www.morphostasis.org.uk

Intentional pathogen killing - or denial of substrate

This article is a sequel to [Tissue homeostasis and immunity: more on models]. It explores the proposal that denial of nutrient substrate by efficient removal is the prime purpose of immune mechanisms.

It was accepted by the Scand J Immunol on the 1st August 2007 and is now lodged in the Dec 2007 edition of this journal.

It can be found at this  [DOI address].

Notes: the following notes help to expand on the ideas in this article

There is always something that I would now prefer to read differently. This time it is the final reference to "intentional pathogen killing" in the penultimate paragraph of the main text (before the appendix). Here it reads:- "So might both be happening? Would it, on the one hand, be foolish to claim that ‘denial of substrate’ plays no part and, on the other, that ‘intentional pathogen killing’ plays no part?" It would be better this way:- "So might both be happening? Would it, on the one hand, be foolish to claim that ‘denial of substrate’ plays no part and, on the other, that ‘intentional microbe killing’ plays no part?"

Interestingly, Elie Metchnikoff wrote these comments:

From "On the present state of the question of immunity in infectious diseases"
Nobel Lecture, December 11, 1908

".... the fact that the undamaged organism does not allow certain morbid agents to spread within it, could be explained simply in terms of the chemistry of the environment. // In the same way that plants will not grow on soil that lacks some substance indispensable to their growth, so microbes, these microscopic plants which cause infectious disease, are unable to grow in an organism which does not give them all the substances they need. //" (But he goes on to add) "This theory is completely logical but contradicted a number of factors to be found in the protected organism." (So once again, "Originality nothing but judicious imitation." Voltaire)

It is also worth emphasising, again, that the term "pathogen" has now become such a universally accepted (and lazy) abbreviation for a "pathogenic (micro) organism" that it has now been effectively high-jacked into a new meaning. This detracts from its original precise meaning, "an agent (of whatever kind it happens to be) that causes damage to tissues". It would have been helpful to add the following sentence after "A pathogen is nothing more than an agent that has caused damage to host tissues (especially cells)." (Second paragraph in the Introduction.)  The term "pathogen" contains nothing that specifies the form of this pathogen. So, while a "pathogenic organism" is, undoubtedly, a "pathogen", the assumption of the corollary, a "pathogen" is undoubtedly a "pathogenic organism" is manifestly incorrect and potentially corrupting. But that inference is the inevitable outcome of the common and lazy use of this abbreviation without considering the logical consequences that have ensued.

Lastly, the whole process of immune function might be better viewed as a nutrient acquisition and sequestration device. It is an extension of a primitive feeding and digestion mechanism. Anything with the potential to be fuel, food, a source of negative entropy is "vacuumed up" avidly by phagocytes and this is aided on by the amplifying and accelerating mechanisms that the phagocytic system enjoys thanks to lymphocytes and the anamnestic/adaptive (memorising) immune mechanisms. It is, at base, a competetive race to acquire and control nutrient resources. Since protozoal organisms frequently feed on bacteria, any directed attack on "pathogens" (really an attack on microbes - "pathogens" are just microbes with a reputation for deliberately damaging cells in order to provoke their own nutrient supplies) is an evolutionary relic of the same process.

All growth is resource dependant. Many - but by no means all - of the resources are nutrients (eg, light, ideal temperature, oxygen or its absence). Commanding, sequestrating, managing and distributing these resources is a zygote derived colony’s primary concern – if it is to succeed against the competition for resource utilisation.
Immune systems that appear to identify and kill invading foreign organisms are the emergent illusions f this basal process.

If you mulch up animals cells in a broth, incubate it at about 37 degrees centigrade you will have a more or less ideal culture medium. Now, the human body (our egocentric preoccupation) is a vast colony of aging cells, many of which are senescing and these are accompanied by those that are plain damaged. Unless the zygote derived colony does something about it, the debris of these sickening and irreversibly damaged cells are going to lie around as resources for a world teaming with opportunists waiting for their next “free meal”.

So the first and most important goal is to address the mass of degenerating cells that this ZDC is constantly generating. Hence the complement system is highly focused on dying cells and their spilt debris. This focus on dying debris is the root process – where it all starts. The ability of cells to recognised microbes through Toll like receptors is likely to reflect the root process of food acquisition by our ancestral free living amoebocytes. It is possible that the recognition of microbes and degenerating cells have come to share common mechanisms of recognition. So, some Toll like receptors might be, aboriginally, used for microbe recognition (used for fuel acquisition) and, subsequently, degenerating self cells began to display ligands that invited reaction with the TLRs that interact with microbial food. Some may be, aboriginally, receptors for recognising degenerating cells and microbes then acquired common reactivity as a way of stimulating immune responses favourable to their persistence or as a way of gaining “Trojan Horse” access to cells. Certainly, there is a growing realisation that this Toll thing is not a simplistic “them and us” recognition system. Toll was first identified in drosophila where its first identified function was in development - not immune function.

This article - below is a fascinating read on denial of resources. Every time I look at sponges in an aquarium I wonder at the efficiency of their immune strategies. This article is food for thought - almost literally.

http://reefkeeping.com/issues/2002-02/hcj/feature/index.php

An important extension of this idea might be observable in plants. It is important to maintain an impeccably tidy extracellular space in plants (ie, between the cell wall and the cell). This is partly achieved by the rigid cellulose cell wall. As Metchnikoff observed, bacterial infection is not a common finding in plants until they die (when they becomes prey to a hoard of different organisms). Fungal infection (hyphal invasion) is much more frequent. The plant responds to this invasion by triggering a hypersensitive response which is, effectively, an apoptosis like response. It does this, not only in the attacked cell but, in a group of surrounding cells. However, if it leaves this apoptotic material where it is, as a damp proteinaceous soup in each cell wall, this will invite invasion. So the adjacent plant cells need to do all they can to suck out this handy meal and re-assimilate it for their own consumption and redistribution. This would probably need to occur through plasmosdesmata and this "scorched earth" effect should be observable by using various tracers.

One more point is worth emphasising. There are only about 50 micro-organism species that are regularly pathogenic for humans. Some 500 are regular gut commensals. Several million species make up the rest and a large number of these occupy a large niche in the balanced ecosystem of life. Many of them are "specialised" to latch onto and break down dead animal and plant matter. This ensures the clearance and recirculation of essential nutrients and they achieve a vital function in facilitating and encouraging the cycle of life. These are the "non-cheaters" that have the courtesy to wait until plant or animal bodies die - for this is what their bread and butter depends upon. We look on this as a rather passive sort of process but it is quite likely that their own survival over the aeons of evolution has depended on not cheating. They are quite likely to be "polite" and co-operative in taking their place in this cycle. They are also likely to take highly specific cues from dead tissues that indicate it is time to enter this cycle. Pathogenic organisms, however, do not wait; they "cheat" to eke an existence in living multicellulates. Nevertheless, they still retain their heritage and this includes a dependancy on decaying/disrupting protoplasm for growth and proliferation. Their trick is to produce this in a living multicellulate.

Note that in the 1907 edition (first edition 1905) of "Immunity in infectious diseases", Elie Metchnikoff frequently refers to "pathogenic (micro-) organisms". He never abbreviates this phrase to the term "pathogen". I have now decided to research where and when this now common abbreviation became commonplace and will update this page once I have researched it.

A medline search for the word "pathogen" reveals that, since 1951, writers have generally abbreviated "pathogenic organism" to "pathogen". It is a long established practice.

For more on this trend to use the term pathogen as a synonym for pathogenic (micro-)organism see this section in the Philosophy section.