What I love about science is its ability to give us insight into aspects of the world that we cannot see or touch – that are invisible to us without the tools it provides. As I discussed in an earlier post, microscopes allowed the discovery of a vast array of microorganisms that were previously hidden to us. In a similar vein, science (specifically the rise of the Germ Theory of Disease) unlocked the understanding that many diseases are caused by these tiny microorganisms.
It is rather fascinating to consider that when we fall ill, this can often be linked back to the invasion of tiny creatures to our bodies and their struggle against a complex system of cells and processes that make up the human immune system. A sort of complex warfare in miniature.
Perhaps some of the most feared diseases (such as cholera, diphtheria and pneumonic plague) can trace their origin back to a particular class of microorganism called bacteria. It is worth considering the difficulties faced by these small, single celled organisms on their colonisation of the human body. How do they so expertly evade the defences of the human immune system?
Today, I’ll give a very brief overview of what bacteria are, before moving on to address a small range of the ingenious techniques they use to survive in the human body.
What are bacteria?
Bacteria are small, prokaryotic, single celled organisms. All cells that make up living things are classed as either ‘prokaryotic’ cells or ‘eukaryotic’ cells. Prokaryotes contain groups of organisms such as bacteria, while eukaryotes include animals, fungi and plants etc.
Prokaryotic cells have various features that distinguish them from eukaryotic. For example, the DNA of a eukaryotic cell is contained within a structure known as the nucleus. Prokaryotic cells, conversely, do not possess a nucleus. In fact, these cells entirely lack membrane bound organelles (organelles being small structures within the cell that have defined functions e.g. mitochondria that are involved in producing ATP, an energy source of the cell). [see the references below for a more detailed description of the differences between prokaryotes and eukaryotes]
Importantly, not all bacteria cause disease! Many bacteria don’t colonise humans at all and may instead live in the soil or in water etc. Of those bacteria that do live within or on humans, many are ‘commensal bacteria’ that are harmless and even beneficial e.g. helping with digestion. Those bacteria that can cause disease are known as pathogenic bacteria, pathogens being the group of infectious organisms that can cause disease (e.g. certain types of bacteria, viruses, parasites and fungi)
What are virulence factors?
Pathogenic bacteria need to be able to enter the human body, multiply and then transmit to new hosts. Considering the defences of the human immune system – this can be a difficult task! Bacteria have evolved a wide range of techniques to achieve this goal.
Virulence factors are defined as molecules produced or strategies used by a bacterium (or other pathogenic organism) that allow it to colonise and multiply in the host. Basically, virulence factors are the toolkit of pathogenic bacteria that allow them to successfully live within a host.
There’s a really astonishing variety of virulence factors, so I’ll just introduce a few.
Attaching to cells
The human body can be a difficult place to live. If we consider areas like the mouth or the bladder, there’s a lot of fluid sloshing around that can easily dislodge a bacterium and stymie its attempts to colonise. Therefore, it’s often essential for pathogenic bacteria to find a way to firmly attach to cells to avoid being dislodged.
Some bacteria achieve this using structures known as pili – these are long, thin filaments made of the protein pilin that appear on the surface of many bacteria. At the tip of these pili are special adhesin proteins that bind strongly to particular molecules on the surface of cells. In this way, these structures can sort of act like anchors to hold the bacterium in place.
Bacteria have numerous structures on their surface (such as the pili discussed above) that allow cells of the human immune system to recognise them and mount a response. These ‘antigens’ sort of act like flags to the immune system, signalling what that organism is and what sort of response is required. One strategy to evade the immune system is therefore to change the proteins present on the surface of a bacterium. This provides a moving target making it more difficult to respond effectively.
A classic example of this sort of strategy is phase variation of certain strains of Salmonella. Salmonella, like many bacteria, possess long, thin flexible structures known as flagella on their surface. These flexible structures allow the bacterium to propel itself forward, but are often recognised by cells of the immune system. To avoid detection, Salmonella can switch between making their flagella from type H1 flagellin protein to type H2 flagellin protein at regular intervals. How is this achieved?
In the DNA of Salmonella are encoded two genes for flagellin (the protein that flagella are made from) – H1 and H2 (see diagram below). At any one time, only one of these genes is active and all flagella will be made from the protein of the active gene. Upstream of the H2 gene, is a sequence of DNA that can be inverted. Basically, it can be present in one of two different orientations. In one orientation the H2 gene is on and this protein is made along with a repressor. This repressor acts on the H1 gene to turn it ‘off’ resulting in the flagella being made of H2 flagellin protein. Via the action of a DNA invertase (called Hin) the sequence can be inverted to a different orientation. In this second orientation, the H2 gene is turned off and the repressor is not produced. Therefore, the H1 gene is turned on and flagella will be made of H1 flagellin protein.
In this way Salmonella varies the composition of its flagella regularly making it difficult for the immune system to recognise them and respond.
Invasion of cells
Another way to evade cells of the immune system is for bacteria to enter cells and ‘hide’ within them. A number of different bacteria make use of this strategy, a good example being Salmonella.
The issue of how to actually get into the cell has been solved in a variety of ways by bacteria. Salmonella enter cells by inducing them to form actin-rich ‘ruffles’ on their surface that engulf the bacterium. [Actin is an abundant protein in eukaryotic cells, actin filaments being important to maintain / strengthen cell shape (along with a number of other roles)] Basically, the Salmonella somehow instruct the cell to produce structures that allow it to enter. How is this coercion achieved?
One of the most fascinating virulence factors is the Type 3 Secretion System (T3SS). Salmonella encodes two different T3SSs in its DNA. These T3SS are highly complex structures made up several subunits and proteins – they act like tiny needles to allow bacteria to inject particular proteins into a host cell.
Salmonella triggers invasion of cells by using its T3SS to inject proteins (such as SipA and SipC) into the host that then act to stabilise and form actin. This induces the ‘ruffles’ that allow the Salmonella to enter.
Once inside the cell, the Salmonella are contained within a Salmonella-containing vacuole (SCV) – a special membrane bound compartment that they replicate and grow inside. T3SS are again essential to the formation and maintenance of the SCV. For example, the proteins SseF and SseG (that are transported via a T3SS) are required to redirect vesicles from the golgi apparatus (a membrane bound organelle in the cell) to the SCV.
So Salmonella, via the use of T3SS, can subvert many processes in the cell to allow it to first enter and then survive inside it.
Moving between cells
Once inside the cell, the bacterium must replicate and then find a way to spread to new cells. To evade the immune system, some pathogenic bacteria have the ability to move directly from cell to cell rather than having to exit then re-enter which risks elimination by cells of the immune system.
One example of this is Listeria monocytogenes, a bacterium that causes listeriosis. Listeria enter cells (by a different mechanism to Salmonella) and then replicate inside them. Interestingly, these bacteria contain a protein on their surface called ActA. This protein
interacts with components of the host to assemble actin filaments. This creation of actin at one end of the cell can be used to propel the bacterium through the cell – at quite a rate, around 1.5 micrometres/second! This propulsion is strong enough to allow the bacterium to penetrate adjacent cells. In effect, these bacteria have found a means to spread from cell to cell without having to expose themselves to the dangers of the environment outside these cells.
[I’ve linked to a video at the end of the references of the movement of Listeria in an infected cell – definitely worth a look!]
Pathogenic bacteria have had to evolve a wide range of virulence factors to survive within the human host – I’ve touched on only a few above including pili, phase variation, T3SS and ActA. It’s rather amazing to consider that bacteria that at first may seem like rather simple organisms, can in fact implement all these ingenious methods to evade the immune system and grow in our bodies. With the continued rise of antibiotic resistance, it is increasingly important to understand these mechanisms fully. Research into bacterial virulence factors will continue to play a key role in this.
References / suggestions for further reading
Bacterial Pathogenesis: A molecular Approach (3rd edition) by Brenda A. Wilson, Abigail A. Salyers, Dixie D. Whitt and Malcolm E. Winkler – an excellent textbook on bacteria and disease
Khan Academy – https://www.khanacademy.org/science/biology/structure-of-a-cell/prokaryotic-and-eukaryotic-cells/a/prokaryotic-cells – a nice introduction to the differences between prokaryotes and eukaryotes
Online Textbook of Bacteriology – http://textbookofbacteriology.net/index.html – a useful general overview of bacteria and disease
Kline, K. A., Fä, S., Dahlberg, S., Normark, S. & Henriques-Normark, B. Cell Host & Microbe Review Bacterial Adhesins in Host-Microbe Interactions. Cell Host Microbe 5, 580–592. DOI: 10.1016/j.chom.2009.05.011 – review on pili
van der Woude, M. W. & Bäumler, A. J. Phase and antigenic variation in bacteria. Clin. Microbiol. Rev. 17, 581–611 (2004). DOI: 10.1128/CMR.17.3.581–611.2004 – review of phase variation
Galán, J. E., Lara-Tejero, M., Marlovits, T. C. & Wagner, S. Bacterial Type III Secretion Systems: Specialized Nanomachines for Protein Delivery into Target Cells. Annu. Rev. Microbiol. 68, 415–438 (2014). DOI: 10.1146/annurev-micro-092412-15572510.1146/annurev-micro-092412-155725 – review of the structure of the T3SS
Coburn, B., Sekirov, I. & Finlay, B. B. Type III secretion systems and disease. Clin. Microbiol. Rev. 20, 535–49 (2007). DOI: 10.1128/CMR.00013-07 – review of the role of T3SS in bacterial disease
Lambrechts, A., Gevaert, K., Cossart, P., Vandekerckhove, J. & Van Troys, M. Listeria comet tails: the actin-based motility machinery at work. Trends Cell Biol. 18, 220–227 (2008). DOI: 10.1016/j.tcb.2008.03.001 – review of use of actin by Listeria monocytogenes
Garland Science – http://www.garlandscience.com/garlandscience_resources/resource_detail.jsf?landing=student&resource_id=9780815344322_CH23_QTM07 –great video of Listeria monocytogenes in an infected cell