Monday, November 12, 2018

BacterioFiles 361 - Figuring Fungus's Forcing Fly Functions

Fruit fly infected with fungus
By Elya et al 2018;7:e34414
This episode: Bringing a fungus that makes zombie flies into the lab makes a good model for studying microbial mind-control!

Thanks to Dr. Carolyn Elya for her contribution!
Download Episode (12.1 MB, 13.25 minutes)

Show notes:
Microbe of the episode: Dipteran brevidensovirus 2

News item

Videos of fly fungus infection progression

Journal Papers:
Elya C, Lok TC, Spencer QE, McCausland H, Martinez CC, Eisen M. 2018. Robust manipulation of the behavior of Drosophila melanogaster by a fungal pathogen in the laboratory. eLife 7:e34414.

Other interesting stories:

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Episode outline:
  • Background: Ability of microbes to influence host behavior is impressive
    • Seems like complicated thing to evolve, though not necessarily
  • But multiple fungi have developed ways to manipulate insects
    • Like Ophiocordyceps that make zombie ants, climb up and sprout fruiting bodies
    • Not sure exactly how they work though
  • Also Entomophthora muscae in flies (speaking of dipterans)
    • Infected flies go to high location and fungus sprouts out of mouthparts to anchor it
    • Then out through chinks in exoskeleton, make spores that launch away to find new hosts
    • If misses, can make new spore-forming structure and try again, until exhausted
    • If hits, bores into host with force and enzymes
  • What’s new: Now, Dr. Carolyn Elya and colleagues Tin Ching Lok, Quinn Spencer, Hayley McCausland, Ciera Martinez, and Michael Eisen, publishing in eLife, have studied the fungus's methods more deeply in fruit flies!
  • Methods: Here's Dr. Elya describing how this study got started: statement
  • Looked for flies around sunset, when pathogen tends to kill them
    • Most spores produced and ejected within 12 hours, none left after 48
  • Isolated fungus from one fly, wild Drosophila hydei, and grew in lab
    • Checked genome sequence to confirm identity
  • Set up in vivo infection system too, exposing lab D. melanogaster to wild cadavers
    • Had some hiccups; preservative in food inhibited fungus
  • Hard to tell if fly is infected when alive
    • Look and act normal until near death
    • Do have scars from spore entry, but sometimes hard to see
    • And sometimes flies survive infection
    • ~80% die within 4-7 days
  • Exhibited same circadian patterns in lab; fungus kills flies near "sunset"
    • If kept in dark, flies die randomly throughout day
    • Healthy flies have circadian rhythm in dark, so infection responding to external signals
  • At end of life, flies stop flying and start climbing up
    • Usu normal speed but sometimes slow and shaky
  • Then proboscis anchor attaches and wings raise, in bursts like balloon inflating
    • Interesting videos linked in show notes
    • ~8% of flies don't raise wings, keep lowered
    • Twitch for a while before stopping
  • Measured gene expression in fungus over course of infection
    • Every 24 hours over 5 days
    • Kinda hard, fungal genome seems to be majority retrotransposons and repeat stuff
    • Some proteins related to circadian clock and light sensing
    • Some others on when host alive but turned off after death
      • Includes apparent sugar and lipid and chitin degrading enzymes
      • Also possible fungal mating-related enzyme
      • Not well known
    • And others that turn on after host death
      • Some more nutrient acquisition/degradation and regulation ones, many unknown
  • Of host genome, expressed at different times, some even more in late infection
    • Not much in infection: energy, egg production
    • Some in infection: nutrient metabolism
    • More in late: sensory pathways and neural processes
    • More in early: immune stuff, carb metabolism
    • In infected vs. uninfected, more amino metabolism, as if flies are starving
  • Stained infected flies after death with different dyes to tell fungus and fly cells apart
  • At 48h, saw fungal cells in nervous system and brain of flies
  • At 72h, fungus throughout body cavity, fat stores somewhat depleted
  • At 96h and beyond, if alive, fungus everywhere, less fat stores
  • After death, gut and gonads consumed, brain being degraded, muscles still intact at first
  • Couldn't really specifically say how fungus controlled fly behavior
    • Could be affecting brain cells, but maybe specific ones hard to see individual changes
    • Also some hormone-related enzymes expressed by fungus
    • Might not even need to get into brain to control fly at all, not clear
  • Then spore-forming structures emerge, launch spores
    • Calculated ~20 mph at launch
  • Summary: Fungus E. muscae has dramatic effects on fly behavior, and this study demonstrated many of the specifics of what, but not clear yet exactly how
  • Applications and implications: Good model for studying microbial/fungal neurologic effects
    • Not just find in wild, but propagate and control in lab
  • Maybe control of pests
  • What do I think: Sounds pretty horrible, except that it's killing flies
    • Flies interesting and important but also can be pretty annoying
    • Definitely could inspire some interesting sci-fi horror like Ophiocordyceps and zombies
  • But most interesting how invader can speak language of host enough to manipulate
    • Need specific evolved mechanism to tap into biochemical signals of another kingdom
  • Works well for fungus, not so well for flies

Author Transcript:
So I do have a fun story about the fungus, and basically the gist is that I isolated it from my backyard in California when I was a graduate student. So I was at the time collecting wild flies for a different project that I was working on in Michael Eisen's lab, and I noticed that in the bait that I had set out to catch these wild flies, there were some dead flies, and these dead flies were peculiar, they had their wings up at a 90 degree angle, and they had evidence that some sort of microbe had grown out through their skin. And very very luckily, I knew that these two features of cadavers are hallmarks of infection by a particular pathogen, fungal pathogen called Entomophthora muscae. So I knew that this was probably Entomophthora muscae, followed this up, confirmed that that was true, and that led me to isolating the fungus and bringing it into the lab to study.

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