilariously misguided and counterproductive criticism the media piled on chloroquine (purely for political reasons) as a viable treatment will now go down as the biggest Fake News blunder to rule them all. The media actively engaged their activism to fight ‘bad orange man’ at the cost of thousands of lives. Shame on them.[/color]
[color=rgba(0, 0, 0, 0.84)]How does chloroquine work? Same way as it does for malaria. You see, malaria is this little parasite that enters the red blood cells and starts eating hemoglobin as its food source. The reason chloroquine works for malaria is the same reason it works for COVID-19 — while not fully understood, it is suspected to bind to DNA and interfere with the ability to work magic on hemoglobin. The same mechanism that stops malaria from getting its hands on hemoglobin and gobbling it up seems to do the same to COVID-19 (essentially little snippets of DNA in an envelope) from binding to it. On top of that, Hydroxychloroquine (an advanced descendant of regular old chloroquine) lowers the pH which can interfere with the replication of the virus. Again, while the full details are not known, the entire premise of this potentially ‘game changing’ treatment is to prevent hemoglobin from being interfered with, whether due to malaria or COVID-19.[/color]
[color=rgba(0, 0, 0, 0.84)]No longer can the media and armchair pseudo-physicians sit in their little ivory towers, proclaiming “DUR so stoopid, malaria is bacteria, COVID-19 is virus, anti-bacteria drug no work on virus!”. They never got the memo that a drug doesn’t need to directly act on the pathogen to be effective. Sometimes it’s enough just to stop it from doing what it does to hemoglobin, regardless of the means it uses to do so.[/color]
[color=rgba(0, 0, 0, 0.84)]Anyway, enough of the rant. What’s the end result here? First, the ventilator emergency needs to be re-examined. If you’re putting a patient on a ventilator because they’re going into a coma and need mechanical breathing to stay alive, okay we get it. Give ’em time for their immune systems to pull through. But if they’re conscious, alert, compliant — keep them on O2. Max it if you have to. If you HAVE to inevitably ventilate, do it at low pressure but max O2. Don’t tear up their lungs with max PEEP, you’re doing more harm to the patient because you’re treating the wrong disease.[/color]

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