Intracellular bacteria have developed various strategies to invade, survive, and multiply inside cells. Many bacterial pathogens including Legionella, Chlamydia, Salmonella and
Brucella co-opt inner membranes to create a specific compartment adapted to their needs. Organelles are among the most prominent features that distinguish eukaryotic from
prokaryotic cells (see Glossary). They form intracellular compartments delimited by at least one membrane. Therefore, they represent attractive targets for bacterial pathogens to hijack host cell function and ensure their own survival. Wounds in barrier epithelia, including the skin, allow pathogens direct access to the interior of the host.1
To specifically attack the fundamental organelles of the cell, certain bacteria use extremely sophisticated techniques that involve multiple levels of DNA codes, manipulation of histone codes, an understanding of how proteins are folded, and how newly produced versions of these proteins will interact in vastly complex pathways and cascades in human cells. They, also, build incredibly complex secretion weapons to send these molecules to particular places in the cell. Much of this is extremely difficult for humans to decipher and is currently unknown. 2
Question: Did God Create Flesh-Eating Bacteria? A Creation Model for the Origin of Human Disease
Human cells, on the other hand, have as well sophisticated mechanisms to deal with invasive pathogens:
Mitochondria Play an Unexpected Role in Killing Bacteria
How do small microbes, a thousandth the size of a human cell, understand how to do this? Meanwhile, our cells must understand the extremely varied attacks of a large number of different microbes and counteract them.
My comment: How can anyone not see that such sophisticated behavior is extremely unlikely due to evolution, but rather by pre-programming by an intelligent creator for specific purposes?
Human cells are massively larger and more complex than bacteria and yet microbes keep up relentless intelligent warfare. Previous posts documented surprisingly sophisticated, multi-level attacks by microbes using protein molecules and micro RNA against plants and animals.
Recently, new microbe techniques have been discovered that specifically target organelles of the human cell. These complex assaults can directly manipulate genes to produce unique proteins. These altered proteins change normal functions to produce new types of activity helpful to the microbe. This activity, somehow, occurs in complex pathways with cascades of interacting proteins. Microbes, also, use epigenetic tags on DNA and histones. In order to use epigenetic techniques, microbes are able to target specific enzymes that alter the function of genes through the histones and other structures protecting them. These assaults alter the gene expression by placing specific tags blocking the functions of regions of DNA. This is done either indirectly by altering the normal enzymes that perform these functions, or directly by placing and removing the tags with their own produced molecules.
To perform these sophisticated manipulations, many levels of interacting codes are utilized. It is hard to imagine how unicellular microbes can understand the effect that a tag will have on the underlying gene that will alter the specific amino acid sequence to alter the exact shape of a protein. This particular protein shape, then, has very particular functions in complex cascades in the human cell. Also, these molecules are injected into the cell by extremely complex secretion systems that look similar to a syringe. This is a highly intelligent activity for a small single-celled creature.
Despite extremely complex functions in the cell’s nucleus, mitochondria, endoplasmic reticulum, and Golgi, these very small intelligent microbes are able to manipulate and commandeer organelles for their own advantage. Attacks are extremely precise and allow the microbe to hide inside the cell compartments to reproduce by disabling surveillance and immune responses. Both eukaryote cells and microbes have methods of attack and cellular level immune defenses.
Organelles Have Particular Territories and Functions
The eukaryote cell is very organized into compartments. These discrete regions of the cell have specific functions. Microbes manipulate the organelle’s unique functions to gain an advantage over the cell.
Mitochondria produce energy and manage programmed cell death (apoptosis); the nucleus maintains and regulates the complex use of DNA and RNA; the endoplasmic reticulum (ER) handles and sorts new proteins and lipids; the Golgi directs secretory pathways where materials are carried to every section of the cell in vesicles.
Microbes have specific proteins that are secreted to attack each of the organelles—called effector proteins—which alter the cell’s functions. The secretion of these proteins is through one of 7 different elaborate secretion systems but especially types 3 and 4 are utilized in this battle between cell’s organelles and bacteria. Microbes are able to direct secretions precisely and at the exact time that can be most effective.
One of the microbe strategies is to make proteins that are very similar to the cell, but that alter function in various ways. They develop these either through evolution in the midst of the battle with the cell or by acquiring the genes.
An example occurs with the amoeba, which makes proteins that are very close to those usually only found in animals and secretes them into the cell. Legionella sends more than 300 different proteins into a human cell. These proteins are otherwise only found in human cells. Other bacteria have been found with the same exact genes by horizontal gene transfer among many microbes. Some microbes, such as Chlamydia and Legionella produce proteins with sections that are similar to a variety of different human proteins and have multiple effects.
The ubiquitin system of labeling molecules in the cell has thousands of variations. The cell designates functions and destinations for molecules by using this very complex tagging system. Microbes have picked this up and use this same tagging system in warfare with cells to counteract functions.
In the normal function of the cell, tags are placed on newly produced proteins and other molecules to show what organelle will be receiving them. Bacteria copy this approach and secrete signals via the type 3 secretion system (T3SS) for the nucleus (NLS or nucleus localization signal) and the mitochondria (MLS or mitochondrial localization signal). The type 4 secretion system (T4SS) can inject DNA. Injection of proteins and genetic material can occur from outside of the cell by E coli and this goes with a tag directly to the mitochondria. Other intracellular bacteria inject both outside and then inside the cell. Salmonella has multiple proteins injected and Legionella has 300 different proteins with different functions.
Another technique is the delivery of toxins without secretion systems either outside or inside the cell. Listeria has a toxin that cuts a hole in the cell membrane and internal membranes.
Targeting the Cell Nucleus
DNA is wrapped twice around histone protein for protection and must be unspooled when used. Molecular tails on the histones can regulate whether the spool will be opened to allow particular genes to operate, or not. These tails are important in regulating enzymes that place a wide variety of epigenetic tags on the histone proteins. There are now known to be more than fifty different kinds of tags and placements on the protein, such as methylation, acetylation, and ubiquitination on a lysine amino acid and the phosphorylation on serine and threonine. These tags are generally called post-translational modifications (PTMs). These have major effects on regulating the operation of genes. 2
While the effects of each type of PTM is very complex and just being discovered, somehow microbes already understand them and hijack this system, particularly related to the cell’s response to identifying the microbe in the cell. The cell has a pattern recognition system to identify microbes called pathogen-associated molecular patterns (PAMPs) that stimulate immune pathways with cytokines. The microbes attack both the cascades that stimulate inflammation and, also, the histone tags.
Major microbes, such as mycobacterium tuberculosis, influence the enzyme for acetylation (histone deacetylase or HDAC). They directly influence the gene that makes this enzyme. This is a remarkably complex mechanism for a microbe to utilize.
Some microbes go after the larger 3D structure of the DNA in the nucleus. Recent research has shown that the regulation of DNA is fantastically complex and now includes three-dimensional structures that hold the DNA in various positions inside the nucleus. (Manipulation of this structure by microbes is an entirely new field called patho-epigenetics.) Somehow, microbes understand much more than we do about how DNA is regulated. First the effector protein from the microbe has to get to the nucleus through special tags that take the molecule in through the very complex nuclear pore mechanism.
Multiple microbes, including E. coli, Shigella and Listeria, make proteins that alter the proteins that hold the DNA in place. First they influence the actin structures and then alter histones through special complexes of proteins.
There are now known to be multiple factors of this type that target the histone and alter their structure, silencing genes. Some of them interfere with extremely complex molecular cascades. One type silences the signals for apoptosis, a cell death signal, which is the ultimate response to a badly infected cell. This leads to lengthy infections.
Microbes Attack the Endoplasmic Reticulum (ER) and Golgi
The very complex secretory pathway was described in a previous post. This pathway related to the ER and Golgi provides very complex lipids in combination with proteins for many structures in the cell, including all membranes. It is the ER that tags the new proteins for their destinations and starts them on this secretory pathway including lysosomes and endosomes. These molecules are placed in particular tagged vesicles that bud from the ER membranes and then in the Golgi they are modified, often with the addition of sugars. The Golgi then sorts them again for transport to all parts of the cell in vesicles.