Expecting the Unexpected: Host response-based detection of respiratory viruses and applications to COVID-19

Transcript

• 00:00But if you have additional questions,
• 00:03so let's now turn to our second Speaker.
• 00:07Doctor Ellen foxman is assistant professor
• 00:09of Laboratory Medison Ann Immunobiology and
• 00:12Ellen received her MD and PhD at Stanford.
• 00:16Her residency training in clinical
• 00:18pathology at Brigham and Women's
• 00:21Hospital before coming to yell and
• 00:24joining the faculty and Ellen is done.
• 00:27Extensive work now really understanding
• 00:29the immune responses and natural
• 00:31responses to respiratory viruses.
• 00:33Which is certainly a very
• 00:35timely topic of research.
• 00:36Uh, in 2020?
• 00:37So we were really pleased that Alan could
• 00:39take the time to share her research with us.
• 00:42So Ellen, thank you.
• 00:43Thank you. I'm
• 00:44happy to be here.
• 00:46And now I'm going to hopefully
• 00:48share the screen and it will.
• 00:49All will go well. Um?
• 00:55All right?
• 00:58Uh. So can you see the slides? Yes,
• 01:02OK, great. OK, well everyone,
• 01:04I'm very happy to be here even though it's
• 01:06by zoom an be able to participate in my
• 01:09first Yale Cancer Center Grand rounds.
• 01:11This actually is not going
• 01:13to be a talk about cancer.
• 01:15It's going to be a talk about COVID-19,
• 01:17which is also a topic on everyone's.
• 01:20Uh, mind these days,
• 01:22so I'll tell you about some of
• 01:25the work our lab has been doing.
• 01:27Looking at host response based
• 01:29detection of respiratory virus an
• 01:32specifically applications to COVID-19.
• 01:34OK, so uh,
• 01:36this is just a disclosure that I'm
• 01:39going to inventor on to patent applications.
• 01:44So today I'll be talking about why are
• 01:46we interested in studying the early host
• 01:49responses against respiratory viruses,
• 01:51or in this case in particular.
• 01:53SARS coronavirus two,
• 01:54the virus that causes cobra 19.
• 01:57I'll give a brief overview
• 01:58on the basics of Cobra 19
• 02:01diagnostics an I'll talk about,
• 02:03then a project that we've been doing
• 02:05since March on screening using host
• 02:07biomarkers for this disease and then
• 02:10future directions of the project.
• 02:14So as I was preparing this talk,
• 02:16I looked back at some of my previous
• 02:19talks and this is actually an intro slide
• 02:21I had from a talk I gave at the end of
• 02:24November to the virology faculty group,
• 02:26and I thought it was kind of.
• 02:28It looks so different in the lens
• 02:30of our current environment that
• 02:32I thought I would show it.
• 02:34So I I used to start my talk by
• 02:36convincing everyone of the importance
• 02:38of respiratory virus infections,
• 02:39which is a much easier sell now,
• 02:41but actually,
• 02:42even before this pandemic,
• 02:43these infections cause.
• 02:44Over 500 million infections
• 02:46per year in the US,
• 02:47so that's more than one per person and
• 02:50granted a lot of those are common colds,
• 02:52but some of those are
• 02:54serious illnesses such as.
• 02:55Influenza with hospitalization or
• 02:57hospitalization for asthma attack or
• 02:59CEO PD Exacerbation which are very
• 03:01often caused by viruses and also
• 03:04there has been this emerging this
• 03:06lingering concern about emerging
• 03:07infections with good reason.
• 03:09As we know now and I usually put
• 03:11up this photo to describe that
• 03:13that's actually a picture of
• 03:15the SARS coronavirus from 2003.
• 03:18But now when we see these pictures
• 03:21it definitely conjures up something
• 03:23else in all of our minds,
• 03:25which is the 2nd SARS Coronavirus SARS Co V2.
• 03:28Uh, which causes the disease cobra,
• 03:3019 and I just checked on the Johns
• 03:33Hopkins Portal an at the moment
• 03:35there's over 7 million cases and
• 03:37over 400,000 deaths described
• 03:38globally from Cobra 19,
• 03:40so this is definitely having a high impact.
• 03:43It's impacting our seminar that
• 03:44were having if I zoom today,
• 03:47it's impacting our work.
• 03:48It's impacting our economy and of
• 03:50course our health and there's still
• 03:52a lot of unanswered challenges
• 03:54were right in the middle of it.
• 03:56Trying to figure out how to deal with it.
• 03:59Um, and even when this acute phase is over,
• 04:02there will be long-term impacts,
• 04:03both on the health of the respiratory
• 04:05system in the patients who are recovering.
• 04:08Or have recovered and we also
• 04:10have to think what lessons can we
• 04:12learn from this that are going to
• 04:14help us with the next pandemic.
• 04:16So this is sort of a just a screenshot
• 04:19of my labs homepage to remind me to
• 04:22tell you a little bit about what
• 04:24we do a little bit more broadly,
• 04:26we really focus on the lining
• 04:28of the respiratory tract,
• 04:30the airway mucosa as you see in this picture.
• 04:33This is actually what the epithelial
• 04:35layer in the upper airway looks like,
• 04:37and these are these cells.
• 04:39The epithelial cells are the target
• 04:41cells of viral infection and viruses
• 04:43replicate all the various respiratory
• 04:45viruses replicate in these cells.
• 04:46And these cells also are the first
• 04:49line of defense that recognizes
• 04:51the infection and sends out signals
• 04:53to the immune system to come to
• 04:56the area and also sends out turns
• 04:58on affecter mechanisms to try to
• 05:00stop the virus from replicating.
• 05:02So there are very.
• 05:04It's a very highly active tissue.
• 05:06The airway mucosa.
• 05:07Our lab is focused on these
• 05:09early steps of host defense,
• 05:11and we're also interested in repair.
• 05:13Actually, because after the.
• 05:14Their way isn't like the skin.
• 05:17It doesn't constantly regenerate,
• 05:18but rather only when damage
• 05:19does it then regenerate,
• 05:20but it has the potential for these
• 05:22stem cells that you see here at
• 05:24the base of the epithelium to
• 05:26proliferate and recreate that issue.
• 05:28And one thing we're interested in
• 05:30is how come that sometimes goes
• 05:31right and sometimes goes wrong,
• 05:33and sometimes when it goes wrong
• 05:35that leads to cancer and that I
• 05:37hopefully I'll be able to come back
• 05:39for a different grounds and talk
• 05:41about that project at some point.
• 05:43But for today I'm going to focus
• 05:44on the upper respiratory tract.
• 05:46As the gatekeeper against infection,
• 05:48so most of the pathogens that
• 05:50come into our airway come in
• 05:52through the nose and mouth throat,
• 05:55and this includes viruses and bacteria.
• 05:57And often if that infection can
• 05:59be nipped in the Bud in the upper
• 06:01respiratory tract that protects
• 06:03the rest of the respiratory
• 06:05system from that that infectious
• 06:07agent getting down to the lungs.
• 06:09So when these offense defenses are
• 06:11effective in the upper respiratory tract,
• 06:14it can really be the difference
• 06:16between miles or asymptomatic illness.
• 06:18Versus a serious illness.
• 06:19And we know that that's happening
• 06:21all the time, not just with SARS,
• 06:23Co V2,
• 06:24but other viruses that often there
• 06:26cleared from the become their
• 06:27detectable in a way for a time.
• 06:29A short time.
• 06:30They and they are cleared without the
• 06:32patient knowing that they were there.
• 06:34That can happen,
• 06:35or you can have the opposite,
• 06:37where the patients in the ICU.
• 06:39So we're interested in factors
• 06:41that modulate those defenses,
• 06:42and we like to think of it as like
• 06:44a marble sitting on a mountain
• 06:46where this is the very beginning
• 06:47of the immune response.
• 06:49That's going to recruit certain
• 06:50activate certain immune cells in
• 06:52the respiratory system and sort of
• 06:53nudging that marble in One Direction.
• 06:55It will roll down the Hill one way,
• 06:57and you'll get one type of response,
• 06:59whereas if you nudge it in
• 07:01the other direction,
• 07:02it can have a very different outcome.
• 07:04So we're very interested in understanding
• 07:06the molecular basis of that.
• 07:09So, uhm,
• 07:09this is a another picture of this as an
• 07:12upper respiratory tract from a child,
• 07:15and so what's something that's kind
• 07:17of interesting about this anatomy
• 07:19is I actually just myself today.
• 07:22Had a swab for this surveillance
• 07:24for the stars,
• 07:25Kobe 2 and we all notice swab goes
• 07:28right in here in the nasopharynx,
• 07:30and that swab also collect some of the
• 07:33patients own cells and some of the
• 07:36proteins made by the patient's own cells.
• 07:39And in a study with Marie Landry
• 07:41of the director of the clinical
• 07:43virology lab back in 2018,
• 07:45we showed that you can actually
• 07:47detect the patterns of jeans and
• 07:50proteins being made in the respiratory
• 07:52tract and the huge changes that
• 07:54occur in the rapid response to
• 07:56viral infection. And if you think
• 07:58about the progression of SARS,
• 08:00Co V2, there's you probably have all
• 08:03seen a figure something like this.
• 08:05And of course this will be refined overtime,
• 08:07but the basic idea seems to be that
• 08:09at this early stage of infection
• 08:12we have upper respiratory tract
• 08:14replication and those kinds of symptoms.
• 08:16Then it moves to the long and
• 08:18then in severe cases there's
• 08:19a host inflammatory response.
• 08:21It causes a lot of damage.
• 08:24Um so.
• 08:25At this early stage,
• 08:27what we can find out using these
• 08:30respiratory swabs is what can we think
• 08:32about alternatives and additional things
• 08:34we can do for the best diagnosis an even,
• 08:37can we understand the difference
• 08:39is an inflammatory response is the
• 08:41very beginning that dictate the way
• 08:43the illness is going to progress?
• 08:46So today I'm not.
• 08:47I'm not gonna talk about bullet .2,
• 08:49I'm gonna talk about bullet .1 today.
• 08:52The diagnosis end.
• 08:54So I'll just start with giving a brief
• 08:56overview on diagnostics for a SARS Co V2.
• 08:59I know we have a diverse audience
• 09:01here an I gave a full length,
• 09:04uh,
• 09:04detailed description of this stuff for one of
• 09:06the Deans workshops that's available online.
• 09:08That this is everything in a nutshell,
• 09:11so I'm going to describe the test
• 09:13that we are currently doing at Yale.
• 09:15New Haven for this virus.
• 09:17The first Test answers a question.
• 09:19Does the patient have the
• 09:20infection right now?
• 09:21And basically what you do for that?
• 09:24Is you do the swab isolate are an RNA.
• 09:27Do RT PCR and ask?
• 09:29Can you detect viral jeans from
• 09:31the viral genome in this patient
• 09:34sample an if the answer is yes,
• 09:36it means a patient has the virus or
• 09:39the viral RNA and their nasopharynx
• 09:41right now and and that test is
• 09:44very specific because we're just
• 09:46looking at the genome of this
• 09:48virus and very specific regions.
• 09:50Sensitivity depends on when your
• 09:52sampling and sample collection
• 09:54and a few things like that,
• 09:56but it's a highly specific test.
• 09:58The other question,
• 09:59of course,
• 10:00is did the patient had the infection?
• 10:02Is there evidence of past infection
• 10:04and that's serology?
• 10:05So that's asking has the patient formed
• 10:08antibodies against the virus because
• 10:09they've already had the infection?
• 10:11Usually for a minimum of two weeks
• 10:13to have an adaptive immune response.
• 10:15And kudos to our clinical lab for having
• 10:18both of these up and running for awhile now.
• 10:21Marie Landry in the virology lab,
• 10:23and, uh, Rick Tourism.
• 10:24The clinical immunology lab
• 10:26have set these up and they're
• 10:28available to order on the patients,
• 10:30and this is this is our go to test to know.
• 10:33The server balance you know
• 10:36someone is infected right now.
• 10:38But there are still challenges.
• 10:40Are there still a lot of challenges
• 10:42that we're facing right now?
• 10:44One is how to expand testing capacity,
• 10:46and there's many different
• 10:47avenues this can go down.
• 10:49There is a group with Nate groove on an
• 10:52Wiley doing great stuff with saliva.
• 10:54Testing is one way,
• 10:56but there are there other ways
• 10:58we can be screening or expanding
• 11:00testing capacity to help make sure
• 11:02we're not spreading this virus.
• 11:04Further, as we restart the economy.
• 11:07Another challenge is that some people
• 11:09who test positive by the PCR tests
• 11:11don't actually seem to be infectious
• 11:13based on a study from South Korea and
• 11:15a few other observations elsewhere of
• 11:17people who recovered and still test
• 11:19positive for a long time but don't seem
• 11:21to spread the virus to their Contacts.
• 11:23So how can we tell the difference there
• 11:26and then finally also very important
• 11:28is how do we find new viruses that
• 11:30are going to be the next pandemic
• 11:32that are going around and causing
• 11:34Ellis in our patient under our radar?
• 11:37And so this is one.
• 11:39These kind of questions are why we got
• 11:41into looking at the host response.
• 11:44In addition to understanding pathogenesis.
• 11:46But sort of on the practical side
• 11:48of how can it help us an once is
• 11:52to die for diagnosis.
• 11:53We're all familiar with them.
• 11:55I mean the basic one for infection is fever.
• 11:58Fever is a host response
• 12:00to infection and fever.
• 12:02Is fever elevated?
• 12:03Leukocyte count?
• 12:03Those are signs that the patient
• 12:06has an infection.
• 12:07They're not terribly specific,
• 12:08but they are a host response
• 12:10has been used for, you know,
• 12:12long time, hundreds of years,
• 12:14even the the fever.
• 12:15But now we can get more granular
• 12:17about it that we have much
• 12:20better techniques to look at.
• 12:22Patterns of gene expression,
• 12:23patterns of protein expression using Multi
• 12:25Plex Technologies like transcriptomics an.
• 12:27The idea is if a patient comes
• 12:29in and is coughing,
• 12:31you don't know what's causing that,
• 12:33but if the if that's being caused by a
• 12:35respiratory virus that's replicating.
• 12:37That's activated,
• 12:38the immune system turned
• 12:39on antiviral defense is,
• 12:40which are different then defenses
• 12:42against an irritant or a bacteria or
• 12:44other things that cause coughing.
• 12:45And if you look at the patterns of Gene
• 12:48and proteins that the body is making,
• 12:50you can sort of interrogate the bodies own
• 12:53diagnosis and and know what's going on.
• 12:56And so,
• 12:57uh, again,
• 12:57this is based on the study from 2018.
• 13:01A very simple question was,
• 13:03are there common patterns to all respiratory
• 13:06viruses that we can look at to say?
• 13:08Is this patient experiencing a respiratory
• 13:11virus infection right now or not?
• 13:13Because you may not know this,
• 13:15but in the winter seasons I'm not
• 13:18talking about this year but in
• 13:20in past years between December,
• 13:22March redo thousands of panels
• 13:25of symptomatic patients testing
• 13:26them for 15 viruses to see.
• 13:28Uh,
• 13:29which virus might be causing their
• 13:31respiratory symptoms and only about 1/3
• 13:33of them actually have a viral infection,
• 13:35so 2/3 of them may have some
• 13:38other process going on.
• 13:39So we asked whether we can look
• 13:41at Biomarkers of the antiviral
• 13:43response to identify who those
• 13:45patients with viral infection R.
• 13:47And this is to this is
• 13:50published something to sum
• 13:51it up very quickly,
• 13:53but the idea is that we found that jeans
• 13:55and proteins that are highly induced
• 13:58during the antiviral interferon response.
• 14:00If you detect those in the nasopharynx,
• 14:03it's a very good good indicator that
• 14:05there's a viral infection there,
• 14:07and this colored graph just shows kcil 10.
• 14:10This is actually one of these
• 14:12interference stimulated jeans.
• 14:14It's a cytokine.
• 14:14And it goes up many orders of
• 14:16magnitude during viral infection and
• 14:18the level of it highly correlated
• 14:20to the presence of the virus.
• 14:22So this is like the level on a log scale,
• 14:25and then these bars indicate
• 14:27that there's a virus present.
• 14:28And we did two different studies at
• 14:31two different times of year with two
• 14:33different viruses circulating an in both
• 14:35of those are represented on these pie charts,
• 14:38which viruses were amongst the
• 14:39virus positives and it's basically
• 14:41any virus that we test for.
• 14:43We could pick up in this way and So what
• 14:46are the potential applications for Koba 19?
• 14:49Well,
• 14:49the first one is we want to know do these
• 14:52pan viral biomarkers pickup COVID-19.
• 14:54It's possible it could be different,
• 14:56and if so,
• 14:57how can this help us fight the pandemic,
• 14:59so there's a lot of more ideas
• 15:01than answers that I have since
• 15:03this is a relatively new project,
• 15:05but I'll just share some of our early
• 15:07data and this project so far has
• 15:09been spearheaded by ready chi Marla,
• 15:11a postdoc in my lab who's been like
• 15:13side by side with me in the lab
• 15:16every day since this pandemic hit.
• 15:18Trying to do the studies I'm going to.
• 15:20Tell you about and get them down the
• 15:22road and I also wanted knowledge.
• 15:24The lab working group.
• 15:26I'll talk about them again at the end.
• 15:28Organized by Albert Cohen,
• 15:29the School of public health who
• 15:31helped us at the beginning all
• 15:33get organised together to get the
• 15:35PCR testing going for research.
• 15:36You sent a support clinical use too.
• 15:39And so this is a graph of Cobra 19 Indiana,
• 15:43the country in our region.
• 15:45Green is the country.
• 15:46The first case was in January.
• 15:49But in our region of Connecticut,
• 15:51in New York,
• 15:52the first case was shown in
• 15:54the blue on March 2nd,
• 15:55Connecticut first case it was in
• 15:58Fairfield County on March 6th.
• 16:00And our testing began on March 13th,
• 16:02which is actually very fast.
• 16:04You may recall there is some
• 16:06snafus with the CDC test and they
• 16:08allowed high complexity in clinical
• 16:10labs like ours to do their own
• 16:13test starting on February 29th.
• 16:14Anna Marie Landry and the folks
• 16:17in the clinical virology lab had
• 16:19it up and running by March 13th.
• 16:21So very fast, but nonetheless,
• 16:23given the patterns that we see here,
• 16:25we wondered,
• 16:26did we miss any cases in those
• 16:28weeks before our testing started?
• 16:30So we performed a screen of the
• 16:32about the two weeks before testing
• 16:34started as shown on this Gray bar.
• 16:37And, uh, first,
• 16:38so during this time period a lot
• 16:41of people have been tested on that
• 16:43complete panel for 15 viruses and
• 16:46376 patients who are symptomatic
• 16:48and had suspected viral infection
• 16:50were negative for other viruses.
• 16:52So we thought, well,
• 16:53maybe some of those might have had SARS,
• 16:56Kobe 2 and we screened with
• 16:59the button marker.
• 17:00I mentioned CL 10 and out of
• 17:02all those negative patients,
• 17:04only about a tenth of them were
• 17:07positive for the biomarker.
• 17:09So it seems a good setup like these are
• 17:11people who tested negative for other viruses,
• 17:13but there's symptomatic.
• 17:14It may have a biomarker
• 17:16that a viral infection,
• 17:18their bodies fighting a viral infection.
• 17:20So then we tested all these
• 17:21people for with the PCR test,
• 17:23and it turns out that among these
• 17:26biomarker positive people were four
• 17:27patients who had actually did have SARS,
• 17:29Co V2, including some surprises like an
• 17:32infant that was seen as an outpatient,
• 17:34that that that was a bit of
• 17:36a surprise to find that.
• 17:39And unfortunately,
• 17:39being here at Yale,
• 17:41we have so many great collaborators
• 17:43with different expertise,
• 17:44we were able to ask Nate Grubaugh
• 17:46slab in the school of public health
• 17:49to sequence those for isolates.
• 17:51This was a paper earlier published by
• 17:53the group lab showing using sequencing
• 17:55of the virus that a lot of the early
• 17:58cases coming to Connecticut were
• 18:00from transmission that were domestic
• 18:02rather than international an the four cases.
• 18:05I hope you can see this,
• 18:07but the four cases that.
• 18:09Uh,
• 18:09we had picked up in those early weeks.
• 18:12Kind of fit this pattern.
• 18:13Three of the case is shown
• 18:16with the sort of red lines.
• 18:18They do a track most closely with North
• 18:20American other isolates from North
• 18:22America as opposed to other countries.
• 18:24And then there was one that tracked most
• 18:27closest to strains from Western Europe.
• 18:29So this kind of fit the pattern will
• 18:32also is really interesting to me.
• 18:34Is that all these for patients that came
• 18:37within a couple of days the hospital
• 18:39none of their viruses were directly
• 18:41related were the same as the other,
• 18:44so this is independent
• 18:45introductions coming in,
• 18:46which was also probably says something about
• 18:48travel back and forth and things like that.
• 18:51So that was quite an interesting
• 18:53bonus of being a in collaboration
• 18:55with other folks at Yale.
• 18:57To find more information
• 18:59about those patients.
• 19:00Uhm,
• 19:00but we also had an idea just looking at this.
• 19:04Well this is interesting.
• 19:05Like here we used up,
• 19:07you know 376 PCR test to
• 19:09test all these patients.
• 19:10But really if we had only tested the 33
• 19:13that were positive for the biomarker,
• 19:16we still would have found all the cases.
• 19:18And so it suggested maybe this
• 19:20is a way of expanding,
• 19:22like conserving,
• 19:23testing capacity or directing
• 19:25it towards people who really are
• 19:27high suspicion to be positive
• 19:28and so we tried that so far just.
• 19:31Piloted one day.
• 19:32We picked one day in March
• 19:34where we were able to get all
• 19:36the residual samples from
• 19:38testing went 144 patients were
• 19:39tested that day for SARS, Co V2.
• 19:42And did the biomarker test an what you
• 19:45can see is again as a smaller proportion
• 19:48of people were positive than negative.
• 19:51And then we compared this to the
• 19:53results from the PCR testing and it
• 19:56turned out that 17 people were PCR
• 19:58positive for SARS Kobe to that day.
• 20:01And 16 of them were among
• 20:03the biomarker positive,
• 20:04but one wasn't one was did not
• 20:06have the biomarker expressed,
• 20:07and that patient also happened
• 20:09to have a very low viral load,
• 20:11which is kind of something
• 20:13we're following up on.
• 20:14So if we had had all 17 up here,
• 20:17we could have said are
• 20:19negative predictive value.
• 20:20If you're negative on this biomarker,
• 20:22you don't have the virus is 100%,
• 20:24but we can't say that we
• 20:26have to say 99% because of.
• 20:28This this one patient out of out of
• 20:32the 144 that were screened and tested.
• 20:35Um, so we that got us interested in
• 20:38biological variables and how they
• 20:40impact this biomarker that's induces
• 20:43approaching that's induced by viral
• 20:45replication within the epithelial
• 20:47cells and possibly infiltrating cells.
• 20:49And we looked at all the positive
• 20:52patients in our initial study,
• 20:53which was 59 patients.
• 20:54If you look at their age distribution
• 20:56there mostly in the older age groups,
• 20:58and if you look at the symptoms by age group,
• 21:01the people in the older age
• 21:03groups had more serious illness.
• 21:04As you might expect much more likely
• 21:06to be hospitalised and have things
• 21:08like pneumonia and hypoxemia.
• 21:10So, uhm,
• 21:11So what about the correlation
• 21:12with the biomarker?
• 21:13Well, if you look at, uh,
• 21:15if you look at viral load
• 21:17versus the biomarker,
• 21:18there's a positive correlation.
• 21:20As you might expect.
• 21:21Because, as I mentioned,
• 21:23the trigger for production of this
• 21:25biomarker is viral replication.
• 21:27Um,
• 21:27interesting if you look at
• 21:29age versus the biomarker,
• 21:30there's a negative correlation
• 21:32where this biomarker is lower and
• 21:34the people with the older age is.
• 21:36But there doesn't seem to be a
• 21:38clear correlation between agent
• 21:39viral load in this same group,
• 21:41so we're still investigating this.
• 21:43So we actually struck up a collaboration
• 21:45with the Pediatrics Department,
• 21:47including Tom Murray and Danielle
• 21:49Pediatrics to delve into this further
• 21:51and see if we can figure out what's
• 21:54going on with this age correlation.
• 21:56I so finally I just want to mention um,
• 22:00what's ahead for this project?
• 22:03I mentioned from these headlines
• 22:04some of the challenges and we would
• 22:07like to know Kenneth biomarker
• 22:08help us to the question of who has
• 22:11live infectious virus versus is a
• 22:13persistent PCR positive but not infectious.
• 22:15Anna question everyone always asked me.
• 22:17I'm just going to preempt it.
• 22:19It would be great to know what this
• 22:21this type of biomarker an in general,
• 22:24what the host response to infection,
• 22:26how it's changing overtime during the
• 22:28course of what can be a long illness.
• 22:31And so we're actively looking at that
• 22:33right now. And I just want to finish.
• 22:36I just want to nod my head to a
• 22:39project that actually was going
• 22:40on a lab before the pandemic hit.
• 22:43Briefly got pause.
• 22:44Dan is getting restarted now of trying
• 22:47to find the next pandemic virus
• 22:49before it hits using this strategy.
• 22:51And this was spearheaded by Amelia
• 22:53Hammer in a Yale School of Public
• 22:55Health Masters student who is
• 22:57in my lab but graduated in 2019.
• 23:00And our idea there was the same
• 23:02idea of let's look at people who
• 23:05their doctors suspected viral
• 23:06infection sent the test.
• 23:08They tested negative for all the
• 23:10viruses on our panel and see if we
• 23:12can find people who who looks like
• 23:14their body was fighting a viral
• 23:15infection and maybe they have a
• 23:17viral infection that we don't know
• 23:19of so we can find out what other
• 23:21viruses are causing disease in
• 23:22our patient population that were
• 23:24not catching with our panel.
• 23:26And so Amelia just took one week
• 23:28of January 2017 and screens 250.
• 23:31One negative samples with our biomarker
• 23:34that we talked about here CL.
• 23:3610 and she had 60 of them that were
• 23:39had high levels of the biomarker
• 23:42at that time.
• 23:44We were not doing testing for
• 23:46the seasonal coronaviruses or
• 23:47parrot influenza virus.
• 23:494 so she did that testing an interesting Lee.
• 23:53Half of these patients had
• 23:55seasonal coronaviruses and
• 23:56that actually tipped our hat.
• 23:58Let us know that seasonal Corona
• 23:59viruses are circulating in our patient
• 24:01population and actually Marie Landry
• 24:03has now added that to the clinical panel.
• 24:05So now that is those four
• 24:06viruses are on our panel,
• 24:08but this also as a proof of concept
• 24:10that our strategy works of picking up
• 24:12viral infections that we're not testing for.
• 24:15Um, Interestingly,
• 24:15we also have half the samples
• 24:17where we didn't.
• 24:18We still don't know exact
• 24:19well for some of them we do,
• 24:21but many of them we don't know what what
• 24:24infectious agents are in the sample,
• 24:26and we're working that up and
• 24:27finding some interesting things,
• 24:28and we hope this will be a good strategy.
• 24:31Going forward to get an even more
• 24:33comprehensive view of the viruses
• 24:35that are circulating so we can be
• 24:37prepared for ones that we aren't
• 24:39necessarily testing for right now.
• 24:41So, just to summarize, um,
• 24:43uh,
• 24:44we're interested in studying the host
• 24:46response to fight coronavirus today.
• 24:48I talked about diagnostic applications
• 24:51were also really interested in getting
• 24:54insights into early stage pathogenesis.
• 24:56And how this differs among people
• 24:58who have different outcomes.
• 25:00Uhm,
• 25:00I talked about a host response based
• 25:03screening test that we've been working on,
• 25:06which allowed us to identify for
• 25:08undiagnosed cases from early March
• 25:10and we're looking at other utilities
• 25:13to sort of fill in the gaps in
• 25:16some of our testing strategies,
• 25:17and hopefully I'll be able to
• 25:20update you in a future talk on our
• 25:23undiagnosed viruses project as well.
• 25:26I saw with that before,
• 25:28I conclude I'd like to thank all the many,
• 25:31many people in this Yale environment
• 25:33have contributed to projects
• 25:35on COVID-19. Definitely could
• 25:36have been done in a silo.
• 25:39It was very great to have lots
• 25:42of collaborators an it still is.
• 25:44I want to acknowledge my my lab
• 25:46members including ready tomorrow.
• 25:48I mentioned who spearheaded the project.
• 25:50I talked about as well as Marie
• 25:52Landry on the clinical virology lab,
• 25:55especially Marino in and Robin Garner,
• 25:57who really helped us alot.
• 25:59Dezhen Zou, who's been helping
• 26:01with our bioinformatics,
• 26:02I didn't really talk about that today,
• 26:05but he's been a great help the whole group,
• 26:08all lab and Nate grew bath for their
• 26:11constant participation and help
• 26:13with the molecular Epidemiology.
• 26:14As well as lab working group depicted here
• 26:17from March 2nd which includes Albert Konate,
• 26:20grew Bhasa Domer Akiko Isaki Marie Landreau.
• 26:23That's me actually.
• 26:24And this was back when there's only
• 26:2745,000 global cases on March 2nd.
• 26:30Uh, so with that?
• 26:31Uhm, I think I made up some time.
• 26:33Uh, in in speaking a little quickly,
• 26:35but hopefully you're able to follow.
• 26:36And if there's any questions I
• 26:38would be happy to answer them now.
• 26:41Thank you
• 26:41Ellen. Thank you and congratulations to
• 26:43you and your entire research group on that
• 26:46impressive body of work in a relatively
• 26:48short time to address the pandemic.
• 26:50and I know we're just about
• 26:52the top of the hour or so,
• 26:54and if folks can submit questions,
• 26:56but let me just offer up a couple.
• 26:59One is specifically.
• 27:00I mean, I think the work you're doing
• 27:02on sort of the biomarkers is really
• 27:04interesting in terms of testing strategy,
• 27:07and you mentioned that you're
• 27:08anticipating one of my questions,
• 27:10which was, how does it change
• 27:12over the course of the illness?
• 27:14But I'm curious,
• 27:15do we have a sense of biomarkers that
• 27:17might predict the severity of illness
• 27:19that is almost to predict who's
• 27:21more likely to need more intensive
• 27:23care at the time of diagnosis?
• 27:26Yeah, that that's very interesting people.
• 27:28There's been a some work already published
• 27:31about blood like cytokines in the blood
• 27:33that could be indicated indicative
• 27:35of that we're looking even earlier.
• 27:37I mean it at the at the early stage
• 27:40of infection, the nasopharynx.
• 27:42And that's one reason why we're
• 27:44really interested in this potential
• 27:46difference between adults and kids.
• 27:48Because, you know,
• 27:49kids are seem relatively protected from
• 27:51pulmonary disease compared to adults,
• 27:53older adults.
• 27:54So that's one reason why we
• 27:56struck up this collaboration with
• 27:58Pediatrics to try to understand.
• 28:00Is there some difference in the robustness
• 28:02of that initial response that could you
• 28:04know that could possibly explain this?
• 28:06There's many explanations,
• 28:07but that's one,
• 28:08so that's that's the kind of thing
• 28:10we're going to we're looking into,
• 28:12but I don't have the answer yet.
• 28:15This is it's very rare to give a talk on a
• 28:18project that started like two months ago,
• 28:21but so that's why there's a more
• 28:23questions than answers at this point,
• 28:25but we hope to find that out.
• 28:27We're looking at the whole.
• 28:29The entire pattern of gene expression.
• 28:31Um and not just this one biomarker to try
• 28:33to get it that in some specific groups
• 28:36of patients with different outcomes.
• 28:39So you know just to follow up on that.
• 28:42So do we think that, uh, I mean,
• 28:44likely the airway response.
• 28:45It is before the subsequent
• 28:47sort of larger immune response.
• 28:48The airway response is likely
• 28:50very different across ages.
• 28:51And you think that could be one
• 28:53of the major explanations why age
• 28:55is such a strong predictor for
• 28:57outcome in this illness. Possibly
• 28:59possibly, I'd like to have the
• 29:01data to answer you definitively,
• 29:03so hopefully will have
• 29:04that soon. Yeah, well,
• 29:06it sounds like more to follow.
• 29:08Well, channel and for two really superb
• 29:10talks and the work that they do.
• 29:13Thank you all for joining us today.
• 29:15I know a lot of folks also watch
• 29:18online as we as the labs reopened but.
• 29:21Enjoy the rest of your day and
• 29:22thank you all for your work.
• 29:24Thank you very much.