https://abs.twimg.com/emoji/v2/... draggable="false" alt="👩‍🎓" title="Woman student" aria-label="Emoji: Woman student">In my PhD, I wanted to discover how pathogens cause human disease.
https://abs.twimg.com/emoji/v2/... draggable="false" alt="🎉" title="Partyknaller" aria-label="Emoji: Partyknaller">Recently, we published an #OA study on how enteropathogenic E.coli/ #EPEChttps://abs.twimg.com/emoji/v2/... draggable="false" alt="🦠" title="Microbe" aria-label="Emoji: Microbe">manipulates human mitochondria to control the death of our intestinal cells.
The story:
1/14 (Results=10-14)
https://abs.twimg.com/emoji/v2/... draggable="false" alt="📚" title="Bücher" aria-label="Emoji: Bücher"> https://msystems.asm.org/content/5/3/e00283-20">https://msystems.asm.org/content/5...
Master Sculptor at Work: Enteropathogenic Escherichia coli Infection Uniquely Modifies Mitochondr...

Enteropathogenic Escherichia coli (EPEC) causes severe diarrheal disease and is present globally. EPEC virulence requires a bacterial type III secretion system to inject >20 effector proteins into...

https://msystems.asm.org/content/5/3/e00283-20
When I started my PhD in the . @FinlayLab, . @sshames83 taught me about EspZ: a protein that EPEC& #EHEC/ #STEC inject through their #T3SS into our intestinal cells.https://abs.twimg.com/emoji/v2/... draggable="false" alt="😯" title="Schweigendes Gesicht" aria-label="Emoji: Schweigendes Gesicht">This bacterial protein travels to our mitochondria &delays cell death from infection!https://abs.twimg.com/emoji/v2/... draggable="false" alt="☠️" title="Totenkopf" aria-label="Emoji: Totenkopf">
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https://abs.twimg.com/emoji/v2/... draggable="false" alt="📚" title="Bücher" aria-label="Emoji: Bücher"> https://iai.asm.org/content/79/12/4784.long">https://iai.asm.org/content/7...
The Type III System-Secreted Effector EspZ Localizes to Host Mitochondria and Interacts with the...

Enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC, respectively) are attaching and effacing (A/E) bacterial pathogens that cause severe diarrheal disease worldwide. To cause...

https://iai.asm.org/content/79/12/4784.long
It& #39;s fascinating & counter-intuitive that some bacterial virulence factors actually PROTECT the human cell during disease caused by the same infectionhttps://abs.twimg.com/emoji/v2/... draggable="false" alt="🤔" title="Denkendes Gesicht" aria-label="Emoji: Denkendes Gesicht">& involves the neat idea of virulence factor interplay.
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https://abs.twimg.com/emoji/v2/... draggable="false" alt="📚" title="Bücher" aria-label="Emoji: Bücher"> https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1001057
https://journals.plos.org/plospatho... class="Emoji" style="height:16px;" src=" https://abs.twimg.com/emoji/v2/... draggable="false" alt="📚" title="Bücher" aria-label="Emoji: Bücher"> https://www.sciencedirect.com/science/article/abs/pii/S0966842X1200039X?via%3Dihub">https://www.sciencedirect.com/science/a...
Bacterial effector interplay: a new way to view effector function

Bacterial pathogens are dependent on virulence factors to efficiently colonize and propagate within their hosts. Many Gram-negative bacterial pathogen…

https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1001057
I was intrigued by how EPEC injects its virulence factors into human cells, with some going to mitochondria.

While #mitochondria are more commonly thought of as thehttps://abs.twimg.com/emoji/v2/... draggable="false" alt="💪" title="Angespannter Bizeps" aria-label="Emoji: Angespannter Bizeps">of the cell, they actually play a hugely important role in host cell death/survival pathways.

4/
So when EPEC infects our intestinal cells and sends virulence factors like EspZ to mitochondria, they& #39;re in the right spot to influence human cell deathhttps://abs.twimg.com/emoji/v2/... draggable="false" alt="☠️" title="Totenkopf" aria-label="Emoji: Totenkopf">, e.g. apoptosis.

5/
So I wanted to focus on what was happening in mitochondria during infection!

To do that, I knew I needed to study proteases, which play essential roles in mitochondrial function, the human immune response, AND in bacterial pathogenesis.
6/

https://abs.twimg.com/emoji/v2/... draggable="false" alt="📚" title="Bücher" aria-label="Emoji: Bücher">Our review: https://www.mcponline.org/content/16/4_suppl_1/S161.long">https://www.mcponline.org/content/1...
Sharpening Host Defenses during Infection: Proteases Cut to the Chase

The human immune system consists of an intricate network of tightly controlled pathways, where proteases are essential instigators and executioners at multiple levels. Invading microbial pathogens...

https://www.mcponline.org/content/16/4_suppl_1/S161.long
Fortunately, we collaborated with protease & mass spec magicians. @OverallLabNews, where I had the immense pleasure of learning from the whole team, particularly Drs. Overall & Theo Klein, who introduced the elegant biochem of TAILS terminal #proteomics.

https://abs.twimg.com/emoji/v2/... draggable="false" alt="📚" title="Bücher" aria-label="Emoji: Bücher"> https://www.nature.com/articles/nbt.1611">https://www.nature.com/articles/...
Isotopic labeling of terminal amines in complex samples identifies protein N-termini and protease...

Many proteases are important drug targets, but identification of their substrates remains challenging. By using polymers to selectively isolate N-terminal peptides generated by proteolysis of complex...

https://www.nature.com/articles/nbt.1611
To study mitochondria during apoptosishttps://abs.twimg.com/emoji/v2/... draggable="false" alt="☠️" title="Totenkopf" aria-label="Emoji: Totenkopf">, we had to overcome some technical& biological challenges, so we applied TAILS to create an organelle-modified approach we called mitochondrial SILAC TAILS (MS-TAILS) and showed it worked to study mitochondria:
8/
https://abs.twimg.com/emoji/v2/... draggable="false" alt="📚" title="Bücher" aria-label="Emoji: Bücher"> https://pubs.acs.org/doi/10.1021/acs.jproteome.8b00675">https://pubs.acs.org/doi/10.10...
Global Profiling of Proteolysis from the Mitochondrial Amino Terminome during Early Intrinsic...

The human genome encodes ∼20 mitochondrial proteases, yet we know little of how they sculpt the mitochondrial proteome, particularly during important mitochondrial events such as the initiation of...

https://pubs.acs.org/doi/10.1021/acs.jproteome.8b00675
After years working w mitochondria & proteomics, I finally got to apply this work back to my core passion: microbiology (small but mightyhttps://abs.twimg.com/emoji/v2/... draggable="false" alt="💪" title="Angespannter Bizeps" aria-label="Emoji: Angespannter Bizeps">https://abs.twimg.com/emoji/v2/... draggable="false" alt="🦠" title="Microbe" aria-label="Emoji: Microbe"> #EPECisEPIC)!
9/
https://abs.twimg.com/emoji/v2/... draggable="false" alt="📚" title="Bücher" aria-label="Emoji: Bücher"> https://msystems.asm.org/content/5/3/e00283-20">https://msystems.asm.org/content/5...
Master Sculptor at Work: Enteropathogenic Escherichia coli Infection Uniquely Modifies Mitochondr...

Enteropathogenic Escherichia coli (EPEC) causes severe diarrheal disease and is present globally. EPEC virulence requires a bacterial type III secretion system to inject >20 effector proteins into...

https://msystems.asm.org/content/5/3/e00283-20
We applied this new approach to study how EPEC infection & its T3SS modify human mitochondria in an in vitro (cell culture) model of EPEC infection:
10/
https://abs.twimg.com/emoji/v2/... draggable="false" alt="📚" title="Bücher" aria-label="Emoji: Bücher"> https://msystems.asm.org/content/5/3/e00283-20">https://msystems.asm.org/content/5...
We found MANY differences across the entire human cell, including several changes in mitochondrial proteins (shown in red). Some were specifically mediated by the presence vs. absence of the T3SS (green). Some had not previously been observed (*).
11/
https://abs.twimg.com/emoji/v2/... draggable="false" alt="📚" title="Bücher" aria-label="Emoji: Bücher"> https://msystems.asm.org/content/5/3/e00283-20">https://msystems.asm.org/content/5...
We found MANY differences across the entire human cell, including several changes in mitochondrial proteins (shown in red). Some were specifically mediated by the presence vs. absence of the T3SS (green). Some had not previously been observed (*).11/https://abs.twimg.com/emoji/v2/... draggable= https://msystems.asm.org/content/5..." title="We found MANY differences across the entire human cell, including several changes in mitochondrial proteins (shown in red). Some were specifically mediated by the presence vs. absence of the T3SS (green). Some had not previously been observed (*).11/https://abs.twimg.com/emoji/v2/... draggable="false" alt="📚" title="Bücher" aria-label="Emoji: Bücher"> https://msystems.asm.org/content/5...">
We found MANY differences across the entire human cell, including several changes in mitochondrial proteins (shown in red). Some were specifically mediated by the presence vs. absence of the T3SS (green). Some had not previously been observed (*).11/https://abs.twimg.com/emoji/v2/... draggable= https://msystems.asm.org/content/5..." title="We found MANY differences across the entire human cell, including several changes in mitochondrial proteins (shown in red). Some were specifically mediated by the presence vs. absence of the T3SS (green). Some had not previously been observed (*).11/https://abs.twimg.com/emoji/v2/... draggable="false" alt="📚" title="Bücher" aria-label="Emoji: Bücher"> https://msystems.asm.org/content/5...">
We found MANY differences across the entire human cell, including several changes in mitochondrial proteins (shown in red). Some were specifically mediated by the presence vs. absence of the T3SS (green). Some had not previously been observed (*).11/https://abs.twimg.com/emoji/v2/... draggable= https://msystems.asm.org/content/5..." title="We found MANY differences across the entire human cell, including several changes in mitochondrial proteins (shown in red). Some were specifically mediated by the presence vs. absence of the T3SS (green). Some had not previously been observed (*).11/https://abs.twimg.com/emoji/v2/... draggable="false" alt="📚" title="Bücher" aria-label="Emoji: Bücher"> https://msystems.asm.org/content/5...">
We were most interested in changes that had NOT been observed in our 1st study (apoptosis with NO infection). These are most likely to represent direct/indirect mechanisms of T3SS virulence factors (like EspZ!).
12/
https://abs.twimg.com/emoji/v2/... draggable="false" alt="📚" title="Bücher" aria-label="Emoji: Bücher"> https://msystems.asm.org/content/5/3/e00283-20
https://msystems.asm.org/content/5... class="Emoji" style="height:16px;" src=" https://abs.twimg.com/emoji/v2/... draggable="false" alt="📚" title="Bücher" aria-label="Emoji: Bücher"> https://pubs.acs.org/doi/10.1021/acs.jproteome.8b00675">https://pubs.acs.org/doi/10.10...
We were most interested in changes that had NOT been observed in our 1st study (apoptosis with NO infection). These are most likely to represent direct/indirect mechanisms of T3SS virulence factors (like EspZ!). 12/https://abs.twimg.com/emoji/v2/... draggable= https://msystems.asm.org/content/5... class="Emoji" style="height:16px;" src=" " title="We were most interested in changes that had NOT been observed in our 1st study (apoptosis with NO infection). These are most likely to represent direct/indirect mechanisms of T3SS virulence factors (like EspZ!). 12/https://abs.twimg.com/emoji/v2/... draggable="false" alt="📚" title="Bücher" aria-label="Emoji: Bücher"> https://msystems.asm.org/content/5... class="Emoji" style="height:16px;" src=" ">
We were most interested in changes that had NOT been observed in our 1st study (apoptosis with NO infection). These are most likely to represent direct/indirect mechanisms of T3SS virulence factors (like EspZ!). 12/https://abs.twimg.com/emoji/v2/... draggable= https://msystems.asm.org/content/5... class="Emoji" style="height:16px;" src=" " title="We were most interested in changes that had NOT been observed in our 1st study (apoptosis with NO infection). These are most likely to represent direct/indirect mechanisms of T3SS virulence factors (like EspZ!). 12/https://abs.twimg.com/emoji/v2/... draggable="false" alt="📚" title="Bücher" aria-label="Emoji: Bücher"> https://msystems.asm.org/content/5... class="Emoji" style="height:16px;" src=" ">
Ultimately, by building these networks that show how human & pathogens proteins interact, we can identify how pathogens like EPEC subvert our defenses & kill our cells.https://abs.twimg.com/emoji/v2/... draggable="false" alt="☠️" title="Totenkopf" aria-label="Emoji: Totenkopf">

This understanding can help us understand how best to tackle these infectionshttps://abs.twimg.com/emoji/v2/... draggable="false" alt="💪" title="Angespannter Bizeps" aria-label="Emoji: Angespannter Bizeps">& limit human disease.

13/
Hope you enjoyed our work! I couldn& #39;t be more grateful for the team that made this happen!https://abs.twimg.com/emoji/v2/... draggable="false" alt="🙏" title="Folded hands" aria-label="Emoji: Folded hands">
. @FinlayLab, . @OverallLabNews, &. @lenjf invested in & supported this research (and me) for years.
. @DocThejoe and Dr. Theo Klein were dedicated researchers here.
& the ENTIRE FinlayLab!
You can follow @MicrobeNat.
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