Tuesday, December 13, 2016

Multi-level study of antibiotic resistant Klebsiella pneumoniae!

In today's edition of "terrifying things I didn't know about, but I'm very glad people are working on!" we're going to talk about multi-drug resistant Klebsiella pneumoniae called KP35


KP35 is an opportunistic pathogen that hangs out in hospitals and gets people who are already down...and if I've got this right you don't even have to get exposed to this strain of the bacteria. If you're exposed to the right conditions -- and antibiotics -- other, much more ubiquitous strains of the bacteria can essentially exhibit become just like this one. 

To investigate something like this is gonna require a big team with diverse skill sets, and these authors show how we can contribute what we do to a team like this. 

The paper starts off with histopathology stuff and establishment of model systems to study KP35, including a mouse model. Hey, I understand why we have to use mouse models, but I think I exhibit an appropriate level of skepticism when I see data from mice. In this study, these authors use their mouse models -- and then validate their observations, for nearly every experiment, in the limited lung fluid samples that they have from patients!  

I don't know all the techniques in use here, but there are a lot -- cytokine signaling assays, immune cell killing assays (??) and qRT-PCR and full genome sequencing of the bacteria (I think) are all in play in studying the patient samples and in validating that the mouse model is valid and then -- the cool stuff happens on the mice.

They take the lung fluid from the mice from their model and pool it, as well as pooling mice from their controls and do some deep proteomics --> high pH reverse phase fractionation before going onto a Fusion running OT-IT for deep coverage. The data was processed in PD 1.4, but the quantification is done in something called QluCore --> something that needs further investigation!  They only take the statistically significant (p<0.05) quantifiable changes (see, this is why QluCore needs further investigation!) and do downstream analysis with DAVID and IPA.

What do they find out after all of this?  Something super weird (IMHO)! Part of the reason that KP35 is so hard to clear when it infects patients is that it has somehow hijacked the immune system!

There are weird immune cells called MSDCs (WikiPedia article)  that actually suppress our immune response and these things seem to highly activate them to protect themselves. I'm sure these cells normally play an important role in keeping our normal immune response from running amock and destroying everything, but it seems pretty scary that a simple bacteria could exploit them!

TL/DR: Solid multi-discipline study of a scary hospital-acquired bacteria figures out why it is so darned hard to kill -- and hopefully gives us new strategies to wipe it out!

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