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Reposted by Michael Shiloh, MD, PhD

Matthew Lawrenz @lawrenzlab.bsky.social · Aug 17

My alma mater is hiring a microbiologist! Assistant/Associate Prof. 👇👇

Assistant/Associate Professor, Microbiology and Molecular Genetics - McGovern Medical School in Texas, United States | Faculty & Physicians at UTHealth Houston

Apply for Assistant/Associate Professor, Microbiology and Molecular Genetics - McGovern Medical School job with UTHealth Houston in Texas, United States. Faculty & Physicians at UTHealth Houston

careers.uth.tmc.edu

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Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · Aug 8

Many thanks to @niaidnews.bsky.social for their support for this work. This project was done at UTSW @utswim.bsky.social in the Division of Infectious Diseases @utswinfdis.bsky.social.

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Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · Aug 8

Together, these results identify USP15 as a conserved and targetable suppressor of xenophagy. Inhibiting USP15 could boost the host’s own ability to control Mtb, indicating a potential path for host-directed TB therapy to augment existing antibiotics or shorten treatment duration.

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Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · Aug 8

A selective small-molecule USP15 inhibitor mimicked the genetic effects of knocking down USP15 in most human donors tested, lowering Mtb burden without harming the host cells.

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Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · Aug 8

We saw the same effects in primary mouse macrophages and in human monocyte-derived macrophages. Even partial knockdown of USP15 reduced Mtb growth and increased LC3 targeting.

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Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · Aug 8

The picture became clearer when we looked at PARKIN. This E3 ligase normally promotes K63 ubiquitination of Mtb, leading to it's destruction. Depleting PARKIN reversed the enhanced antibacterial effects seen in USP15-deficient cells, pointing to a direct antagonism between PARKIN and USP15.

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Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · Aug 8

Restoring wild-type USP15 to macrophages genetically lacking USP15 rescued Mtb growth, while a catalytically inactive mutant did not — highlighting the importance of USP15's enzymatic activity for its immune-suppressive role.

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Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · Aug 8

Without USP15, K63 ubiquitin piled onto Mtb-associated structures, LC3 recruitment increased, and bacterial replication was reduced. Blocking autophagy initiation removed this benefit, showing the effect depends on canonical autophagy.

LC3B (green) surrounding intracellular Mtb (red) in macrophages lacking USP15

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Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · Aug 8

We screened murine deubiquitinases for effects on intracellular Mtb growth. One stood out — USP15. Knocking it down or knocking it slowed the growth of Mtb in macrophages.

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Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · Aug 8

Macrophages can mark Mtb-associated structures with K63-linked ubiquitin, drawing in LC3 and the autophagy machinery to degrade the bacteria. But some host enzymes remove these marks, tipping the balance in favor of the pathogen.

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Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · Aug 8

Congratulations to Kathryn Rahlwes and the rest of the team on the new preprint from our group. We identify USP15, a deubiquitinase, as a key brake on macrophage immunity to Mycobacterium tuberculosis (Mtb). Remove it, and macrophages control Mtb far more effectively.
www.biorxiv.org/content/10.1...

Deubiquitinase USP15 restricts autophagy and macrophage immunity to Mycobacterium tuberculosis

Autophagy enables macrophages to degrade intracellular Mycobacterium tuberculosis (Mtb), and this defense depends on E3 ubiquitin ligases such as PARKIN and SMURF1, which tag Mtb-associated structures...

www.biorxiv.org

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Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · Jul 31

Congrats @samuelalvarez.bsky.social and the entire team on this work characterizing established (i.e. M cells) and new cells in the mucosal immune system! The new cells we named WISP cells as they are found in both adenoid and tonsils. Read the paper to find out so much more!

Samuel Alvarez-Arguedas @samuelalvarez.bsky.social · Jul 31

🚨 New paper out in Mucosal Immunology!
We used snRNA-seq + spatial validation to map human adenoids and found:
• Immature & mature M cells
• New interferon-responsive cells: WISP cells
• Key epithelial–immune interactions
Read it here 👉 doi.org/10.1016/j.mu...

#MucosalImmunology #MCells

Redirecting

doi.org

Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · Jul 30

Similar to this study.
academic.oup.com/ofid/article...

A Diagnostic Stewardship Success: Implementing a Urine Culture Reflex Policy in the Emergency Department of a Large Safety-Net Hospital

AbstractBackground. Urinalyses and urine cultures (UCs) are frequently ordered simultaneously in emergency departments (EDs) to increase efficiency and dec

academic.oup.com

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Reposted by Michael Shiloh, MD, PhD

Linsey Marr @linseymarr.bsky.social · Jul 18

Quantifying Dissemination of Antibiotic Resistance Genes in Air from a Dairy Farm and Swine Farm, led by PhD student David Kormos, now published! We found ARGs in a range of particle sizes, indicating potential for inhalation exposure and long-range transport.

pubs.acs.org/doi/10.1021/...

Quantifying Dissemination of Antibiotic Resistance Genes in Air from a Dairy Farm and Swine Farm

Farms are a suspected source of dissemination of antibiotic resistance genes (ARGs) to the atmosphere, but their contribution remains poorly quantified. This study investigated the concentrations, emi...

pubs.acs.org

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Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · Jul 1

Congrats to Dhananjay Naik from @tedpricethepainguy.bsky.social's lab at UT Dallas on their new preprint deeply characterizing the nociceptive activity of SL-1 on mouse & human neurons.
www.biorxiv.org/content/10.1...

Mycobacterium tuberculosis sulfolipid-1 (Sl-1) increases the excitability of mouse and human TRPV1-positive sensory neurons in a YM254890-reversible fashion

Cough is a hallmark sign of tuberculosis and key driver of transmission. While traditionally attributed to host-driven inflammation, we previously demonstrated that Mycobacterium tuberculosis lipid ex...

www.biorxiv.org

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Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · May 23

Enjoyed celebrating John Neff’s PhD graduation ceremony yesterday.

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Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · May 9

I get the cartoonist's point, but, if I'm going to be pedantic (and scientifically accurate), since measles is an airborne disease with the highest transmissibility of all pathogens, the girl on the left would have been exposed/infected in the top left panel.

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Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · May 8

I wish I could find it online, but 30 years ago my PhD advisor had a cartoon on his door (maybe New Yorker?), with 3 spinning-wheels. On one was "eggs, butter, fat, sugar, coffee, etc.", then "causes, cures, etc." and the last "cancer, heart disease, stroke, etc." So, I think the answer is "yes".

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Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · May 7

Thank you Olivier!

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Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · May 7

Thank you Kat!

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Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · May 6

This project would not have been possible without the financial support of @niaidnews.bsky.social ws.bsky.social, @bwfund.bsky.social nd.bsky.social, and @thewelchfoundation.bsky.social. 14/14
tenor.com/view/ted-las...

Ted Lasso Thank You GIF - Ted lasso Thank you Mercy buckets - Discover & Share GIFs

Click to view the GIF

tenor.com

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Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · May 6

All credit belongs to Kubra Naqvi, PhD (not yet on Bluesky), who led this project from the start. We are also indebted to our chemistry collaborators at @unileiden.bsky.social and neuroscience collaborators @utdpaincenter.bsky.social. 13/14

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Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · May 6

Please check out and share our preprint relating to the aerobiology of one of the most successful human pathogens, Mtb. 12/14 @idsainfo.bsky.social sky.social @utswinfdis.bsky.social is.bsky.social @carlzimmer.com
#InfectiousDisease #Purinergic #DrugDiscovery
www.biorxiv.org/content/10.1...

Mycobacterial Phenolic Glycolipid Triggers ATP-Mediated Neuronal P2X3 Signaling and Cough

Cough drives respiratory pathogen transmission, yet how microbes directly engage host sensory neurons to trigger cough is largely unknown. We previously demonstrated that the Mycobacterium tuberculosi...

www.biorxiv.org

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Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · May 6

We propose that Mtb evolved to produce multiple neuron activating molecules to co-opt the host cough reflex, thus facilitating its own spread from person to person. Therapeutically, P2X3 antagonists may help reduce airborne transmission of Mtb. 11/14

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Michael Shiloh, MD, PhD @michaelshiloh.bsky.social · May 6

PGL triggers rapid extracellular ATP release from host cells through pannexin channels. ATP then binds neuronal P2X3 purinergic receptors. Blocking P2X3 with a specific antagonist inhibits PGL-mediated neuronal activity. ⚠️. #anti-tussive 10/14

An image showing the role of ATP in neuronal activation

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