Monday, April 16, 2018

BacterioFiles 336 - Phages Fortify Friendly Fighters

Neutrophil captures Pseudomonas
By Paulo Henrique Orlandi Mourao,
CC BY-SA 3.0
This episode: Phage therapy can work very well when combined with an effective immune response from the host!

Download Episode (12.9 MB, 14.1 minutes)

Show notes:
Microbe of the episode: Gammapapillomavirus 8

News item about "nightmare bacteria"

Journal Paper:
Roach DR, Leung CY, Henry M, Morello E, Singh D, Di Santo JP, Weitz JS, Debarbieux L. 2017. Synergy between the Host Immune System and Bacteriophage Is Essential for Successful Phage Therapy against an Acute Respiratory Pathogen. Cell Host Microbe 22:38-47.e4.

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    Episode outline:
    • Background: Antibiotic resistance becoming more and more serious
      • Some microbes resistant to almost all drugs now
      • Each drug has some resistant to it
      • Reports from CDC of "nightmare bacteria", linked
    • Not easy to find/develop new ones; low-hanging fruit mostly picked
      • Takes a lot of time and resources to get approval
    • Using phages for treatment can work well sometimes
      • But hard to get consistency in some cases
      • Need to understand it better to be able to make sure it’s effective
    • Issues: phages rely on hosts to multiply; fewer hosts means fewer phages
      • Hard to get the last little bit
      • Unless flooding with huge dose initially like antibiotic?
      • But this selects for resistant bacteria very quickly
    • But our immune system also plays role in treatment
      • If working well, can take over where phages leave off
      • But too much infection can overwhelm defenses
    • What’s new: Now, Dwayne Roach and Joey Leung, Marine Henry, Eric Morello, Devika Singh, James Di Santo, Joshua Weitz, and Laurent Debarbieux, publishing in Cell Host & Microbe have shown that phage therapy is most effective when there is good synergy with the host immune defenses!
    • Methods: Used Pseudomonas aeruginosa as model microbe
      • Mostly causes pneumonia in compromised patients
      • Found in multi-drug resistant varieties
    • Phage used is PAK_P1, lytic
      • Previously found to be able to cure mice of P. aeruginosa
    • So used bioluminescent bacteria
      • Delivered phage by inhalation 
      • in immunocompetent mice, cured all
      • emitted light decreased after 2 hours, gone after 48
      • Without treatment, light increased and mice died
    • Theory and observation didn't always line up
      • More phage =/ always more killing of bacteria
      • Possibly phages have trouble reaching some cells (obstacles)
      • Or if too many phages, multiple attack one cell, less efficient
      • So take into account in treatment
    • What about immunodeficient mice?
      • Tried some that had trouble signaling detection (MyD88 deficient)
      • Pathogen killed very quickly, had to decrease dose
      • Phage improved survival only 15% over control
      • Reduced luminescence almost below detection, but bacteria bounced back with resistance
      • Predicted that phage therapy should work well if immune activation at least 20-50%
      • Not all immune deficiencies make phages ineffective, as demonstrated
        • Lymphoid – more adaptive, not as important initially, for phage therapy (T, B)
        • Myeloid – more cells that consume/destroy, essential (macrophages, neutrophils)
      • So base phage therapy decision on patient myeloid cell status
        • Maybe don't use for patients with severe neutropenia (from chemo or genetic)
    • So good for phage therapy, but what about prevention/prophylaxis?
      • Antibiotic type often used when people exposed to risky situations
      • Here, found that dose of phage could protect mice from bacteria up to 4 days
      • Might have extra time to penetrate into crevices and be more effective that way
    • Wondered if phages might pre-activate immune system themselves
      • Evidence says no
      • Not a bad thing; activation can mean inflammation and cell damage
        • Means phages are safer
      • Also didn't see body attacking the phages, getting rid of them sooner
    • Summary: Here’s one of the first authors, Joey Leung, summarizing the work: statement
    • Applications and implications: 
    • Clarifications if necessary: mice
    • What do I think: Phage and immune system complementary approaches
      • With just one, easier to gain resistance
      • With both, each can take out germs resistant to the other
    • Using multiple phages targeting same pathogen can help even more
      • But probably still not enough on its own usually
      • Or combine with antibiotics
    • Soon won't have to worry about killing or being killed by bacteria
    Author Statement:
    The idea of using phage, or viruses that only infect and kill bacteria, has been around for nearly a century. Phage therapy had largely been forgotten by Western medicine after the discovery of antibiotics, but is of renewed interest due to the spread of antibiotic-resistant pathogens. Yet, clinical trials of phage therapy have so far produced mixed results. One potential explanation is that the host immune response varies between individuals. Using a combination of animal experiments and mathematical models, we have shown that phage can work synergistically with the innate immune response to cure an otherwise fatal bacterial lung infection in mice. In other words, in this system, phage-induced clearance of bacteria works in tandem with the immune response. Our work suggests new mechanisms of action for phage therapy and provides an additional rationale for incorporating the immune status of patients in clinical trials.

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