For 25 years, the Toll-like Receptor pathway was considered a series of distinct protein complexes that drive inflammation. Today, we report that the entire pathway, from receptor to transcription factor, is executed from within one complex—the myddosome.
Who wants to be a Harvard Professor?
Calling all postdocs. I am running a search for a new junior faculty member. Specific area of biology is not specified--we are merely interested in smart people who want to change the world. Deadline November 1.
Microbial signals are not enough. PAMPs are not the only information gathered by our immune system. Oxidation of our own lipids—which occurs during infection-associated tissue injury—is the sister signal we use to gauge threats to the host.
Despite the view of PRRs as pathogen sensors, >24 PRRs in animals and plants are best-suited to detect infection failures that result from low fidelity virulence strategies (i.e. infection fidelities).
Today I was promoted to full professor at Harvard. While this honor goes on my CV, in reality it is due to the efforts of my scientific family. Their discoveries have made my career what it is. I love them all.
#luckyboss
@harvardmed
@BostonChildrens
Grad school is hard when you love it and impossible when you do not. With PhD interview season beginning, applicants should note that you are interviewing us. Do not be passive. Get your questions answered and make the right decision for your life. Then go change the world!
Honored to share this big fat review on Toll-like Receptors, which was a collaboration with Kate Fitzgerald. Many thanks to the editors at
@CellCellPress
for their enthusiastic support. And thanks to Janeway for showing us the way.
@FitzgeraldKate
Everything you wanted to know about the Big Three DNA Sensors: AIM2, cGAS, TLR9. Several suppritive characters also discussed. A must read authoritative review by Fitzgerald.
@FitzgeraldKate
If someone ever asks you “What is the function of cGAS?”, the response should be—which cGAS? Our new study reveals three functionally distinct classes of cGAS proteins in nature, each differing in the mechanisms of self-DNA induced interferon responses
If you want to live forever, don’t rely on therapies that target CD8 T cells.
We found that checkpoint inhibitors protect young mice from cancer, but not elderly. In old mice, NLRP3 inflammasomes in hyperactive DCs prevent cancer via CD4 (not CD8) T cells
Ever wonder what happens when ecosystems clash? Our new study describes how the rules of pattern recognition are defined locally, not globally. We went to the deep Pacific Ocean to test the limits of our innate immune system.
What do cats, tigers, bears, seals and cheetahs all have in common? None of them use inflammasomes to link LPS detection to IL-1. And dogs? They don't detect cytosolic LPS at all. See our new study on the evolution of LPS detection.
@pascal_devant
Want to know which innate immune pathways are needed to induce anti-tumor immunity?
We discuss the five key dendritic cell activities that induce durable T cell immunity, and the immunotherapies that trigger them to protect for life.
A new approach to cancer immunotherapy. Hyperactive dendritic cells enable the use of tumor lysates as immunogens, thus bypassing the need for neo-antigen identification.
#cancer
#immunotherapy
An ancient posttranslational modification controls an innate immune signaling protein. Gasdermin D must be oxidized on cys192 to induce pyroptosis. So proud of my fantastic student Pascal Devant and his co-authors Elvira Boršić & Elsy Ngwa.
Calling all postdocs! We are looking to hire the next Harvard Professor. Will it be you? If you are skeptical of dogma and love to talk data and big ideas, then we would love to meet you. Deadline November 1. All areas of biology considered.
The pyroptosis executioner gasdermin D (GSDMD) is a redox sensor. Our new study demonstrates that GSDMD is oxidized to potentiate its oligomerization and pore forming activities, with Cys192 playing a critical role in ROS responsiveness.
Evidence continues to emerge that inflammasomes operate in living cells. Superb study by Latz et al showing gut bacteria metabolites in NLRP3 activation in live macrophages. Kudos to the authors.
cGAS evolution, IFN and cancer, oh my!.
Our new study describes the ways cGAS detects self DNA and drives IFN responses in cancer. Mouse and human and chimp cGAS all behave differently. Preclinical implications abound.
cGAS is a PI(4,5)2 binding protein. Membrane localization as a means of self nonself discrimination. So proud of my student Kat for a great job
@katbarnett3
@harvardmed
A vaccine that is effective in the elderly. Pleased to share our study on the use of hyperactivator adjuvants to stimulate anti-tumor immunity in the young and old. All other vaccine adjuvants, and even checkpoint inhibitors, failed to do so.
You are so manipulative!
Lung bacteria trick our immune system to induce the wrong type of inflammatory response--resulting in allergy instead of anti-bacterial defense. Kudos to Medzhitov and colleagues on this terrific work.
@RMedzhitov
@YaleMed
Why do we itch? Ask your immune system, and Dr. Sokol and colleagues. They provide a simple and elegant answer to this timeless question. Kudos to the authors on this fascinating discovery.
@sokol_mdphd
@harvardmed
Synthetic Biology meets Innate Immunity. Design of myddosomes that induce interferon responses or necroptosis and inflammasomes that induce interferons. So proud of my postdoc Yunhao Tan for his excellent study.
@harvardmed
@bostonchildrens
“I get by with a little help from my friends”
-The Beatles
Gasdermin D needs help to oligomerize and form pores. This help comes from reactive oxygen species (ROS), controlled by the Ragulator-Rag-mTORC1 pathway. Very pleased to share our new study.
So incredibly excited that Ruslan Medzhitov is receiving the Excellence in Mentoring Award from AAI. I cannot think of a more deserving person. The number of leaders he has trained is astonishing--and growing every year. Kudos my friend!
@RMedzhitov
@ImmunologyAAI
LPS is directly modified by ubiquitin in the cytosol of human cells. Major implications for basic biology, infection biology and immunology. Kudos to
@FelixRandow
and colleagues on a very interesting study.
30+ years after caspases were found to be interleukin-1 converting enzymes (ICE), the first caspase-cytokine structure is revealed. We identify caspase-4 as a specific pro-IL-18 converting enzyme and describe the CryoEM structure of this enzyme-substrate interaction.
So pleased to see Ruslan Medzhitov recognized by the National Academy of Sciences for his foundational discoveries of innate immunity. Many congratulations to a great scientist, mentor and human being.
@YaleIBIO
@RMedzhitov
#innateimmunity
Congratulations to HHMI Investigator Ruslan Medzhitov, who has been awarded the 2024
@theNASciences
Jessie Stevenson Kovalenko Medal for foundational contributions to the understanding of innate immunity!
Learn more:
#NASaward
When asked why you study what you study, your only answer should be: Because it is cool sh*t.
If that is not the answer, find something else to work on.
Normally, I would offer an alternative lead-in to a cool study than the title. But in this case, the title says it all:
"Bacterial gasdermins reveal an ancient mechanism of cell death"
Congrats to Kranzusch and Sorek on this outstanding study.
Thinking on the best way to support innovative science. Of the studies we have published over last decade, most (by far) were based on random ideas. Few were designed to serve an Aim in a grant. Anyone else have similar experience? Shall we rethink how we fund research?
For the trainees: Every translational opportunity we have to treat disease derives from basic science exploration. Understanding how things work is a first principle. Applying knowledge of how things work to treat disease is a second principle.
I am honored to receive the Blue Flame Award from
@Addgene
. Given to those whose plasmids have been distributed to the community many times over. Love their system, which makes reagent (and therefore knowledge) transfer easy.
Who wants to be a new PI at Harvard Immunology?
Any area of Immunology is of interest. We are especially excited about diversifying (no matter how you define this term) the makeup of the dept. Come join a great group of scientists.
Gasdermin proteins as membrane channels that operate in living (hyperactive) or dead (pyroptotic) cells. We review how these ancient proteins assemble into channels (aka pores) and control inflammation, tumor immunity and host defense from infection.
COVID comment: Phagocyte inflammasome activity may not be the whole source of IL-1. In the lung, the amount of IL-1alpha present in epithelial cells is massive. This must be considered in any discussion of IL-1 in this organ, as any form of cytolysis will cause its release.
LPS detection-the centerpiece of innate immunity-is not as common in nature as one would expect. The terrific Anna Gauthier reviews knowledge of LPS detection and discusses which PAMPs may be universally detected by metazoans as a defense strategy. Spoiler--it is not LPS.
cDC2s, critical for T cell mediated immunity, can finally be ablated. Ken Murphy and colleagues reveal how these dendritic cells are produced and how they can be manipulated. Kudos on this very important study.
Cancer and infection and cGAS-STING, oh my! A review on the molecular links between these important aspects of health and disease. Kudos to my student Kenta on a terrific job.
@kntmsllnjd
@harvardmed
Why are there so few drugs that target innate immune signaling pathways? Maybe bc we know so little about the natural protein interactions (and dynamics) that mediate innate immunity. A bottleneck for drug discovery may be understanding endogenous innate immune cell biology.
Many think that a magic moment in your career can be reached when it gets easier. This process of Waiting for Godot is the cause of much frustration. This magical moment does not exist. The magic moment is when we finally realize that today is the best day. Not tomorrow.
Move over STING, TRIF and MAVS. IRSp53 and GMIP join the club of pLxIS proteins that stimulate interferons. So pleased to share our new study, which used synthetic biology to reveal multiple mechanisms that lead to anti-viral immunity. With a surprising link to metabolism.
STING is a membrane channel.
Findings help explain why STING has all those transmembrane domains, a question that has puzzled many (including me) for years. Kudos to Hacohen, Irvine and Bingxu Liu on this interesting discovery.
@BingxuL
@MIT
I would love to live in a world where all grant reviews involved in-person interviews, so the applicants would have the chance to rebut BS critiques in real time. I would also love to live in a world where unicorns are real.
On certain days, I see so much hatred of academia on Twitter. On those days, I think about how much good fortune can contribute to success. I had the tremendous fortune to train with two fantastic mentors: Craig Roy and Ruslan Medzhitov. If only we could all be so lucky.
There is a lot of faith in the job of a PI. Faith in ideas noone likes. Faith in people who have not proven themselves. Faith in ourselves to not be one-hit-wonders. There is a kinship among those who do this job-even among competitors. That kinship is why this job is great.
2023 Nobel Prize in Medicine. A wonderful example of how the study of innate immunity can impact human health.
Somewhere Charles Janeway Jr. is smiling today.
#NobelPrize2023
#innateimmunity
#TLRs
#COVID19
A very important message here. And I would amplify that calling anyone out on Twitter, as opposed to communicating directly, is poison for the community.
Lupus as a disease of innate immune dysfunction.
Toll like receptor signaling changes, linked to defective endosomal trafficking, are revealed as drivers of lupus symptoms. Kudos to Majer and colleagues on this important discovery.
@MajerOlivia
#lupus
In every review on innate immunity, a model of pathway operation is depicted. How much of any model has been proven experimentally? In the TLR pathways, not much. Endogenous innate immune cell biology is an almost non-existent field.
The family of cGAS like receptors expands 1000 fold. Beautiful structure-function analysis of new innate immune signaling proteins by Kranzusch et al. Kudos to the authors on this important discovery.
@harvardmed
@DanaFarberNews
The BIG 3 innate immune pathways: TLRs, RLRs and STING. These all use a pLxIS motif to control anti-viral interferon responses.
Dozens of orphan pLxIS proteins are present in humans and mice. I wonder if pLxIS orphans represent new innate immune pathways.
Jorge Galan explains how Salmonella can be killed by our own cells.
#Immunometabolism
and
#hostdefense
at its finest. The newest of a lifelong list of classic studies by a living legend.
@YaleMed
Evidence continues to emerge that gasdermins can operate in living cells. A beautiful study of how living neutrophils use gasdermin D to mediate inflammation. Kudos to the authors.
In 1776, a small group of dedicated individuals disrupted political norms and changed the world. A new study in Nature demonstrates the same principle applies in science. Small groups are most innovative.
Honored to share our perspective on how inflammasomes (and the entire innate immune system) detects threats to the host.
Thanks to Charlie Evavold for writing this and to the fantastic Immunity editors for their support.
These types of honors are bestowed on me as the PI, but they are a testament to the skills, passion and hard work of my trainees. The best
#sciencefamily
I could ever wish for.
The increasing use of kits in science disturbs me greatly. Plasmid kits prevent students from understanding biochemistry. And organelle kits like this one are even worse--buffer ingredients are not listed. Speed should never bypass understanding.
So proud of this fantastic scientist, the newly minted Dr. Anna Gauthier. She defended her dissertation today with a tour de force discussion of LPS biology and innate immunity.
@RatherLargeNerd
@RandiRotjan
@harvardmed
More evidence that Gasdermin pores promote IL-1 family cytokine release in the absence of cell death. In addition to IL-1b, IL-33 is now found to be released from living cell via Gasdermin D. Kudos to Sun et al on this interesting study.
NLRP3 does not associated with the Trans Golgi. A new study found that stalled endosomes contain a common TGN marker--these organelles recruit NLRP3 to promote inflammasome assembly and activation. Kudos to the authors on this important study. @
More evidence that lncRNAs are misnomers. A lncRNA encodes a protein that regulates inflammasome activity. Fascinating study by
@FitzgeraldKate
at
@UMassMedical
De novo creation of an innate immune LPS receptor. Anh Cao identified the principles of LPS detection by caspase-11, revealing the CARD as a bipartite lipid binding module. This knowledge allowed us to convert an ancient CARD-like protein into a functional LPS receptor.
What can Tuberculosis teach us about Parkinson Disease?
The fantastic Patrick & Watson lab takes this approach and reveals novel connections in cell death pathways. Many congrats on these important discoveries.
@The_PW_Lab
@TAMU
TLRs never stop teaching us about host-pathogen interactions. Madhani et al reveal a fungal ligand for TLR4 that drives allergic inflammation. Congrats to the authors on this important discovery.
@hitenmadhani
USA, fighting for freedom since 1776.
NY Yankees, fighting for (and winning) World Series since 1923.
Gasdermins, fighting infections since before multicellularity emerged.
A review on gasdermin biology by the fantastic Pascal Devant.
A new function for a set of DAMPs: Prevention of viral entry. Most DAMPs promote host defense by inducing inflammation, but we found a set that does not alter inflammatory or interferon responses during infection.
NOD2, one of the first described innate immune receptors, gets a big boost from the Hornung lab. A kinase acts upstream of NOD2 to control inflammation by this pathway. Kudos to the authors on this exciting discovery.
@v_hornung
@LMU_Muenchen
A link between anti-mitotic cancer drugs and inflammation via cGAS-STING. Beautiful study by Mitchison and colleagues shows that chromatin bridges-not micronuclei-are platforms for cGAS signaling. Kudos to all authors.
@harvardmed
A new ligand for the NLRC4 inflammasome.
Human macrophages can sense a virulence factor from Salmonella, which enables them to use inflammasomes to fight infection. Kudos to Sunny Shin and colleagues on this important discovery.
@SunnyShinLab
Many congrats to Kate Fitzgerald on receiving the Meritorious Career Award from AAI. She has been a role model for us all, as a person and explorer.
@FitzgeraldKate
@ImmunologyAAI
@UMassChan
A "fly" new way of antiviral immunity. cGAMP/STING induced transcriptional responses pre-date evolution of interferons. A beautiful study in Drosophila by Imler and colleagues that has significant implications for the field.
How do cells secrete (release) interleukin-1, a key cytokine needed to promote inflammation and memory T cell functions. The fantastic Charlie Evavold discusses current knowledge on this important topic in our review.
@Synth_Immune
Regulation of inflammasome mediated pore formation and pyroptosis extends further than we thought. See our new study identifying Ragulator-Rag complex as factors required for pore formation after gasdermin d has been cleaved.
An immune cell help you avoid food allergens.
Florsheim and Medzhitov discover mast cells as key agents that link food allergens to avoidance behavior.
Kudos to the authors on this important discovery.
@florsheim_eb
@RMedzhitov
@YaleIBIO
I want to work with creative people who have a burning desire to prove to the world that they are as good as they think they are. Doesn't matter if you are white, black, green or purple. Passion comes in all colors. If your boss doesn't feel the same way, get a new boss.
Ever wonder if
@harvardmed
and
@BostonChildrens
are a great place to work, just give me a call. Their support over the years has been a game-changer for my lab and my trainees.
Kill the executioner.
A bacterial virulence factor causes gasdermin degradation to prevent human cell death and promote infection. Congrats to Dixit and colleagues on this important discovery.
@dixitvishva
@genentech
Our stem cells use RNAi to protect against viral infections, just like flies and other ancient organisms. Major implications for our understanding of host defense evolution. Kudos to Reis e Sousa and colleagues on this important discovery.
@ReiseSousaLab
Ever wonder how cytosolic PRRs can detect intra-phagosomal bacteria? Steph Ragland discusses the known mechanisms and offers perspectives on the many observations that remain unexplained.
@StephRaglandPhD
@harvardmed
@BostonChildrens
Assistant Professor in Innate Immunity. Come join a great group of scientists at Harvard. Zoom interviews are planned, to ensure safety and to allow flexibility for those with family responsibilities.
Toll-like Receptors restrict the genetic diversity of pathogens that try to infect us. A fascinating study by Hullahalli and Waldor.
@harvardmed
@KHullahalli
LIVE at Cold Spring Harbor Labs in Nov. 2022.
Executive Producers: Art Weiss, Sasha Rudensky, Ellen Rothenberg and Jon Kagan are pleased to present the conference:
"Gene Expression and Signaling in the Immune System"
Stars and supporting cast to follow.