Bryan Bryson
@thebrysonlab.bsky.social
Tuberculosis, systems immunology, innate immunity, vaccines, computational biology
Thanks to our many collaborators at the @ragoninstitute.bsky.social and across the broader community and our funders #tbsky #tuberculosis
Congrats especially to Owen and Rachel, the two fearless graduate students who led this work -- y'all are the best <3
Congrats especially to Owen and Rachel, the two fearless graduate students who led this work -- y'all are the best <3
November 20, 2025 at 4:27 PM
Thanks to our many collaborators at the @ragoninstitute.bsky.social and across the broader community and our funders #tbsky #tuberculosis
Congrats especially to Owen and Rachel, the two fearless graduate students who led this work -- y'all are the best <3
Congrats especially to Owen and Rachel, the two fearless graduate students who led this work -- y'all are the best <3
We're excited! This study supports the concept that there are multiple ways to transfer proteins from the phagosome to the cytosol, and that Mtb specifically takes advantage of this.
November 20, 2025 at 4:27 PM
We're excited! This study supports the concept that there are multiple ways to transfer proteins from the phagosome to the cytosol, and that Mtb specifically takes advantage of this.
2. For those of you who know Mtb, you'll know that Mtb mutants lacking the virulence lipid, PDIM, partially phenocopy ESX-1 mutants. We asked if PDIM mutants have a similar MHC-I phenotype. They didn't! This argues there is a specific role for the ESX-1 secretion system in MHC-I presentation
November 20, 2025 at 4:27 PM
2. For those of you who know Mtb, you'll know that Mtb mutants lacking the virulence lipid, PDIM, partially phenocopy ESX-1 mutants. We asked if PDIM mutants have a similar MHC-I phenotype. They didn't! This argues there is a specific role for the ESX-1 secretion system in MHC-I presentation
So, we were stuck. Our data point to a role for ESX-1 in presentation but was it the secretion system or some other response that is downstream of ESX-1? So we did 2 experiments
1. We did discovery MS with macrophages infected with an ESX-1 mutant and asked if we could see Mtb-derived peptides. No!
1. We did discovery MS with macrophages infected with an ESX-1 mutant and asked if we could see Mtb-derived peptides. No!
November 20, 2025 at 4:27 PM
So, we were stuck. Our data point to a role for ESX-1 in presentation but was it the secretion system or some other response that is downstream of ESX-1? So we did 2 experiments
1. We did discovery MS with macrophages infected with an ESX-1 mutant and asked if we could see Mtb-derived peptides. No!
1. We did discovery MS with macrophages infected with an ESX-1 mutant and asked if we could see Mtb-derived peptides. No!
We examined the role of newly identified host pore-forming proteins (MPEG-1) to define their role in presentation of Mtb-derived peptides, and they were dispensable.
November 20, 2025 at 4:27 PM
We examined the role of newly identified host pore-forming proteins (MPEG-1) to define their role in presentation of Mtb-derived peptides, and they were dispensable.
OK, so ESX-1 controls galectin recruitment to the phagosome. Can we figure out a way to restore galectin positivity to the phagosome of an ESX-1 mutant? Yes, we used some previously identified small molecules and restored galectin positivity, but it did not rescue presentation.
November 20, 2025 at 4:27 PM
OK, so ESX-1 controls galectin recruitment to the phagosome. Can we figure out a way to restore galectin positivity to the phagosome of an ESX-1 mutant? Yes, we used some previously identified small molecules and restored galectin positivity, but it did not rescue presentation.
We first tested an antigen expression hypothesis -- is the loss of presentation of Mtb-derived peptides on MHC-I explained by loss of expression of these antigens in the ESX-1 mutant in macrophages? No! If anything, we see elevated gene expression in the mutant.
November 20, 2025 at 4:27 PM
We first tested an antigen expression hypothesis -- is the loss of presentation of Mtb-derived peptides on MHC-I explained by loss of expression of these antigens in the ESX-1 mutant in macrophages? No! If anything, we see elevated gene expression in the mutant.
ESX-1 activity controls a lot in phagocytes, and we had previously demonstrated that the loss of presentation we saw was independent of interferon production. We still had a lot left to explore, and this preprint does just that.
November 20, 2025 at 4:27 PM
ESX-1 activity controls a lot in phagocytes, and we had previously demonstrated that the loss of presentation we saw was independent of interferon production. We still had a lot left to explore, and this preprint does just that.
In our previous paper, we showed that loss of ESX-1 disrupts presentation of Mtb-derived peptides on MHC-I using immunopeptidomics. Here, we first corroborated those findings using a T cell clone specific for one of the peptides we saw by MS.
November 20, 2025 at 4:27 PM
In our previous paper, we showed that loss of ESX-1 disrupts presentation of Mtb-derived peptides on MHC-I using immunopeptidomics. Here, we first corroborated those findings using a T cell clone specific for one of the peptides we saw by MS.
Last, a major thanks to our funders and excellent collaborators!
Please reach out if there's anything in the paper that interests you!
Please reach out if there's anything in the paper that interests you!
November 17, 2025 at 6:20 AM
Last, a major thanks to our funders and excellent collaborators!
Please reach out if there's anything in the paper that interests you!
Please reach out if there's anything in the paper that interests you!
We think this work is important because:
1. It helps us think about species differences in new ways
2. It highlights a metabolic gate in Mtb-host interactions
3. It may help resolve long-standing challenges in translating concepts from mouse studies to humans
1. It helps us think about species differences in new ways
2. It highlights a metabolic gate in Mtb-host interactions
3. It may help resolve long-standing challenges in translating concepts from mouse studies to humans
November 17, 2025 at 6:20 AM
We think this work is important because:
1. It helps us think about species differences in new ways
2. It highlights a metabolic gate in Mtb-host interactions
3. It may help resolve long-standing challenges in translating concepts from mouse studies to humans
1. It helps us think about species differences in new ways
2. It highlights a metabolic gate in Mtb-host interactions
3. It may help resolve long-standing challenges in translating concepts from mouse studies to humans
There's a lot more in the paper than I'm including in this summary so I encourage you to take a read!
November 17, 2025 at 6:20 AM
There's a lot more in the paper than I'm including in this summary so I encourage you to take a read!
So we took a step back and realized that in our hands human macrophages have more lipid droplets (LDs) at baseline than murine macrophages, so we tested the hypothesis that human LDs regulated the ability of Mtb to acquire and store lipids. Inhibition of host TAG synthesis did the trick (partially)!
November 17, 2025 at 6:20 AM
So we took a step back and realized that in our hands human macrophages have more lipid droplets (LDs) at baseline than murine macrophages, so we tested the hypothesis that human LDs regulated the ability of Mtb to acquire and store lipids. Inhibition of host TAG synthesis did the trick (partially)!
We spent a full year trying to break the phenotype (macrophage culture media, macrophage and Mtb mutants) or small molecule perturbations (initially focusing on well-characterized species differences). TL, DR: these perturbations didn't do all that much
November 17, 2025 at 6:20 AM
We spent a full year trying to break the phenotype (macrophage culture media, macrophage and Mtb mutants) or small molecule perturbations (initially focusing on well-characterized species differences). TL, DR: these perturbations didn't do all that much
Many of these Mtb genes were associated with lipid metabolism, so we orthogonally validated these observations by tracking Mtb acquisition and storage of lipids using established techniques and found that Mtb readily forms intracellular lipid inclusions in mouse but not human macrophages
November 17, 2025 at 6:20 AM
Many of these Mtb genes were associated with lipid metabolism, so we orthogonally validated these observations by tracking Mtb acquisition and storage of lipids using established techniques and found that Mtb readily forms intracellular lipid inclusions in mouse but not human macrophages
Here in work led by postdoc Jonathan Padilla-Gomez, we asked that question using an vitro model of Mtb infection of either primary human or mouse macrophages. To our surprise, we found many differentially expressed Mtb genes across host environments
November 17, 2025 at 6:20 AM
Here in work led by postdoc Jonathan Padilla-Gomez, we asked that question using an vitro model of Mtb infection of either primary human or mouse macrophages. To our surprise, we found many differentially expressed Mtb genes across host environments
We often use mouse and human macrophages interchangeably to study Mtb-host interactions, but an open question in the field is how (if at all) different species impose unique stresses on intracellular Mtb
November 17, 2025 at 6:20 AM
We often use mouse and human macrophages interchangeably to study Mtb-host interactions, but an open question in the field is how (if at all) different species impose unique stresses on intracellular Mtb
And importantly -- thank you to Owen, Forest White and our many amazing collaborators!
Please get in touch if you want to chat more or have questions!
And watch this space for the next two chapters of the Mtb-MHC saga (coming soon, they are very very exciting)
Please get in touch if you want to chat more or have questions!
And watch this space for the next two chapters of the Mtb-MHC saga (coming soon, they are very very exciting)
November 5, 2025 at 9:57 PM
And importantly -- thank you to Owen, Forest White and our many amazing collaborators!
Please get in touch if you want to chat more or have questions!
And watch this space for the next two chapters of the Mtb-MHC saga (coming soon, they are very very exciting)
Please get in touch if you want to chat more or have questions!
And watch this space for the next two chapters of the Mtb-MHC saga (coming soon, they are very very exciting)
We're super excited! These are needle in the haystack measurements out of the BL3 that Owen executed beautifully. These studies also provide us a path to antigen discovery and vaccine optimization in human cells. And it's generalizable -- we can definitely extend to other pathogens!
November 5, 2025 at 9:57 PM
We're super excited! These are needle in the haystack measurements out of the BL3 that Owen executed beautifully. These studies also provide us a path to antigen discovery and vaccine optimization in human cells. And it's generalizable -- we can definitely extend to other pathogens!
TL, DR:
(1) Type VII secretion system substrates strike again -- enriched for presentation on MHC-II.
(2) Lysosomal targeting enhances presentation on MHC-II by multiple orders of magnitude.
(3) Coexpression of natural heterodimeric pairs can enhance presentation of Mtb-derived peptides.
(1) Type VII secretion system substrates strike again -- enriched for presentation on MHC-II.
(2) Lysosomal targeting enhances presentation on MHC-II by multiple orders of magnitude.
(3) Coexpression of natural heterodimeric pairs can enhance presentation of Mtb-derived peptides.
November 5, 2025 at 9:57 PM
TL, DR:
(1) Type VII secretion system substrates strike again -- enriched for presentation on MHC-II.
(2) Lysosomal targeting enhances presentation on MHC-II by multiple orders of magnitude.
(3) Coexpression of natural heterodimeric pairs can enhance presentation of Mtb-derived peptides.
(1) Type VII secretion system substrates strike again -- enriched for presentation on MHC-II.
(2) Lysosomal targeting enhances presentation on MHC-II by multiple orders of magnitude.
(3) Coexpression of natural heterodimeric pairs can enhance presentation of Mtb-derived peptides.
Here, we apply immunopeptidomics in primary human phagocytes to identify Mtb peptides presented by infected cells on MHC-II and then optimize mRNA vaccines encoding these antigens.
November 5, 2025 at 9:57 PM
Here, we apply immunopeptidomics in primary human phagocytes to identify Mtb peptides presented by infected cells on MHC-II and then optimize mRNA vaccines encoding these antigens.