Bacteria & Cells' Collaboration

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Watching Host Cells Collaborate in Bacterial Infection

By PHILIP J. HILTS

Published: June 17, 1997

 

WHEN people suffer something as unpleasant as diarrhea, they tend not to think of it as a form of intimacy with bacteria.

 

Nevertheless, says Dr. Julie Theriot of the Whitehead Institute for Biomedical Research in Cambridge, Mass., the process of infection and the progress of disease can profitably be thought of just that way: as bacteria becoming intimate with the cells of our body.

Her specialty is the process of pathogenesis, the attack of infectious organisms on the body. She makes videotapes of the pathogens as they approach, attack and even enter cells.

 

''Watching pathogenesis in real time,'' as Dr. Theriot puts it, and videotaping the process is a revelation for microbiologists, and it has taken off in recent years.

 

''You can measure their movement and watch what happens when you inject things into the cell -- all the while you can see things happening,'' said Dr. Joseph Sanger, who with his wife, Dr. Jean M. Sanger, a fellow cell biologist, was a pioneer with the technique in the early 1990's at the University of Pennsylvania School of Medicine. ''It's kind of ghoulish because these pathogens are giving a lovely performance as you watch them moving,'' he said.

 

There is much scientists can see live under the microscope that they cannot see by other methods, he said.

 

When the Sangers began their work, only one or two laboratories were looking at pathogenesis with videos. Now dozens of laboratories have installed video cameras to watch the microshow.

 

And, as Dr. Theriot puts it in the language of a recent scientific paper, the interaction between the peaceful cells and their aggressive acquaintances, the pathogens, ''can be characterized as advancing levels of intimacy in host-parasite contact.'

 

At a recent talk in a seminar called ''Modern Plagues'' held at the Whitehead Institute and Massachusetts GeneralHospital in Boston, Dr. Theriot showed her videotapes and other researchers described in detail the dance of the pathogen and host.

 

One of the scientists, Dr. John Mekalanos, chairman of microbiology at Harvard Medical School, said the new work showed that the process by which a pathogen attacked a cell was hardly the simple assault researchers had thought. The message of the new technique, he said, is that it takes two to tango. The cells being attacked must actually give aid, mistakenly biologists assume, to the advancing bacteria. In some cases, researchers have learned, the cells even provide the bacteria with artificial devices called ''clouds'' and ''comet tails,'' which greatly speed bacterial action.

 

''In virtually all cases, the damage that happens in infectious disease is the body's fault, so to speak,'' Dr. Theriot said. ''It's not the invading organism itself that does the damage, but the body's mistaken responses to it.''

 

She says the way to begin thinking about the issue is to consider different infections as successful, and increasing, forms of pathogenic intimacy.

 

There is a base of acquaintance between organisms and the body's cells to begin with: infection, or bacterial colonization, rarely if ever occurs just because bacteria are present in the body. The agents of disease are always there, in small numbers. Disease begins when the organisms get aggressive.

 

Two infections that may be characterized as level one of intimacy are botulism brought on by Clostridium botulinum, and staph infection brought on by Staphylococcus aureus. In both cases, the organisms just secrete damaging toxins into the body where they are growing. The toxins then masquerade as some useful substance, and the cell willingly accepts them on its receptors.

 

The next level of infection occurs when the whole organisms attach themselves to the surface of host cells. Cholera is in this category, as Vibrio cholerae attaches to the cells and hangs on there while secreting its toxin.

 

Dr. Mekalanos said the details of the back and forth between host and disease agent had been clarified in ''amazing detail.''

 

He said for example that the cholera bacterium itself must be infected by a virus before it can become virulent. During the infection, the virus donates to the bacterium the gene that makes cholera toxin. So, in order to cause disease, the bacterium must itself first be a victim.

 

Next in order of intimacy are the cases in which the bacteria attach to the body's cells and send out a signal that causes significant changes in the shape or behavior of the cell. Escherichia coli, a common gut bacterium that can cause diarrhea, which in rare cases can be fatal, is in this category. E. coli bacteria coax the cell into shedding its own outer filaments, called microvilli. Next they induce the cell to provide even a place to ''sit,'' pedestals where E. coli attach, above the cell's close-in defenses.

 

Dr. Sanger, who has studied the virulent E. coli on videotape, said that once the E. coli attach to an intestinal cell, they are able to use the pedestals to move all over the surface of the cell. He is now experimenting with ''laser tweezers'' to see if he can pluck the bacteria off the intestinal cells.

 

The final stages of intimacy between parasite and host, and the stages Dr. Theriot has worked on extensively in the last few years, are those in which the pathogens not only meet and greet the body cells, but pierce and enter them.

 

They do this by sending a chemical signal of their presence to the cell, which tricks the cell into accepting the bacterial Trojan horse. The cell itself then extends its walls outward, to grasp and surround the bacteria. The bacteria quickly put out enzymes that break a hole in the extended skin cell wall; the bacteria have made it inside where they may then become chronic boarders, hiding out in protected sacs, the vacuoles.

 

In the cases of several bacteria and viruses, they use the protected vacuoles as launching pads to start a new and ''rather sneaky'' wave of infection, Dr. Theriot said. In this version, they move stealthily and rapidly from cell to cell, without ever having to emerge into the body's spaces where the immune system is on patrol.

 

As scientists have recently found, this approach requires much ''cooperation'' from the invaded cells themselves.

 

For infections like dysentery brought on by Shigella, and meningitis brought on by Listeria, and a few others identified so far, the next step is crucial to whether an infection turns into a raging illness.

 

The bacteria secrete a chemical -- at least two different ones are known -- that orders the cell to make ''comet tails'' for the bacteria. These tails, made of the protein called actin, act like jets to propel the bacteria around inside the cell. The tails are not directly attached to the bacteria, but rather the bacteria sit on top of a column of actin. New protein is rapidly inserted between the bacteria and the towering ''tail,'' which does not itself move. Thus, the bacteria move, like a person rising up in a chair by inserting one phone book after another atop the seat.

 

This occurs just as the cell is trying to produce a defense, marshaling killer immune cells for an attack. But the movement of the bacteria by using actin rockets is fast enough that it may infect and move on faster than the body can respond.

 

The bacteria use their new tails to race to the cell wall, where they break out into a neighboring cell to repeat the cycle.

 

These ''tails'' are important in different infections by very different organisms. Thus, researchers hope they can exploit the feature by devising treatments for a range of infectious diseases. Without the aid of comet tails, Dr. Theriot said, the Shigella and Listeria infections stop dead. Deletion of a single part of a gene in the bacterium can prevent it from using comet tails to speed the infection.