Jonathan Kagan
@jkagan1
Scientist at Boston Children's Hospital, Professor at Harvard Medical School, Husband, Father
Pyrimidine-containing CDNs are thought to be too small to adequately engage the STING binding pocket. We solved the crystal structure of STING with 2′3′- or 3′3′-cUMP-AMP. These structures revealed distinct CDN-STING interactions, as compared to purine-based CDNs.
Using a library of bacteria producing diverse CDNs, we identified a new PAMP. 2′3′-cUMP-AMP and 3’3’-cUMP-AMP are the first pyrimidine-based STING ligands. The former is active in diverse animal species.
We determined if our engineered, 3′3′-c-di-AMP-producing non-pathogens (“dacA+”) could be killed (to optimize safety) and still stimulate STING-driven anti-tumor immunity. Multiple tumors, including a GEMM for liver cancer, were treated with dacA+ but not control bacteria.
Several CDN transporters have been reported. Intriguingly, some of these transporters, including SLC46A2 and LRRC8A have endosomal localizations. We found that both mediate STING activation to phagosomal, CDN-producing bacteria.
E. coli engineered to produce 3′3′-c-di-AMP (“dacA+”) stimulated STING after bacteriolysis in a mature phagolysosome, suggesting phagosomal CDN transporters are involved.
Given the paradigm that cytoplasmic sensors are strictly pathogen sensors, our finding that CDN-producing non-pathogens stimulate STING was surprising. Yet, we found that even pathogens like L. monocytogenes could stimulate STING without its membrane-perturbing factors.
As many CDN-producing bacteria are commensals, we assessed a link between commensals and IFN in vivo. The presence of diverse bacterial CDNs in mouse tissues correlated with basal STING-dependent IFN. Diverse CDNs were also detected in humans and increased in IBD patients.
TLR-independent IFN was mediated entirely by the cytoplasmic, cyclic-dinucleotide (CDN) sensor STING. STING detects bacterial CDNs or cGAMP, a CDN produced by the DNA sensor, cGAS. ~25% of bacteria synthesized CDNs to stimulate STING, independently of cGAS.
We tested these paradigms by assessing cytokine responses to dozens of bacteria, including commensal non-pathogens. TNFα and interferon (IFN) responses (IFNβ and IP-10) were universally produced to bacteria. Yet, only TNFα required TLRs.
Two paradigms of host-bacteria interactions permeate the literature: Of all PRRs, TLRs are general sensors of bacteria, regardless of virulence. Cytoplasmic PRRs strictly detect pathogens with membrane-perturbing factors. Will these paradigms hold true for every response to any bacteria?
Pyrimidine-containing CDNs are thought to be too small to adequately engage the STING binding pocket. We solved the crystal structure of STING with 2′3′- or 3′3′-cUMP-AMP. These structures revealed distinct CDN-STING interactions, as compared to purine-based CDNs.
Using a library of bacteria producing diverse CDNs, we identified a new PAMP. 2′3′-cUMP-AMP and 3’3’-cUMP-AMP are the first pyrimidine-based STING ligands. The former is active in diverse animal species.
We determined if our engineered, 3′3′-c-di-AMP-producing non-pathogens (“dacA+”) could be killed (to optimize safety) and still stimulate STING-driven anti-tumor immunity. Multiple tumors, including a GEMM for liver cancer, were treated with dacA+ but not control bacteria.
Given the paradigm that cytoplasmic sensors are strictly pathogen sensors, our finding that CDN-producing non-pathogens stimulate STING was surprising. Yet, we found that even pathogens like L. monocytogenes could stimulate STING without its membrane-perturbing factors.
As many CDN-producing bacteria are commensals, we assessed a link between commensals and IFN in vivo. The presence of diverse bacterial CDNs in mouse tissues correlated with basal STING-dependent IFN. Diverse CDNs were also detected in humans and increased in IBD patients.
We tested these paradigms by assessing cytokine responses to dozens of bacteria, including commensal non-pathogens. TNFα and interferon (IFN) responses (IFNβ and IP-10) were universally produced to bacteria. Yet, only TNFα required TLRs.
Two paradigms of host-bacteria interactions permeate the literature: Of all PRRs, TLRs are general sensors of bacteria, regardless of virulence. Cytoplasmic PRRs strictly detect pathogens with membrane-perturbing factors. Will these paradigms hold true for every response to any bacteria?
On way home from a magnificent conference in beautiful Hyderabad, where the best in innate immunity showcased unpublished work. And a quick stop in Dubai to stand on top of the world. @embo.org
Honored to be included in Clarivate's Highly Cited Researcher list for 2025. Working with the best people in the business makes the discoveries easier, and more fun. Cheers to my lab (present and former). @clarivatelsh.bsky.social @bostonchildrens.bsky.social @harvardmed.bsky.social
Harvard Dean George Daley inspiring a new generation of PhD scientists at graduation today. The talent of these doctors is as large as their potential impact on the future. #Harvard @harvardmed.bsky.social
Thus, akin to Picasso’s exploration of the essence of a bull (image below), complex immune responses follow simple biochemical rules.
This is a list of blockbuster drugs in 2024. Guess how many can trace their origins to NIH funded research? All of them.
Introducing Dr. Anh Cao! So proud of this outstanding scientist, who defended his thesis today. @harvardmed @Anh_Immunology