Molecular Cloaks of Invisibility

One of the subjects in biology that I find really interesting is how the immune system and micro-organisms interact with one another, and how their respective defense and attack moves have evolved relative to one another. This was the first essay I wrote on the subject, and it’s about how some bacteria can hide from the host immune system by wearing an invisibility cloak.

This essay was originally written for the Biochemical Society Science Communication competition, April 2011. (It was not short-listed.) This is a revised version.

In these modern times one cannot escape knowing that our bodies are colonised by many millions of micro-organisms, those that the media tells us are the ‘good bacteria’. These organisms inhabit our skins, noses, mouths, stomachs, intestines and genitalia, typically the ‘mucosal surfaces’; those areas open to the outside. Such regions are constantly patrolled by guards – the immune cells: macrophages and dendritic cells. Cells making up the mucosal surfaces, the epithelial cells, also sense their boundaries, poised to send out danger signals to the patrolling guards if a breach in their membrane is sensed. The micro-organisms are allowed to live quite happily in these patrolled regions of our bodies, provided they stick to the rules and don’t become too rowdy.

Disease can be considered to be a perturbation in the ‘normal’ or natural environment of the body, and is generally associated with pain, dysfunction and pathology – in terms of infectious disease, this is damage caused by either the invading micro-organism or by the immune system as collateral damage. The discovery of an intruder causes alarm bells to be raised, which mobilises immune cells; those specialised for fighting are activated to do so, others are responsible for co-ordinating the fight. The co-ordinators ensure the right fighters are present by sending out chemokines, and ensuring the environment is locally inflammed to give the fighters an advantage. Molecules called cytokines are sent out to increase blood flow to the area, enabling increased access for the fighters and local swelling to enlarge the fighting arena. (This gives a redness to the skin and increases the heat). Already one can imagine a boiling pot of noise and whistle-blowing; rarely would an intruder want to trigger the alarms to put in motion this sequence of events. Chances are they will be out-numbered in battle and be overcome before being able to achieve very much at all.

There are of course many advantages in penetrating inside the body, where food and shelter is plentiful. Far better than a costly fight is to achieve invasion without being noticed at all. It may be important to note at this point that although the relationship between the immune system defending a human being from an invading micro-organism lends itself very nicely to the analogy of guards defending a castle from attack, a key difference (other than scale) is the concept of ‘seeing’. A cloak of invisibility, or perhaps the ability of an invader to hide in the shadows, enables the person in question to become part of the background as though invisible. In some societies, such as the ninjas in feudal Japan, this ability to move around undetected was considered to be an essential skill – undetected here, within the spectrum of visible light. If one viewed the same ninja using an infra-red camera (forgive the anachronism), the stealthy person becomes a beacon of yellow and red. By contrast, the sentinels of the immune system gather information about their surroundings in terms of chemical or protein shape. The ‘antigen-presenting cells’ (the guards: macrophages and dendritic cells) are constantly sampling the environment, gobbling up proteins and other debris in their surroundings, processing it and presenting snippets on their surface in special carrier molecules. These cells are unaware of the difference between host/human (self) and foreign/microbe (non-self), and so present the processed material to cells that can tell the difference, in this case T lymphocytes (T cells). T cells have a receptor on their surface which has been expertly trained not to recognise self molecules, thereby detecting foreign peptides, and responding by instructing other immune cells to sharpen their swords. A trained ninja, having obtained passwords or other means to enter a castle, would avoid arousing suspicion once inside by hiding in the shadows, walking silently and perhaps obtaining a disguise so if seen would not look unusual, or at least rapidly change identity so the character the guards have been alerted to look for can no longer be found.

Invading pathogens use similar approaches to hide from the immune system and obtain a ‘cloak of invisibility’. Both methods involve making a cloak of host proteins; by one method, the micro-organism gathers actual host proteins to cover its surface, and in the other the invader synthesises its own cloak components to look like host proteins, in a process known as ‘molecular mimicry’. The cloak has several advantages: as well as allowing the invader to blend into its surroundings, it also acts as a shield or armour to protect the micro-organism’s fragile membrane beneath from penetrating weapons should the need arise.

Schistosomes are trematode worms whose adult forms live in the blood of vertebrates. It has been reported that adult schistosomes may survive for years or even decades in the blood, gaining all the nutrients that they require to live. It is only when the worms mate and lay eggs that the immune system is alerted to their presence. The eggs are released into the environment in the human faeces, and if the eggs find freshwater and their intermediate host, freshwater snails, they can develop into their larval form (cercariae), able to infect humans. From freshwater, the free-living cercariae are able to recognise humans and other mammals, and will penetrate through the skin, into the body. Within hours the cercariae lose their outer membrane to avoid recognition by the immune system, and rapidly gather host molecules to cover themselves, perhaps like stealing clothes from a washing line in the castle grounds to facilitate a disguise as a servant. The schistosome is now able to exist unhindered in the blood before mating and laying eggs, thus beginning the schistosome lifecycle once more.

Aside from stealing a disguise once inside the castle walls, numerous micro-organisms have evolved coat components that look like host proteins – like a true ninja they have done their homework in advance and brought with them an appropriate disguise. For example, Neisseria meningitidis (a causative agent of meningitis) expresses proteins comparable to those expressed in the embryonic brain, Mycoplasma pneumoniae (causing a form of pneumonia) expresses proteins similar to those on the surface of red blood cells, and Trypanosoma cruzi (American trypanosomiasis, Chagas disease), has a coat of proteins resembling those of the heart and nerves.

An alternative approach to wearing a single disguise is to frequently change appearance to confuse the immune system. If a member of the castle staff by chance comes across a ninja prowling the corridors, he or she would then raise the alarm and give a description of the intruder to the attending guards. The ninja, having succeeded in getting away from this civilian, then changes his identity so that he is no longer looks like the wanted person. In time the search party would give up looking, allowing the ninja to proceed unhindered until he is discovered once more.

In a similar way many bacteria, viruses and protozoa have developed methods to change their appearance to avoid capture, a mechanism termed ‘antigenic variation’. This may be achieved either by a high rate of mutation of a single protein (‘antigenic drift’), such that the form of the capsule protein changes sufficiently for it to no longer be recognised as belonging to the invader. This is one strategy employed by the human immunodeficiency virus (HIV), explaining why it is so difficult for the immune system to control infection caused by this virus. Micro-organisms also achieve this feat by ‘gene switching’, whereby the micro-organism actually changes the whole protein expressed on its surface. The best example of this is seen for Trypanosoma brucei (the causative agent of African trypanosomiasis, sleeping sickness). These protozoa carry genes for more than one thousand distinct surface molecules called variant-specific glycoproteins, which cover the entire surface of the trypanosome. The trypanosome can switch from the use of one coat protein to another, enabling it to persist whilst the immune system is constantly trying locate an invader that appears to have vanished. This results in a sequence of unrelated infections – occasions upon which the immune system is poised to fight the intruder – at approximately one-week intervals.

The relationship between the human body and invading micro-organisms is a continual battle between the defending castle guards and the intruder. Although the immune system has developed many ways to protect the body from invasion, micro-organisms constantly surprise us with counter mechanisms; development of a molecular cloak of invisibility is just one way that micro-organisms are able to out-smart the detection systems in place.

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