Episode 43 about CAR-Macs was MACnificent. I shared this episode with a journal club paper I presented discussing a macrophage therapy where IFNy “backpacks” are loaded on macrophages before delivery. Here is the link, I think it is open-access:
These backpacked macs keep their anti-tumor M1 activation inside of tumors because the backpacked IFNy provides a localized pro-M1 signal. In this paper, the authors delivered IFNy-backpacked macs to a breast cancer metastasis mouse model and showed that backpacking promoted tumor destruction and mouse survival. Additionally, the IFNy carried on the macrophages helped promote more of an M1 phenotype in the endogenous tumor associated macrophages.
In summary, they backbacked the macs an INFy snack that sustained them on the tumor track. The macs also shared the IFNy snack from their backpacks with the tumor macs to put them on the attack.
With a backpack on the mac, make the cell M1;
This tumor will come undone.
Thanks for sharing new immunology inside and outside of COVID-19. I look forward to the next episode regardless of topic. Maybe soon we’ll hear the long promised episode on bat immunology. Either way, I will be tuning into the next episode, same bat-time, same bat-channel.
Hi Immune team,
I’m a PhD-holding academic research scientist, but have no training in immunology other than what I’ve learned through osmosis. I often listen to your podcasts two or three times over while doing my own research in biochemistry, just to catch every tidbit, in addition to all of the other This Week in… relatives. I have a few questions for your fabulous team.
#1. In an episode of the Johns Hopkins Public Health on Call podcast (#168, “A Theory on Blood Clots and COVID-19”), host Dr. Joshua Sharfstein speaks with Dr. Robert Brodsky discussing a research publication in the journal Blood (https://doi.org/10.1182/blood.2020008248). They speak at length about SARS-CoV-2 interacting with heparan sulfate at the cell surface and activating the “complement” immune system, leading to some of the more nefarious thrombotic events seen in COVID disease. Can you speak about the “complement” arm of the immune system more? Previous to this podcast, I had only heard of the innate and adaptive immune systems.
#2. In September, Derek Lowe’s Science Magazine blog In the Pipeline discussed a potential grand unifying hypothesis for SARS-CoV-2 effects centering around the “bradykinin hypothesis” (https://blogs.sciencemag.org/pipeline/archives/2020/09/08/bradykinin-and-the-coronavirus; original paper here: https://elifesciences.org/articles/59177). There he discusses a “bradykinin storm” as being at root of the severe complications we see in this disease as opposed to a “cytokine storm”. Can you discuss this possibility? Are there other diseases in which a bradykinin storm has been observed? Are there other diseases that go off the cytokine path to create other small molecule or peptide “storms” that yield severe complications?
Thanks for your great discussions!
Sarah Wynia-Smith, PhD
Research Scientist, Smith Lab
Department of Biochemistry
Medical College of Wisconsin
Hello immune team
it was great to see all of your faces on zoom (finally) so I could connect the voices to the people. I had imagined you smiling and wasn’t wrong
Here is a nice article I found (that you can talk about some time in 2022 when COVID is over) about sleep and the immune system. My question is if sleep is so important (and nobody knows about it? or do they just ignore it?) then shouldn’t medical staff’s working schedules be changed to something that amounts to more sleep for them? (36 hour working days/100 hr working weeks: why are they a good idea in the first place?). Shouldn’t this be a law under the health and safety umbrella? my guess is, if these scientists are right, then there is no wonder why medical staff showed higher death rates during the pandemic: they didn’t sleep!
thanks again and stay safe!
Dear Masters of the Immuniverse,
Thank you for continuing these very valuable podcasts. Even though I still don’t understand immunology since the days of my first undergraduate course decades ago, my current level of not understanding is far less terrifying and much more enjoyable.
I have a brother who is a vibrant 78 and living in Burnet, Texas. Not that far (by Texas standards) from Buda. He lives alone and when he shops for groceries, he drives his truck that has only one bumper-sticker: the small bat bumper-sticker ubiquitous among cavers. He has been caving since he was in high school, mostly in Mexico and Texas, but hasn’t gone underground for several years, although he is still active in the caving community. I went caving with him only once, but I have seen thousands of his photos from extended underground trips, and listen to stories of the groups wading through waist-deep bat guano, swimming in underground lakes and rivers, and camping for days underground. I imagine they have been exposed to some nasty things.
After listening to your podcasts, it occurred to me that these hard-core active caving enthusiasts, ranging in age from teens to the seventh decade, might have antibody and adaptive immune cell profiles worth studying. As they have annual gatherings during non-pandemic years, they could perhaps donate the appropriate body substances prior to the drinking and tall-tale telling. Would something like this even be possible and useful? Many of these cavers live in or near Austin, and perhaps Rich Condit could suggest how this could be arranged.
On another topic, in Immune 35 you mentioned a paper – the literature review with one of the co-author institutions here in Bangkok called AFRIMS (Armed Forces Research Institute of Medical Sciences). AFRIMS operates under WRAIR and has been here for more than sixty years (the US CDC also has a branch here). I brought up a question (read in a previous episode) about factors in Thailand that might have resulted in the very low per-million population mortality ratio and seeming higher tolerance to SARS-COV-2 infections, and among those factors could be lifetime exposure to enteroviruses, coronaviruses, dengue, and other bad stuff. Thai compliance with mask-wearing and physical-distancing has probably played a major role in keeping hospitalizations and reported cases down to about 3500 total (in a country of 69 million) and a 58 deaths (case fatality ratio of 1.6%, correct?). I know some studies are being done here, but my sense is that far more research could be done given we have such a large advanced hospital system and places like AFRIMS. Perhaps one of your group or some colleagues could propose immunological studies here that could be funded and take full advantage of the resources and population? Just a thought.
Thanks again for your efforts and stay well.
Hi, Immune crew,
I am a regular listener but this is my first time writing in. Among other subjects, I teach immunology to undergrads at Albright College located in Reading, PA. It is my favorite subject to teach with virology being a close second! I like listening to Immune to keep me updated on recent developments in the field and to stay informed of areas of immunology that I wouldn’t normally be exposed to. You all do an excellent job.
After coming to Albright, I shifted my research program to in vitro studies of host/virus interactions; I use ectromelia virus (mousepox) as a model. It is safe for undergrads to work with and produces many host modulatory gene products. However, my PhD thesis work was quite a bit different! I worked under the amazing direction of Mike Betts at the University of Pennsylvania. My primary project focused on the study of HIV-specific CD8 T-cell responses from “elite controllers” vs. normal progressors. I would collect and re-stimulate human PBMCs with peptides all the time. I did so many intracellular cytokine staining assays that I started to dream about flow cytometry at night!
Therefore, I listened with great interest to your most recent discussion of the study titled “Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans”. You brought up many interesting points and critiques of the study. One particular aspect that you kept coming back to is the 14 day incubation period following peptide stimulation and trying to differentiate between naive and memory responses. I agree this could be hard to tease out.
I am wondering if memory T-cells are selectively expanded in this culture system simply because they are already antigen-experienced and no longer require co-stimulation to proliferate. As you know, a naive T-cell requires both antigen (signal 1) and co-stim (signal 2) to start dividing and differentiating. These signals are typically delivered by dendritic cells in a lymph node. I am wondering if naive T-cells can even really be activated in the system used by the study authors whereby T-cells were stimulated ex vivo by exogenous peptides. In such a system, there should not be an inflammatory stimulus (e.g., PAMP detection) to turn on expression of co-stim molecules, such as CD80/86, on antigen-presenting cells in the culture. Could this explain why the expanded T-cells were most likely an amnestic memory response and not a recently activated naive T-cell? I’m not sure. In my grad work, I only ever stimulated for 6 hours before staining for cytokine production. Therefore, I was only ever detecting effector or memory T-cells.
This is my line of thinking and would love to hear your feedback to see if this is a plausible explanation.
Thank you again for the time you put into doing Immune.
Adam Hersperger, Ph.D.
Associate Professor of Biology
Chair, Biology Department
Good Morning Immune Podfessors,
Thank you again for these awesome podcasts. You make the world of immunology accessible to mortals. This is not a trivial achievement. I have tried in the past to get a grasp of the subject only to be beaten back by the crazy nomenclature. Since I started listening I have started jumping over the barriers that the subject has placed in front of me. Thanks for the leg up. I just finished listening to episode 4 on CAR T cell therapy. Could you do an update? Perhaps you could talk about oncolytic virotherapy. The idea of infecting a tumor with a virus to destroy the tumor is super cool. When I heard about using a polio virus to infect a brain tumor I was just flabbergasted. Thank you for giving my idea consideration.
PS this is where I heard of oncolytic virotherapy https://www.youtube.com/watch?v=vzHROtsoJDY
Hi Immune Gang!!
Before I start just wanted to do a quick and HUGE thank you for everything you have doing in terms on creating a medium where scientific inquiry and discussion are the basis for all discussions pre and during the pandemic. The Microbe TV empire is a true gem and a corner stone in scientific discussion.
My name is Chirag and I’m a grad student at Northwells’ Feinstein Institute for Medical research on Long Island (where it is a sunny 77 degrees F). Most of my projects in the lab center around B cell functionality in autoimmune diseases. Something that Brianne said in Immune 34 during the question section really sparked my interest. She was talking about how immunity induced by an infection may be different/ not as robust as immunity induced by a vaccine. I did a little digging and came across this Cell Pre-proof: https://www.cell.com/cell/pdf/S0092-8674(20)31067-9.pdf
Basically this paper is saying that the virus could potentially prevent a specific, durable antibody response due to the lack of germinal centers. Germinal Centers are something we are interested in the lab, so I am now doing a journal club paper presentation on this in a few weeks and looking forward to it!! My question is, Do we know if other coronaviruses cause a similar immune (or lack of immune) response or is this SAR-COV-2 specific? This paper is indicating a reduction in TFH cells- do we see that in other coronaviruses as well? It would make sense since common coronaviruses can reinfect individuals, indicating an eventual waning of antibodies.
This pandemic has been a real catch 22 for me, as I am furiously reading and enjoying all the immunology papers that are coming out about the virus and disease however, immediately feel guilty as I see so many people dying and suffering due to the medical and economical effects of the pandemic. I’d like to thank you guys again for keeping both the Science and the human aspects of this pandemic prevalent in your discussions and I look forward to listening to future episodes of the Microbe Tv-verse.
Hello my name is Gordon and I’m a woodcarver from Tennessee with no medical background or training but I did enjoy your recent podcast because I find all of this about coronavirus very interesting.The reason I am emailing is the topic at the end of the podcast about the man in Hong Kong re-infected but not sick was intriguing because I watched the numbers in Italy on worldometer all through the height of the infections. If you look at infections today in Italy the closed cases 242000 toal 206000 survived 35000 died and that’s 15% of the closed cases died, but what is very interesting to me is the Active cases they have today 20,000 people infected but only 69 in critical care. back at the height of the infections if they had 20,000 infected they would have several hundred or more in critical care which makes me think that maybe the 20,000 active right now contain a large portion of reinfected people who are not getting seriously ill.
[as Daniel says, doctors are learning how to take care of patients]
My name is Thomas from Sonoma County Ca. right in the middle of the LNU fire! I love your show, especially the video version where I can see you interact. I previously watched many of Dr Vincent Racaniello’s virology lectures. I have an engineering background with no formal biology training. I’ve read many papers trying to understand the immune system and its practical aspects like “antibody testing reliability” and “vaccine design reliability” but few papers are able to answer specific questions. I have just enough knowledge to be dangerous. Two question came up for me while watching your episode 34.
1) Many of the most prominent COVID vaccines appear to be the equivalent to a subunit (single protein or peptide out of many) vaccine which would seem to be limited in immune response to the one spike protein. The idea of neutralizing antibodies (or blocking ACE2 cell entry) is broadly hyped but how can there be enough antibodies to actually block potentially billions of virus particles and stay ahead of their dramatic reproduction rate. It seems foolish to think its possible to block every virus entry and then stay ahead of the population. If that fails then it seems that these are just subunit vaccines that could trigger a limited and possibly meager antibody and T Cell ( all types) response. This may not “stir up” the most complete overall response plus may be very susceptible to genetic changes in the few epitopes amino acid sequences. It would seem that a better strategy would be to use a carefully genetically altered full viruses full array of proteins plus the neutralizing protein ( via mRNA) so as to achieve both the cell access blocking AND widespread antibody and T Cell epitope recognition over all peptides and broad enough to resist genetic changes. This in turn would seem most likely to establish both the quickest and robust future adaptive immune response given all the positive feedback (cytokines etc..) signaling back and forth to the innate system needed for a robust response and not just blocking or neutralizing. Is there something I’m missing in my simple analysis? My understanding is all HSV subunit vaccines have failed miserably in part for this reason. Could you give your thoughts as I know its a very complex problem.
2) Many viruses and all pathogens have many surface exposed proteins each which have hundreds of potential peptide epitope sites and some have widely varying strain/species (epitope variation due to changes to Amino Acids) yet cause the same disease. How does an antibody test designer choose a specific (or a few) epitopes and an associated few antibody set to find in the blood that has a high enough specificity ( the right pathogen), sensitivity (low false negative rate) and sufficient blood levels ( e.g. I have low total IgG and subtypes) for detection accurate enough to be useful? How good are typical antibody tests such as in COVID unless they test for many possible separate antibodies (and not cross react with the cold viruses) as might be done in a Western Blot where the levels and multiple specific antibodies ( e.g. 10 or more) can be “seen individually” to allow excellent discretion. But even a Western Blot can be “fooled” by a sufficiently distant strain or species that results in the same disease. Could you give your thoughts on this difficult problem?
thanks and regards,
My warm greetings to the immune triad.
I am Raghu from India, An Undergraduate Pre-final year Biotechnology student. I have just been introduced to my Immunology coursework and have started listening to the immune podcast. I find immunology very interesting and inquisitive, mostly because I feel there is a certain enigma to the subject.
I have certain doubts regarding MHC molecules, thought you all might be able to help me with it.
- Every individual has 6 different possibilities of MHC class 1. Will they express all 6 MHC class 1 or any 1 among the 6 possibilities?
- Since the MHC molecules don’t bind to all peptides equally, is there a possibility that any 1 type (among the 6) of MHC 1 can effectively present a type antigen to Tc Cells compared to the other 5?
- If a person/newborn is diagnosed with HIV is it possible to mutate a class of HLA – B to HLA -B27 to decrease the progression of the disease?
I hope I didn’t waste your time.
Hello Immune team,
I have been listening to TWiV for a few weeks and I recently listened to Immune episode 33. I am really enjoying the podcasts, and I hope that over the course of listening, I am starting to become a more informed consumer of information about the immunology and virology of COVID-19.
As a (retired) statistician, I am writing this in hopes that I can return the favor and assist the team in helping your listeners become more informed consumers of the statistics in papers. To that end, I’d like to discuss a couple of serious statistical concerns about the paper you reported on in Immune 33.
My first concern is that when one analyzes a data set with a large number of variables and looks at a lot of relationships among variables, you are likely to get some artifactual findings (i.e. findings that show up as statistically significant but are in fact due to chance). The first part of this paper reports a large number of findings, without, as far as I have been able to determine, any indication that the study should be treated as more appropriate for hypothesis generation (to be tested in a later confirmatory study) than for drawing firm conclusions. I believe that one of the Immune team mentioned this when talking about the paper, but mostly the message got lost in the excitement of the presenters trying to make sense of the immunological results reported in the paper. As an example, the association found between lower immune response and less severe disease is intriguing, but it appears that the “low immune response” group (immunotype 3) is just 20 cases among the hospitalized patients, and with a small number of cases and a large number of immune variables to choose from, there are many possible ways to find an apparent relationship that is in fact spurious. At a minimum, I would have liked to see some mention in the discussion section of the exploratory nature of the study.
The second concern is with the claim that “distinct immunotypes” have been found. In looking at figures 6D and 6E, which show two versions of the UMAP components 1 and 2 in scatterplots, I see no indication of a breakpoint in the distributions, except for a clear distinction between the active disease group and the others. Similarly, a scatterplot of the first two principal components of the flow cytometry data (figure 2A) show distributions without breakpoints except for the break between active COVID-19 and the RD/HD group. These scatterplots strongly suggest that the “immunotypes” are not in fact “types,” i.e. categories, among active COVID-19 cases, but rather are arbitrary cutpoints of continuous distributions of characteristics. Similarly, immunotype 3 is simply made up by taking the lower 50% of the distribution on 5 variables, with no indication that this is a natural grouping. There are statistical tests for the existence of gaps in statistical distributions and for natural clusters in multidimensional data, but as far as I could find, this paper reports no such tests.
In Immune 33, I would have liked to hear some discussion of these statistical issues. In general, along with the high-quality information you present on virology and immunology in your podcasts, I would encourage you also to take notice of strengths and weaknesses of the statistical analyses when you are discussing research papers.
Dear Vincent, Stephanie, Cynthia, and Brianne,
I’m a new Immune listener and plan to continue to tune in as part of my prep to teach Immunology next year (it’s been a while – I’m rusty!). In episode 39, your discussion of the cost of publishing and the focus on high impact journals for tenure and promotion caught my attention. My institution chose a path you did not discuss. Granted, I work at a small college, so our publication pressures are different than R1 institutions and maybe this would never work elsewhere. But, several years ago, we voted as a faculty to publish in open access journals whenever possible. In order to support this, the college established a fund to help us pay for the additional cost associated with publishing in open access journals. It became an institutional priority with full support of the faculty and monetary support of the administration. And while we’re still excited if a colleague publishes in Science or Nature, that is not our focus. It’s a refreshing change.
Thank you for all you do – I’m looking forward to future episodes!
Tricia Humphreys, Ph.D.
Associate Professor and Chair of Biology