by Daniel Keays

Listeriosis

Milk Bug

Defense avoidance

And lifestyle alterations.

Cunning predators.

 

            Macrophages of all types and descriptions are designed to efficiently kill and remove bacterial invaders.  They also play the vital role of digesting the beast and displaying little parts of it on their surface to initiate the process of acquiring sustained immunity to the organism.  Through eons of trial and error, Listeria has achieved the power to circumvent the macrophage’s operations and direct its activities.  It literally seeks out and enters the cell designed to kill it. Indeed, the species name for the organism is monocytogenes, or “monocyte generating.” The genus name is in honor of an infectious disease pioneer, Joseph Lister.

            Listeria is a genus of a Gram-positive rod that lives in two very different environments. One day, it may be out in an open field, sitting on a blade of grass. The next day it can find itself inside a mammal being devoured by a macrophage designed to kill it. Amazingly, the microbe has successfully adapted to both environments.

 

               When a macrophage encounters a microbe, a section of the macrophage surrounds the bug. The host cell membrane, where the microbe attaches, disengages from the rest of the membrane.  Following a series of reactions, this tiny bit of membrane-encircled microbe is incorporated into the host cell.  This structure is known as a phagosome, a little “jail cell” the host sets up to encase invading microbes.

            Bacteria have a lot of genes in their DNA that they don’t express.  Why produce some material that is not immediately needed but requires much energy to make?  The proteins the organism needs for the external environment are considerably different from those needed when the bug is inside a macrophage or other mammalian cell. The trigger to release these sequestered genes is a protein called PrfA.

             Mammalian cells, unlike the outside environment, are rich in glutathione, and that seems to be the substance to which PrfA reacts. Additionally, elevated temperature plays a role. Once exposed to glutathione and body temperature, PrfA acts like a zipper, unleashing the genes already present on the Listerial chromosome, enabling them to be transcribed and their protein products released. This set of about 15 previously suppressed proteins allows Listeria to circumvent the host cell’s defense mechanisms and exist with impunity within the macrophage or other cell designed to kill it.  

            Residing within all nucleated mammalian cells are small vacuoles containing digestive enzymes.  Known as lysosomes, these digestive vacuoles clean up regular activity within the cell, a process known as autophagy or “self-eating.”  Their role is essential, keeping the cell environment clear of toxic products. When a microbe-bearing enters a cell, the lysosomes are activated. The lysosome fuses with the phagosome, and the microbe is in real trouble.

 

            Cells invaded by microbes are programmed to begin a process by which they kill themselves, the action known as apoptosis.  Better to let one easily replaceable cell perish than have it serve as a factory for producing pathogenic microbes.  The enzymes inside the cell responsible for the destruction are known as caspases.  (The term “caspases” comes from the fact that the active part of the molecule is cysteine, starting with “c,” and it attacks regions of molecules that contain aspartic acid, the “asp”). Caspases aren’t just floating around randomly destroying enzymes but are present in a non-active form known as procaspases. When the signal is given, the procaspases aggregate, and their proximity leads to their activation. Once the process begins, there is no turning back. The cell has hit the self-destruct button.

            These activities, destruction of the microbe within the phagosome and self-destruction, are usually more than enough to prevent microorganisms from gaining a foothold.  But the clever little Listeria has found a way around it.

            

            A substance known as listeriolysin is the first protein to become active once the organism is inside the host cell. Listeriolysin breaks down part of the phagosome membrane, enabling the bacteria to escape before the deadly lysosome hooks on.  The organism is then free to roam around the host cell.

            Key to the activity of Listeria inside the macrophage is its ability to take over part of the cell’s actin proteins and use them like little propellers to go gliding through the cell. In the outside environment, Listeria has flagella located at one end. Inside the macrophage the flagella are shut down, and movement is turned over to the hijacked actin proteins. This allows the organism to go directly from one cell to another without ramping up the immune system.  

            An interesting characteristic of Listeria is its ability to alter itself according to temperatures.  Refrigeration is used to preserve foods, but Listeria not only survives refrigerator temperatures, but it also multiplies.  Cheese with only a few organisms will have a lot more if left in the refrigerator for several days or weeks.  At the other end of the temperature spectrum, flagella production is shut off at higher temperatures, and the organism becomes non-motile.  

            Listeria is not rare in developed countries.  It’s quite a common bug.  It is most likely found in dairy products, especially soft cheeses, but it is common in lunch meats and some produce.  That’s because Listeria colonizes the bowels of mammals.  Like E. coli, Listeria is eliminated with fecal waste from farm animals and can follow a similar pattern of occurrence in various foods.  

            The obvious question is if Listeria is so common and an effective pathogen, why aren’t more cases of it seen clinically?  Annually in the U.S., about one to two thousand cases of listeriosis are reported.  Most cases are serious, sometimes fatal, but of limited scope, despite the relative abundance of the organism.  An important reason for this is that not all strains of Listeria monocytogenes are created equal.  There are 13 recognized strains of Listeria, but only 3 (4b, 1/2a, and 1/2b) are pathogenic for humans.  If we have Listeria in our food, it may not be a potentially dangerous strain.  Also, Listeria is very susceptible to acid.  It dies if the pH drops below 5.5.  Stomach acid is normally much below that.  For the organism to make it through the stomach, the individual potentially infected must consume very large amounts of the organism, over 10 million bugs.  Even though the organism grows at low temperatures, that’s a very high infective dose.  Food containing the proper strain would have to be left out at room temperature or warmer for prolonged periods.  Or, of course, the infected patient may have reduced stomach acid, which can occur when taking antacids.  

            Even though the organism possesses mechanisms to help it avoid the immune system, it is not foolproof.  Its intracellular habitation reduces the effectiveness of complement, antibodies, and neutrophils, but it is still vulnerable to macrophages.  Macrophages (those that are uninfected) can destroy an infected cell and the bacteria along with it.  TNF-a is a great help in directing this destruction of infected cells.  Once free of the dying host cell, Listeria is fair game for passing members of the innate immune system and is quickly disposed of.

            An intact immune system is necessary to take care of Listeria.  Those most vulnerable to infection are people whose immune systems are compromised, either by a disease condition or therapy.  One group of people with a reduced immune response to intracellular pathogens is women in their third trimester of pregnancy.  Adding to their vulnerability is the organism’s propensity to infect the placenta. It has a great affinity for the cells of that organ, and once attached, it is hard for wandering macrophages to enter the placenta and dislodge it.  The baby is at significant risk since its immune system is not developed.  

            Another organ Listeria has a great attraction for is the central nervous system, especially the meninges. Meningitis is the most common infection caused by Listeria other than those in the placenta and babies. Listerial meningitis is most common in people with immune systems that are not functioning properly. Sometimes, elderly people with no known immune deficiency become infected.

            

            Listeria is Gram-positive and very susceptible to the penicillin class of antibiotics. Once the diagnosis is confirmed, usually by blood or spinal fluid culture, either penicillin or ampicillin is an effective therapy. Of course, the sooner the diagnosis is made and therapy initiated the better the prognosis.

            Because of its unique ability to enter and survive inside human cells, Listeria has become the focus of an experimental anti-cancer treatment. Attenuated strains of the bacterium have been loaded with anti-cancer molecules. The organism is used as a “Trojan Horse” to carry these compounds inside the cancer cell and help bring about its destruction. 

 

 



  Listeria monocytogens.
 (Image from the Public Health Image Library, CDC)

Prev Next