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.

Here are the links to the original article:

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 (in italics) 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 (exceptions include 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 illusion of 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".(Nb; I am warming to alternative perspectives on the origin if toll and TLRs. It is possible that their earliest function was in identifying suspect self cells – those in need of early disposal. These represent potential "free meals" for bacteria; so, to get yourself invited in to the location of the free meal and then hope for impaired phagocyte digestion and assimilation may have proven to be a reasonable loss–leading strategy. Alternatively, MAMP expression for most species of intestinal commensals/symbionts leads to a tolerant adaptive immune response - not an aggressive one. Without the MAMP expression, this route to intestinal tolerance and habitation would probably prove harder to assert. Daniel Corcos has recently published an article on "food-nonfood discrimination" as the process that might have triggered the emergence of the adaptive immune system (AIS). It is worth reading. My main critique, here, would be that food-nonfood discrimination is required in free living amoebae too; and all the species on the way up to and the subsequent radiation of many unique vertebrates. This is not something that suddenly changes (or emerges) at the appearance of notocordal animals (roughly the time when the AIS "took off"). I discuss this point in "A fairly simple explanation"

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. Microbes could then pervert this common reactivity into ways of stimulating immune responses that would be 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 embryonic development - not immune function.

This article 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.

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.

In the section "Re-interpreting the facts" the use of anthropomorphic would probably be better replaced by anthopocentric.

At the end of the section ""So why does it seem to be 'intentional pathogen killing?'", I suggest that spilt bacterial innards might be a potent stimulator of the innate immune system. Indeed, the Herxheimer reaction is, quite likely, just this.

In the appendix I have made some suggestions for further investigating the role of gap junctions. "Do cells pass significant quantities of nutrients between themselves by GJs?" There is fair evidence, already, that this is an important function in the lens of the eye - if not the only way it receives its nutrients (note how vascularity is undesirable here). This recent paper on the cochlea lends further support for the distribution of metabolites through GJs.

In the section, "Denial of substrate" and at the end of the second paragraph on page 606, I have written "so increasing the prevalence of interstitial infection". This would be better written as "so increasing the prevalence of interstitial colonisation".

Note that in the 1907 edition of "Immunity in infectious diseases" (first edition 1905), 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. (Nb, this has now evolved into a third article in the Scand J Immunol.)

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.

Entropy and disorder

In this article, I had gone along with the generally held conviction that there is some sort of close synonymity between entropy and disorder. Some people see them as deeply synonymous. However, having written the article, I felt some dissatisfaction that I did not fully understand entropy and so attempted to get this clearer in my mind. This resulted in the "Entropy" section at this website. The conclusion I settled on in this exploration was that the commonly held view that high entropy equates to disorder (and vice versa, low entropy = order) is wrong. Entropy certainly is the nemesis of order but we need to explore why. Order (roughly fractal patterns) are formed when energy flows from sites of extremely low entropy (focal concentrations of homogeneous high potential - as for example in a canister of high pressure gas, a vessel of superheated steam, an electrical battery) to sites of extremely high entropy (where the previously stored and initially contained high potential diffuses out into a homogenous, diffuse and highly entropic distribution). Order and the subsequent collapse of order (disorder) are not seen at either the extremely low entropic states or at high entropy states. They emerge and then pass into extinction in the middle, in the flow between low and high entropy states. So, entropy is a constant threat to morphostasis; morphostasis is constantly attempting to claw itself up this energy–flow–gradient to maintain form. On planet Earth and in our parish of the universe, we are in a hectic flow of high to low potential energy – even though the illusion we get is that we are pretty "static".