The issue you are discussing is highly variable from one "species" to another.  The relative level of diversity within what humans have labeled as a "species" of Clostridium botulinum for example is not the same as the diversity found in Escherichia coli.  Some bacterial pathogens are very highly clonal and some are not.  For some, the pathogenicity is largely or completely carried on a plasmid, and for others the pathogenicity involves dozens of genes spread all over the major chromosome of the genome.  In other cases, such as some of the E. coli isolates that have picked up a Shiga toxin gene, there are additional genes which can allow the E. coli with the toxin to be extra pathogenic, such as genes which facilitate adhesion of the bacteria to the host gut epithelium.

Genome sequencing and comparative genomics provides insights on the evolutionary dynamics and pathogenic potential of different H-serotypes of Shiga toxin-producing Escherichia coli O104.

Yan X, Fratamico PM, Bono JL, Baranzoni GM, Chen CY.

BMC Microbiol. 2015 Apr 3;15:83. doi: 10.1186/s12866-015-0413-9.

PMID:

25887577

Hi Brian

I do some a Clostridium perfringens research myself and it is a very hot topic of whether virulence is plasmid mediated, chromosomal or both.  But actually, genome is genome, it doesn't really matter much how mobile the element is.  The forced mental separation of plasmid and chromosome is almost irrelevant in terms of pathobiology  .... either the gene is there or its not  .... A bacterial cell comes as a whole unit.

When a bacterial  cell naturally acquires a plasmid, stabilizes it, and then leverages it to spread into a niche it becomes a brand new entity in terms of pathobiology.

Clostridium perfringens is a classic example of a trigger pathogen.  It can exist in human and animal hosts and do absolutely nothing undesirable for the entire lifespan of the host.

When perfringens is properly tuned to its host it becomes very difficult to provoke into causing disease.  When it moves to new hosts, or the animal host is stressed or grown in closely packed genetically identical hosts, perfringens that are easily triggered to cause disease can emerge by natural selection. How many cases of gas gangrene in humans have there been outside of war where host were stressed to near death? Almost zero.

Clostridium botulinum doesn't seem to be able to make a stable relationship with human hosts so it is outside the discussion of this post.

Clostridium difficile is an interesting one that seems to play the middle field between "stable coexistence with the host" and "burning down the house to keep warm". However the rapid promiscuous sporulation and diarrhea is a very good indication that this organism's lifestyle is more  tuned to burning through the host like a fire, so it may indeed be more clonal and again this post isn't really applicable.

And E. coli is an opportunist.  For some lines,  just picking up a plasmid changes it to a brand new entity and shifts it from coexistence to "burning down the house".

Really, in terms of being meaningful bacterial classification, clonality and pathobiology needs to completely re-evaluated in the light of new genomic data.

 Hi Brian

Thanks for your interest in my posts.

I notice you are a HIV researcher and I have a question for you.

In the frame of reference of a HIV particle and natural selection, is HIV in a stable neutral interaction with human hosts or is it "burning down the house to keep warm"? In its own time frame can it really be considered a pathogen at all as it may take a billion generations to hurt the host.  Does the time frame discrepancy between us and HIV preclude natual selection for neutral  stable coexistence in our time frame.

Does this make HIV more or less dangerous?s

In essence I am asking if natural selection has a time frame break limit beyond which there is a disconnect between genome (host and microbe) and outcome?

Can this potential break point be virtually modelled?

You might read Nesse and Williams (George, the preeminent Natural Selection scholar) from 1994 variously titled "Evolution and the Origins of Disease" and "Why we get sick" as well a the Red Queen (Ridley) about arms races in evolution.

I see no particular time constraint on the process. Think it is more to due, as usual, with  environmental circumstances (behavior and proximity of host and pathogen in this case) and the conditions for opportunism.  

In answer to Glenn Soltes' questions about HIV, I would say that all of the lentiviruses should be considered to be pathogens.  They might not all be "deadly pathogens" but they are pathogens.  In my opinion, the basic human desire, and especially a desire of computer scientists and modellers, to classify things into "bins" such as "pathogens" and "nonpathogens" creates problems.  Many things in the real world are analog with a complete spectrum of values which do not lend themselves well to binary yes-no classification.

There is some "dogma" in virology that viruses adapt over time to become less pathogenic to their host.  This caused many people to claim for years that the primate lentiviruses were nonpathogenic to their natural hosts while being more often pathogenic whenever they were able to switch hosts.  Likewise the FIV of lions was assumed to be nonpathogenic to lions while FIV of housecats was known to be pathogenic to housecats.   As time went on however, and researchers were able to follow wild primates infected with their lentiviruses, and wild lions infected with FIV-lion, it has become clear that the infections are often detrimental to these "natural hosts".

A virus that is detrimental or deadly to individuals can be beneficial to populations, for example by killing off old and weak individuals more quickly to make room in the environment for younger and stronger animals of the same species.  I think I read in the book _Virus X_ by Frank Ryan about theories along this line, but I do not recall if they were Frank Ryan's own theories or if he was pulling them from peer reviewed literature.  Anyway, it is often stated that predators such as wolves increase the population health of their prey, and in the same way a virus could be seen as a "predator" of its host species.

Brian, Your answer echoes something of what is discussed by Nesse and by Williams in the book I mention and some other literature in evolutionary medicine.

The host switching idea is key and the book also discusses the correlation of pathogenicity to the ability of pathogens to spread from one host to another. If transmission is easy, the pathogen can completely exploit the current host and then expect to find another easily. An excellent example is the 1854 London water pump handle and the easy spread of cholera.

From my BLOG

Host Focusing; An Type of Applied Scientific Thinking in Bacterial-Host Relationships

Background and Founding Principles

Why Does a Bacterial Group "Burn Down the House to Keep Warm" ?

Some bacterial groups have adopted a mode of being that involves burning down the house to keep warm.  Essentially this means their genomes and regulatory networks are tuned for rapid proliferation and spread with little or no "concern" for the well being of their animal hosts.  This article does not relate to these groups of bacteria. They have a evolutionary history and mode of being fairly distinct than most bacteria and tend to be unstable (Note that HIV is not part of this group as it takes millions of generations of HIV to significantly harm the host and this makes them benign in their time frame)

Every Available Niche on Animal Hosts will be Filled at All Times

Bacteria are ubiquitous in the environment and on every external surface and most internal surfaces of animal hosts and are spread host to host rapidly by obligate host to host social behaviors and obligate host to environment behaviors . Due to our stability, longevity and energy rich nature we and our domestic animals are one of the most valuable environments for bacteria and they compete intensely for the benefits of being on and in us.  We also benefit for this nutritionally and by crowd competition exclusion.

Fundamentally this means that we have no power to choose whether we have bacteria on or in us, and only a limited conscious and innate ability to choose which groups of bacteria occupy any given niche on us.

Trigger Bacterial "Pathogens"

This article relates to bacterial groups that closely and stably associate with animal hosts but do not normally cause any adverse effects and perhaps benefits the host by crowding competition, masking of adhesion sites and mutualistic nutritional effects. Almost all of these groups can be triggered to cause undesired consequences (pathogenicity and disease), it is only a question of how tuned they are to their host and how easily they are triggered.  One obvious trigger is the impending death of the host, but their are many more including mortal stress, reproduction, starvation.

There have been vast amounts of human scientific effort directed at these groups of bacteria and very little of useful regarding the understanding of these relationships and generating methodology to promote host bacterial relationships that we desire that are relatively evolutionary neutral.

Evolutionary neutral means that they do not impose intense selective pressure on bacterial groups that may reduce their diversity and promote marginalization.  Antimicrobial agents are not evolutionary neutral as they both reduce overall and group diversity and they marginalize plus the antimicrobial selects for inter and intra group gene transfer (theft).  Antimicrobial agents fixed and inflexible antagonists of bacteria and are thereby extremely easy to circumvent.

The only stable and evolutionary neutral method to foster desired host bacteria relationships is a continual dance where we pit bacteria against each other.  This is not the method of creating attenuated live bacteria to act as vaccine antigens.  Vaccination almost only works on bacteria that burn down the house to keep warm.  Vaccine methods tends to work very poorly if at all against bacterial groups that form a stable relationship with the host and can be triggered to cause disease.

Host focusing is a methodology whereby we study a group of bacteria with a stable relationship with the host and we nudge it gently into a closer relationship with that host and make them less easily triggered to cause undesired host effects disease.  Also in this process we seek to make them better competitors not weaker ones.

Host Focusing Methodology

 1) Proper definition of Bacterial Group

A group is how you define it and can perhaps have multiple "species" as a community. Until relatively recently science did not have the tools to reasonably define any group below genus, especially bacterial that have close relationships with animals.  Methods involving rRNA, cytochome oxidase have their place but are next to useless at defining what an isolate is.  A complete genome and the tuning of their regulatory network is what a bacterial isolate is. Both these define it and unless you have both you can't understand or define any group.

2) Understanding of the Chosen Bacterial Group =  Part I Sampling

To understand your group you need to sample it feasibly.  This is a daunting task full of much bias and the source, during sampling, and at any enrichment stages.  This is beyond the scope of this article except to say much research fails at this stage making any subsequent results also misleading or inaccurate.

2) Understanding of the Chosen Bacterial Group =  Part I Investigation

Here is a generalized method to investigate your bacterial group:

a) Perform MALDI methodology to get a first impression of the proteome of isolates in your group and to apply the tag of genus and rough "species".  MALDI is important because it acts as a reality check for later genetic methods as it looks at the bacteria is a unique generalized way.

b) PCR out a chosen cytochrome oxidase gene (if present), another good housekeeping gene and perhaps rRNA if they aren't too messy.  DNA sequence them all and then make relatedness trees for all of them.  Have a good looks at them to see how the trees are similar and different. Ask yourself how many functional groups you are actually dealing with.  In answer to the above questions, pick a good number for a reasonably complete genome sequencing.  In the near future there will be no reason to not sequence them all.

c) Assemble the genomes and view the patterns of similarities and differences of all of them at the same time with CGView Comparison Tool by Stothard Research Group.  The patterns of similarities and differences in the pretty picture it generates is probably the closest understanding the diversity and what your group actually is humanity has ever made.  Look at the picture hard and decide what it means regarding diversity, clonality, and inter and intragroup competition.

d) Look at all the parts of the genome that are the same and call them CORE but don't believe it.  Looking the same and being the same are different.  Genes in the CORE of the genomes may not be regulated the same or regulate the same. Even if they have greater than 95% protein similarity they may not act the same or do the same as it takes only a few different amino acids to significantly change how a protein behaves.

 e) Look at all the parts that are different, especially if they are on mobile elements.  Call this part DIVERGENT.  Divergents are very interesting especially if you have something interesting to correlate the divergences with.  Usually you do not.  Virulence testing experiments, Koch's postulates, and isolation of bacteria from sterile sites are usually meaningless and biased with bacteria that cause disease only when they are triggered.  A gene divergence is not necessarily meaningful to what a bacteria is, because any given gene may have been just carried along for the ride with something that is relevant, or may have been an chance dead end gene transfer that doesn't do anything at all except take up space (That is the messy evolutionary process).

f)  Guesstimate your best relatedness tree as applied to the question of HOST FOCUSING using all of the above data.

3) Picking the Best Competitors that are the Hardest to Trigger Adverse Host Conditions

a) Have a look at the toxogenicity potential of all the members of your group and try to guess which ones have the least host directed toxicity and the most extragroup and intragroup toxicity. Note that eliminating all host directed toxicity may not be a good plan as bacteria use very tightly regulated host toxicity bursts to spectacularly expel potential competitor after they have invested protected sites (diarrhea, vomiting).

b) Study the adhesin genes of the member of and ask and answer questions like which isolates have the highest diversity and which will probably adhere best to your chosen host.  Do some in-vitro and in-vivo adhesion studies to reality check.

c)  Establish a library of animal hosts each with a mono-culture of a given isolate confirmed by PCR. Stress out each member of the animal library in ways designed to trigger adverse host conditions.  See which bacterial mono-cultures are the hardest to trigger to cause adverse host conditions.  Note that IP or IV injection of these types of bacteria does not relate well  to what actually happens in natural problematic bacterial host events.  In real life there are established communities of bacteria that get triggered en-mass by a host condition OR newly introduced bacterial groups interact with existing bacterial communities to trigger as adverse host condition due to one or both of the bacterial communities.  Injecting bacteria into normally sterile sites generates almost irrelevant results.

3) Tuning the Best Competitors to Make Them Even Harder to Trigger Adverse Host Conditions and Even Better Competitors

a) Pick a few of the most competitive isolates for your group to HOST FOCUS

b) Grow these isolates under a variety of triggering related in-vitro and in-vivo to generate real time regulatory phospho-protein profiles for each isolate for each condition (This technology already exists at the Univ of Montreal).  Attempt to understand triggering and how to make directed genomic changes to make them less sensitive to triggering adverse conditions in the host.

c) Play with the adhesin genes to tune them to your desired animal host while tuning them away from human hosts and other animals

4) Testing

Realize that your HOST FOCUSED bacterial isolate will hopefully be very good persisting in the animal group you innoculate them into, but they may be unable to spread or displace other bacterial groups if they are already there.  Attenuating their host directed toxicity may make them unable to compete or displace a established microbiome. The HOST FOCUSED bacterial isolate make need to be gives near birth of the target animal so it is first.