Yogi Berra, Forrest Gump, and the discovery of Listeria actin comet tails - PMC

Yogi Berra, Forrest Gump, and the discovery of Listeria actin comet tails - PMC
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. 2012 Apr 1;23(7):1141–1145. doi:
10.1091/mbc.E11-10-0894
Yogi Berra, Forrest Gump, and the discovery of
Listeria
actin comet tails
Daniel A Portnoy
Daniel A Portnoy
Department of Molecular and Cell Biology and School of Public Health, University of California, Berkeley, Berkeley, CA 94720
Find articles by
Daniel A Portnoy
1,
Editor:
Doug Kellogg
Department of Molecular and Cell Biology and School of Public Health, University of California, Berkeley, Berkeley, CA 94720
University of California, Santa Cruz
*Address correspondence to: Daniel A. Portnoy
portnoy@berkeley.edu
).
Roles
Doug Kellogg
Monitoring Editor
Received 2011 Dec 12; Revised 2012 Jan 30; Accepted 2012 Feb 1.
© 2012 Portnoy. This article is distributed by The American
Society for Cell Biology under license from the author(s). Two months after publication it
is available to the public under an Attribution–Noncommercial–Share Alike 3.0
Unported Creative Commons License (
).
“ASCB®,” “The American Society for Cell
Biology®,” and “Molecular Biology of the Cell®” are
registered trademarks of The American Society of Cell Biology.
PMC Copyright notice
PMCID: PMC3376002  PMID:
22461646
Abstract
In 1988, eminent cell biologist Lew Tilney and newly appointed Assistant Professor of
Microbiology Dan Portnoy met at a picnic and initiated a collaboration that led to a
groundbreaking paper published in
Journal of Cell Biology
entitled
“Actin filaments and the growth, movement, and spread of the intracellular
bacterial parasite,
Listeria monocytogenes
.” The paper has been
cited more than 800 times, the most of any publication in the careers of both
investigators. Using an electron microscope from the Sputnik era, they assembled a
stunning collection of micrographs that illustrated how
L. monocytogenes
enters the host cell and exploits a host system of actin-based motility to move within
cells and into neighboring cells without leaving the host cell cytosol. This research
captured the imagination of cell biologists and microbiologists alike and led to novel
insights into cytoskeletal dynamics. Here, Portnoy provides a retrospective that shares
text from the original submission that was deleted at the time of publication, along with
reviewers' comments ranging from “It is really just a show and tell paper
and doesn';t have any meat” to “the finding will have major impact in
cell biology and in medicine. Potentially, the paper will be a classic.”
In 1988, I arrived at the University of Pennsylvania as Assistant Professor of Microbiology.
My primary research focus was on intra­cellular pathogens, which then, as now, are
responsible for an enormous amount of morbidity and mortality worldwide. The research began
during my final year of postdoctoral training at the Rockefeller University and during two
subsequent years as an Instructor at Washington University. In St. Louis, we developed
quantitative assays to examine the interaction of bacteria and cultured cells, which years
later would be referred to as the “bread and butter” of the Portnoy lab.
Although
Listeria monocytogenes
was obscure to most cell biologists, and
frankly scared many of them, it had been extensively studied for 25 years in a murine model of
cell-mediated immunity (
Unanue, 1997
) and is an
important food-borne pathogen (
Farber and Peterkin,
1991
). However, in 1986, virtually nothing was known about its determinants of
pathogenesis or the cell biology of infection, and there was no genetic system to speak of.
The first goal was to sort out the nuts and bolts of
L. monocytogenes
pathogenesis, then merge this information with immunological studies and ultimately apply this
knowledge to generate vaccines that would be protective against intracellular pathogens.
Prior to my move to the University of Pennsylvania, we did know a few things. We knew that
L. monocytogenes
replicated (doubling time of ∼40 min) as rapidly in
mammalian cells as in rich bacterial broth and grew in most, if not all, adherent mammalian
cells. We also knew that a secreted pore-forming hemolysin called listeriolysin O (LLO) was
required for
L. monocytogenes
intracellular growth, and there was evidence
that its role was to allow internalized bacteria to escape from a phagosome into the host cell
cytosol (
Gaillard
et al.
, 1987
Portnoy
et al.
, 1988
). By simply observing
stained cells infected with
L. monocytogenes
, it was obvious that the
bacteria spread directly from cell to cell, even in the presence of gentamicin at levels that
killed extracellular bacteria. Remarkably, a single cell could be infected, and by 8 h, 10
cells were infected. The first paper to demonstrate cell-to-cell spread was published in 1986
by Ed Havell while he was studying the interferon response to infection (
Havell, 1986
). In addition, Chihiro Sasakawa at the University of Tokyo had
identified a locus in
Shigella flexneri
essential for cell-to-cell spread
Makino
et al.
, 1986
).
One of the first ideas to provide a possible explanation for cell-to-cell spread was
suggested to me by Joel Swanson, then Assistant Professor at Harvard and a long-time friend
and colleague whose lab was next door when we were postdoctoral fellows at Rockefeller
University. Joel posited that spreading might require microtubules and recommended that I
examine the effects of nocodozole. Although nocodozole caused the cells to round up, the
bacteria still spread cell to cell. Larry Hale, who worked on
S. flexneri
at
Walter Reed Army Institute of Research, offered the first substantial clue that led to the
discovery by Tilney and Portnoy. Larry told me that spreading of
S. flexneri
was blocked by cytochalasin D, a chemical inhibitor of actin polymerization (
Pal
et al.
, 1989
). Sure enough,
cytochalasin D, at remarkably low concentrations, completely blocked the capacity of
L. monocytogenes
to spread within an infected cell; the bacteria grew as
cytosolic microcolonies. Next, I heard through the grapevine that Philippe Sansonetti from the
Pasteur Institute presented evidence at a Gordon Conference that intracellular
S.
flexneri
were coated in filamentous actin, whereas mutants defective in
cell-to-cell spread did not (
Bernardini
et
al.
, 1989
). Finally, before I departed from Washington University, I did a
few experiments with John Heuser, a brilliant and eclectic electron microscopist, that
provided evidence that
L. monocytogenes
enters the cytosol and becomes
enshrouded in host material that we suspected contained actin filaments. Apparently, electron
microscopists all seem to know each other, and John told me to look up Lew Tilney when I got
to Penn.
As I rarely passed up a party, it was not surprising that I ran into Lew Tilney at a Biology
Department picnic on the Penn campus in September 1988. Honestly, as a bacteriologist, I had
never heard of him or his classic work on the actin-based acrosomal reaction of starfish sperm
Tilney
et al.
, 1973
). I was soon to
appreciate that Lew was a monumental figure among cell biologists and a truly colorful and
unconventional character. Mentioning that I knew John Heuser, along with having a couple of
cold ones, helped break the ice. I shared with Lew all we knew about
Listeria
and the possible role of actin. When I told him about the cytochalasin D results, he grumbled,
“People who use inhibitors are inhibited.” Nevertheless, he agreed to meet on
Monday. Lew later recalled, “Portnoy crashed a department picnic and insisted I look at
his damn
Listeria
—I couldn't even spell
Listeria
—then I took one look, and bam, you're hooked”
Powell, 2005
).
On Monday morning, I met Lew in his lab. (If he had an office, I never saw it.)
That evening, I laid down some J774 macrophage-like cells onto bacteriologic Petri dishes so
that the cells could be easily dislodged, and on Tuesday, we did our first experiment using
wild-type and LLO-deficient
Listeria
. I infected and fixed cells in my lab
and walked the dishes to Lew's lab, where his long-time technician Pat Connelly did all
of the postfixation processing and microscopy, using an electron microscope from the 1950s. We
met nine days later to review the results. I had never seen such beautiful micrographs! Lew
identified what he later called an actin cloud around the bacteria, which he was sure
consisted of actin filaments. He noted, “Of considerable interest is that most of the
Listeria
that are found free in the cytoplasm have now acquired a cloud or
mat of material that surrounds them. Higher resolution of this ‘mat’ shows that
it is fibrillar in nature, being composed of dots (the filaments cut in transverse section)
and short segments of filaments (oblique section). These filaments tightly surround the free
Listeria
” (
Tilney and Portnoy,
1989
).
However, we were unable to determine the spatial relationship of the actin filaments to the
bacteria since we had scraped the infected cells from the dish. Lew decided that we should do
a time course and fix in situ on plastic tissue culture-treated Petri dishes. Again, I laid
down cells on Monday and brought him the fixed samples on Tuesday. Most of the figures in
Tilney and Portnoy were derived from this experiment, and here he coined the term
“comet tails.” In subsequent experiments, we verified that the filaments were
actin and examined their polarity by staining with the S1 fragment of myosin. The results
excited me, but I did not appreciate the big picture until Lew sent me a draft of a manuscript
from Woods Hole during winter break. Of importance, he had an artist draw a cartoon derived
from the micrographs (
Figure 1
). This figure eventually
landed in many textbooks of microbiology and cell biology and seems to be used during the
introduction to almost every
Listeria
seminar. The impact of this figure
cannot be overestimated.
FIGURE 1:
Open in a new tab
Stages in the entry, growth, movement, and spread of
Listeria
from one
macrophage to another. Photographs illustrating all these intermediate stages have been
presented in the figures in Tilney and Portnoy (1989). With copyright agreement from
Rockefeller University Press.
Fortunately, I saved a folder that contains the original drafts of the paper, reviews, and
rebuttals. The first draft blew me away. The writing was masterful although highly
unconventional. One line in the
Results
section, which made it to the
published version, reads, “Thus, this insidious beast has managed to multiply and
spread cell-to-cell without ever leaving the cytoplasm of its host.” However, the
phrase, “Machiavellian deviousness,” which Lew wrote to describe intracellular
parasites in a draft of the
Discussion
section, had to go. We submitted the
paper to
Cell
in February, and it was returned in March, rejected. Here is
one of the reviewer's comments: “The paper is technically flawless and of good
quality, albeit a bit lengthy. However it just is a ‘show and tell’ paper and
really doesn't have any meat. It is not the type of paper readers would expect to see
in
Cell
. The system has the potential for some very exciting cell biology of
the sort Tilney lists in the last paragraph of his discussion, but it hasn't happened
yet. My suggestion would be to reject this one but to encourage Tilney to submit the follow-up
paper (and perhaps hint that it might be treated favorably) because it can be expected to be
even more exciting.”
Another reviewer wondered why we had not tried one of the “modern fixatives that
preserve actin filaments better.” However, our study used Lew's magical cocktail
consisting of glutaraldehyde and osmium tetroxide (called “the mixed fix”). This
ideal brew allowed most of the cytosolic components to escape fixation while highlighting
cellular membranes and actin filaments.
After a failed attempt at a rebuttal to
Cell
, we sent the manuscript to the
Journal of Cell Biology
. Here, one of the reviewers also believed the paper
should be rejected, because it was “really a look and see report.” This reviewer
recommended, “For publication in the
JCB
I would expect some more
experimentation on some aspect of the cell biology of the system.” Fortunately, the
other reviewer saved the day: “The observations constitute a really new
finding—nobody knew this before! What's more, the finding will have a major
impact in cell biology and in medicine. Potentially, the paper will be a classic.” The
second reviewer had a few memorable comments about the other reviewers; one of my favorites:
“What a disaster that many good scientists no longer recognize the validity and clarity
of information that we obtain with our sensory organs—how do these scientists manage to
get around on a day-to-day basis?” Fortunately, the editor, Tom Pollard, accepted the
paper. One note: Lew often included Pat Connelly on papers, but in this case, he did not. He
told me that Tilney and Portnoy would benefit my career more than Tilney
et
al.
Thank you, Lew!
The final paragraph of the original discussion, written entirely by Lew, was ultimately
deleted by the editors, but provides such insight that I include it here verbatim:
As with most scientific studies we are left with more questions than we
started with. For example, if the membrane of a phagolysosome is dissolved by the
hemolysin of the bacterium, why is the host cell not sicker because of the release of the
lysosomal enzymes into the cytoplasm? In the same vein, since hemolysin of
Listeria
has an pH optimum of 5.5 with no detectable activity at 7.0
(Geoffroy
et al.
, 1987), how can
Listeria
get out of the
double membrane compartment it is in when it spreads from one cell to the next? The
hemolysis should be in the inner vacuolar (formerly pseudopod plasma membrane of the old
host cell) membrane, but lysosomes would only fuse and acidify the outer portion of the
phagosome. How does the new host macrophage ‘know’ to phagocytose only the
specific pseudopods of donor macrophages that have a
Listeria
at their
tips? How does it break off from the old host? What is the time course of the events of
Listeria
spreading, seconds, minutes, hours? Does the cell wall of
Listeria
bind to actin filaments or does it induce polymerization of
monomeric actin to filaments and if so, how? How does a comet tail form from a circular
mat of actin filaments around a
Listeria
? How does the comet plus tail
move to the cell surface and make a pseudopod? Why is the tail of the comet composed of
randomly oriented filaments rather than a bundle of cross-bridged filaments and why does
the presentation of the
Listeria
to a new host occur at the tip of a
pseudopod rather than the tip of a microvillus, a structure one would imagine would be
easier to build? Many of these questions can be answered by looking at living cells
(Schaechter
et al.
, 1957) and will give us information not only on
Listeria
and its proliferation and for that matter certain
intracellular parasites generally, but also help cell biologists learn more about the cell
biological processes. We live in fascinating times.
Can you imagine writing his final sentence today?
There are a few reasons this research garnered so much attention. For one, Lew was well
known, respected, and had a dedicated fan club. Also, an article in
Nature
's News and Views entitled “The pushy ways of a
parasite” appeared the month following the publication of Tilney and Portnoy and
highlighted the work with a reproduction of the model figure from the paper (
Donelson and Fulton, 1989
). In his rebuttal to
Cell
, Lew had argued with the editor that the paper deserved publication
because of all the attention is was generating: “the reviewers have no way of knowing
this, [but] our work has already fascinated a large number of biologists because Portnoy loves
to give seminars and has stimulated a number of investigators to carry this project
forward.” Indeed, between 1989 and 1992, I gave 45 seminars, including 20 at national
and international meetings. The notoriety was gratifying, but unfortunately,
Sansonetti's and Sasakawa's work on
S. flexneri
had not been
acknowledged in the publication or the News and Views (
Bernardini
et al.
, 1989
Makino
et al.
, 1986
).
One of the cell biologists intrigued by our findings was Tim Mitchison, who heard about the
work from Lew during the summer at Woods Hole. Tim and Lew debated whether the tails moved,
perhaps using an unknown motor protein, or remained stationary in the cell cytosol. Tim, then
Assistant Professor at the University of California, San Francisco, shared the work with his
doctoral student, Julie Theriot. In October 1990, Julie proposed as part of her doctoral
research to use
Listeria
to identify host factors that control actin
polymerization to complement her primary research on the control of actin polymerization at
the leading edge of keratinocytes. Julie and Tim used fluorescence photoactivation and
time-lapsed video microscopy to study the dynamics of actin filament polymerization in living
cells (
Theriot and Mitchison, 1991
). Lew suggested that
I visit Julie and Tim, so in November 1991, I flew to San Francisco, bacteria in hand (have
Listeria
, will travel) and initiated what would become a long-term
collaboration with Julie that has lasted from her time as a Whitehead Fellow through today, as
a faculty member down the road at Stanford. On the first morning, we infected PtK2 cells, and
using their home-made video system, Julie filmed what remains among the best movies of
Listeria
actin-based motility (
www.youtube.com/watch?v=sF4BeU60yT8
). The next day, Julie did the experiment
that led to a
Nature
paper, coauthored with Lew, entitled, “The rate
of actin-based motility of intracellular
Listeria monocytogenes
equals the
rate of actin polymerization” (
Theriot
et
al.
, 1992
). Here she demonstrated that the comet tails do not move and
that the actin filaments are rapidly turning over, with a half-life of ∼30 s. She
effectively argued that actin polymerization alone could provide the propulsive force
necessary for actin-based motility. These observations, combined with the work of Fred
Southwick and the Sangers, clearly showed that actin filaments polymerized at the interface of
a bacterium and its actin tail and that the actin filaments in the tail were stationary (
Dabiri
et al.
, 1990
Sanger
et al.
, 1992
). Also in 1992, Pascale Cossart at the
Pasteur Institute and Trinad Chakraborty, Werner Goebel, and Jurgen Wehland in Germany made
the critical codiscovery of the
Listeria
ActA protein (
Domann
et al.
, 1992
Kocks
et al.
, 1992
). Each group, along with Julie Theriot and Greg Smith
in my lab, later used novel approaches to show that ActA is not only necessary, but also
sufficient, to mediate actin polymerization (
Brundage
et al.
, 1993
Pistor
et
al.
, 1994
Friederich
et
al.
, 1995
Kocks
et al.
1995
Smith
et al.
1995
).
In a second paper I coauthored with Lew (
Tilney et al.,
1990
), he proposed that
Listeria
might lead us to the elusive actin
nucleator: “We have stumbled upon a biological system in which we have an excellent
chance of isolating, purifying, and characterizing a natural actin filament nucleator.”
A few years later, Matt Welch, then postdoctoral fellow in the Mitchison lab and now a close
colleague at University of California, Berkeley, used
Listeria
overexpressing
the ActA protein and conventional biochemistry to discover that the Arp2/3 complex was the
host cell nucleator (
Welch
et al.
1997b
). Matt later established that purified ActA was a direct activator of the
complex and the founding member of what are now called actin nucleation promoting factors
(NPFs;
Welch
et al.
, 1998
). Matt and
others showed that ActA is a molecular mimic of cellular NPFs, such as proteins in the WASP
family (
Skoble
et al.
, 2000
Boujemaa-Paterski
et al.
, 2001
). A few
years later, Mary-France Carlier at the Centre National de la Recherche Scientifique in France
accomplished in vitro reconstitution of
Listeria
actin-based motility using
the Arp2/3 complex, actin, cofilin, and capping protein (
Loisel
et al.
, 1999
).
By 1993, Lew was out of the
Listeria
business, although he continued his
career as one of the world's great observationists, working on, among other things,
Drosophila
wing hairs and bristle cells (
Tilney and DeRosier, 2005
). He retired a few years ago and currently lives a bit
reclusively in Massachusetts and chose not to be a coauthor of or comment on this
retrospective, but he did thank me for thinking of him. In 1997, I moved to Berkeley and
continued to work on the role of ActA until 2003 (
Skoble
et al.
, 2000
2001
Lauer
et al.
, 2001
Auerbuch
et al.
, 2003
), then changed to a more
immunological research focus (
Witte
et al.
2012
). One particularly gratifying consequence of the actin-based motility research
was the observation that ActA-deficient strains make extremely potent and safe
immunotherapeutic vaccines (
Brockstedt
et al.
2004
), which have shown promising results in clinical trials for pancreatic and other
cancers (
Guirnalda
et al.
, 2012
Le
et al.
, 2012
).
I suspect that the reader may be wondering about the title of this retrospective. As one
interested in pathogenic microorganisms, I view myself as Forrest Gump in the world of cell
biology, lucky to have worked and collaborated with such creative and accomplished cell
biologists like Lew, Julie, Matt, and Tim. For me, microbial pathogenesis “is like a
box of chocolates; you never know what you are gonna get.” But most remarkable to me is
that so much of what we learned came from simply looking through the microscope. As Yogi Berra
famously remarked, “You can observe a lot by watching.”
Acknowledgments
I thank the editors of
Molecular Biology of the Cell
, David Drubin and
Doug Kellogg, for inviting this retrospective. Between 1993 and 2003, four doctoral students
(Greg Smith, Justin Skoble, Peter Lauer, and Vicki Auerbuch) coauthored with Julie Theriot
all of my lab's papers related to
Listeria
actin-based motility and
ActA. For comments on the retrospective, I thank Neil Fischer, Vic DiRita, Matt Welch, and
Bernard Portnoy. I owe a debt of gratitude to Susan Craig at Johns Hopkins University, whom
I later learned was the reviewer who convinced Tom Pollard to accept the Tilney and Portnoy
paper. But most of all, I thank my wonderful collaborators: Lew Tilney, for his open mind,
intellectual curiosity, and willingness to put up with me; Tim Mitchison, for opening his
lab to me on multiple occasions and for allowing me to be senior author on our coauthored
Nature
paper. I thank Julie for her brilliance, kindness, and loyal
friendship; and Matt Welch for being a wonderful collaborator, colleague, and friend. I am
supported by National Institutes of Health Grants R01 AI27655 and P01 AI063302. I have a
consulting relationship with, and a financial interest in, Aduro Biotech, which stands to
benefit from the work conducted in my lab.
Footnotes
DOI: 10.1091/mbc.E11-10-0894
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