Wednesday 5 February 2020

Plague, a Brief Scientific Background

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Without any doubt Yersinia pestis is the greatest catastrophe to ever visit mankind. ‘Yersinia’ is a family of bacteria and ‘pestis’ is short for ‘pestilence'. It became known as 'The Plague' or simply 'plague'
"Yersinia pestis is the nastiest thing alive. It's the most virulent bacterial organism known to mankind.” Olaf Schneewind.
How Bacteria Evolve
Bacteria can evolve by two methods:
(a) mutation. This often results in a defective gene but sometimes it can be successful.  
(b) the major method of bacterial evolution is receiving genetic material  from another bacteria.
The donating bacteria sends a bundle of genes that ‘teaches’ the receiver how to survive in different environments, resist antibiotics or fight a host’s resistance, something the donating bacterium can already do. It is more common with related species but can occur across species and then it results in a major change in the recipient.
There are three ways this transfer of genetic material can happen. 
1. Certain viruses (phages) attack bacteria. They replicate viruses inside their host by placing their own genetic material inside the bacterial DNA.  Eventually they will release a protein that dissolves the cell membrane and kills their host, spreading the infection. Some, ‘temperate’ phages don’t immediately kill their bacterial host, being content to survive inside it for a time. They even protect their host in several ways, one of which might be introducing genetic material that is helpful to the host, often taken from elsewhere.  Bacteria have their own immune system so they may survive the viral attack and keep the genetic ‘gift’.
The more important way bacteria can give and receive new genes (and abilities) in a process called conjugation, where two bacteria construct a bridge-like connection joining their protoplasm.
Transfer of a plasmid (wiki)
2. In one form, the ‘host’ detects that the recipient is missing useful genetic material and makes a copy of a section of its own DNA which it sends across the bridge between the two cells.
3. Presumably this process is the origin of the third and maybe the most important form of transfer,  the copying and transfer of a bundle of useful genetic material called ‘plasmids’. Plasmids are small circular independent DNA fragments separate to the main genes of the cell and having the power to replicate independently of the rest of the DNA.
Of course, evolution of a particular (strain or) species of bacteria using Plasmids isn’t as simple as that. Once transferred the plasmid has to find a way to live and replicate in the (new cell or) new species, and the receiving bacterium has to evolve (through natural selection and more genetic changes) to make use of what the plasmid is offering it, if that is possible.
Evolution of Y. Pestis
Sometime in the late Neolithic period,  Y. Pestis evolved from Yersinia pseudotuberculosis, a soil-living bacterial infection that can cause colitis in rodents (and other animals). It can rarely be transmitted to humans through ingestion (e.g. water contaminated by faeces). It is very different type of infection to plague and while it can be nasty enough, it is usually not fatal or spread from human to human.
Y. Pestis is like nothing seen before or since.
Like all infections, there are different strains, there is something like 36 known strains of Y. Pestis (some living, some extinct) and several have significantly differences between them.
What makes Plague so virulent is only just starting to be understood with recent major advances in DNA analysis but contradictory opinions still abound.
With the change from Y. Pseudotuberculosis to Y. Pestis there was the addition of at least 6 genes and inactivation of as much as 13% of its genome. (It doesn’t want to waste its resources producing proteins it no longer needs). This gives an idea of the tremendous change in life style it underwent.
New plasmids were added. Many of these aren’t held in common across all species of Y. Pestis and are referred to as ‘cryptic’ (role unknown). Even for those we think we understand, there are variations in size of the same plasmid, so plasmids in different strains that we have given the same name to may have different amounts of genetic material.
Three plasmids are involved in the virulence of Y. pestis.
 (a) ‘pYV’ was already present in Y. Pseudotuberculosis and is especially nasty. It gives rise to something called the ‘type III secretion’ system. The surface of the bacteria produce needle-like probes which can detect environmental conditions and attach to host cells and inject toxins directly into them, killing the cell, avoiding the extracellular fluid and avoiding much of the immune response. 
Worse, it preferentially attacks the body’s first responders (macrophages, neutrophils, or dendritic cells) crippling the immune response and allowing the infection to establish itself inside lymph tissue.

Perhaps this is why surviving an episode of plague only gives partial immunity. It may be part of why frequent recurrences of the same strain of Y. Pestis in the same area is the rule rather than the exception. Sometimes the same patient can be re-infected by the same strain.
The plague may form a reservoir in wild rodents, waiting to re-infect, and while it doesn’t like fresh air and sunshine it can remain in soil and water in endemic areas. It can live inside the single celled organism amoeba proteus that likes to swallow and digest bacteria.Whether soil and water reservoirs can contribute to recurrences (through ingestion, mainly by rodents but possibly other animals and even humans) is unknown. 
Two additional plasmids are unique to most strains of Y. Pestis.
b) The first one  pPCP1 is critical importance and allowed Y.Pestis to attack the respiratory system (Pneumonic Plague) and blood (Septicaemic Plague), both clinical variants are almost always fatal if untreated.
The primitive form of Y. Pestis was able to totally devastate neolithic communities throughout the West but we are unsure of how it manifested and how it spread, more on this in next month's blog.
The next step and the rat flea.
Around 2,000 BC (during the Bronze Age) the pestilence evolved again by the incorporation of another major plasmid. It was a quantum change what was already a very dangerous infection.
This third important plasmid (called the pFra or pMT1) gave Y. Pestis a number of  adaptations that allowed it to colonise and block the rodent flea’s midgut.
Infected rat flea (wiki)
Fleas bite to drink blood from their hosts and use two mouth parts. One part sucks blood from the host. The other part squirts saliva in to prevent blood clotting and because of this second part, fleas (like mosquitos) can readily transfer a range of diseases from one host to another.
The new plasmid contained genes that allowed the Y.Pestis to survive and replicate in the toxic environment of the foregut of the flea, resist being ingested and form a biological film which blocks the flea’s digestion.
Being unable to swallow the flea now regurgitates blood into the bite site to clear its blocked digestive track and this is teaming with bacteria. The bacteria no longer has to rely on saliva to transfer infection, it has a far superior method.
Successful infection relies on a combination of the virulence of the organism, the resistance of the host and the dose of infection. A higher the dose of infection in the initial assault is more likely to overwhelm a new host’s initial resistance and establish a solid beach head of infection.
Most (but not all) fleas have adapted to live, reproduce, and preferentially feed on a narrow range of hosts. They don’t spend all their time on the host, they (and their lava) live part of their life in nests and surrounds. The tiny rat flea is one of the more selective ones, but, having their digestive track blocked, they start to starve and they become voracious feeders, not only biting nearby rodents repeatedly, but much more readily biting dogs, cats, and humans.
Y. Pestis was already very lethal but now it truly became the worst pestilence to ever be visited on mankind.
What are the main rodents?
The main reservoir of the plague is wild rodents (e.g. gerbils, marmots, prairie dogs, chipmunks, wood rats, ground squirrels, deer mice and voles). It may be fatal in these animals but they usually have high resistance. Cats, rabbits, some wild carnivores, goats, camels, and sheep can also get the Plague.
It usually gains entry to humans via ‘domestic’ rats which also roam in the wild and encounter the infection from the ‘reservoir’ in the wild. A major player was the black rat (roof rat) and still is in some parts of the world. This rat prefers to build their nests high and dry. Wood structures and thatched roofs especially suited it. It likes temperate, not cold climates but the larger, burrowing,  brown rat (sewer rat, Norwegian rat) was important in transmitting plague in colder climates.
The Main Clinical Forms of the Plague
Plague can loosely take three (main) clinical forms.
They are all caused by the same organism  attacking at different sites of the body.
(Image from Centres for Disease Control)
Bubonic form, is the major presentation, accounting for 85 % and more of cases in most epidemics. It is most usually caused by the bite of an infected flea though rarely it can be caught handling contaminated material when there is an open wound on the skin. It attacks the lymph glands (groin, armpit or neck ) which become very painful and swollen by inflammation and necrotic tissue. It is accompanied with sudden onset of fever and chills, headache, fatigue or malaise and has a staggering mortality of 50%. 
Septicaemic form may also come from a flea bite which avoids the lymphatic system, maybe causing a local abscess and reaching the blood directly (no buboes). More commonly it is a complication of bubonic or pneumonic plague. It occurs in 10% to 15% of cases with a mortality of a 100% in untreated cases.
Death usually occurs at a terrifying speed (2-3 days after onset). The plague toxins cause shock, multi organ failure and something called disseminated intravascular coagulation (showing up as bruising, bleeding and gangrene at the extremities).
Pneumonic form is the rarest clinical type of infection (less than 5 %) but can be far higher in some strains. It also has 100% mortality in untreated cases and death occurs in 2 to 6 days.
It can be a complication of septicaemic plague but mostly it is passed directly from human to human. It is the only clinical form of plague that can readily pass from human to human directly.
It takes close proximity with the victim (less than six feet). While the bacteria can live in the soil for up to a year, it is readily killed by sunlight and fresh air and can only last for less than an hour in droplet form in the air. Patients are most infectious when they develop a moist cough in the final stages.
Bubonic and Septicaemic plague are almost never transferred directly from human to human.
(Caution: While I say the bubonic form is not highly infectious beyond flea bites, all care needs to be taken in handling infected patients and their body fluids. There are exceptions to every rule.)
Climate and the Plague
Plague is a complex story of humans, rats,  rat fleas and probably human fleas (see below). Climate can impact incidence in contradictory ways. For instance, in medieval temperate Europe, black rats and their fleas are less active in winter and sometimes plague followed this pattern (not always).
On the other hand, famine almost always preceded a serious human pandemics (weakening human resistance)  and famine could be triggered by a sudden burst of cold weather and poor harvests. Climate changes may impact on the behaviour of wild rodent populations and so on.
Is there something missing in all this?
Only about 30 of the approximately 3000 known species of fleas are proven plague vectors and Xenopsylla cheopis (the Oriental rat flea) is thought to be the most effective.
The rodent flea story is a compelling one and there is a lot of evidence for it.
How did Primitive Plague decimate the neolithic farmers of Europe
There is no doubt that the primitive forms of Y.Pestis was highly virulent, but this occurred before  Y.Pestis ‘learned’ to colonise and block the foregut of the rat flea.
We have to postulate another way of entry into human settlements and its ongoing propagation.
Hunters and gathers are at higher risk of being bitten by hungry fleas of recently deceased rodents lying in wait in nests. This would cause a bubonic infection.
If a form of primitive Y.Pestis was more lethal to rats living in close proximity to humans in some wholesale way, this would result in a lot of hungry rat fleas close to humans. Obvious rat deaths (so called ‘rat falls’ of sick and dying rats from ceilings) is not usually a feature of later plague outbreaks, but they have occurred. Such an event could cause an outbreak of bubonic plague even with the more primitive strain but it would only spread via rats, not from human to human. 

Another idea suggested was that maybe this early (primitive) plague may have been mainly a pneumonic form. Ingestion of poorly cooked infected meat gives rise to a ‘pharyngeal’ plague variant. It can mimic tonsillitis and be transmitted to humans in droplet form, resulting in a pneumonic outbreak in contacts of the initial case. Cats develop a similar form of plague and can introduce a pneumonic form into a human settlement.
While Pneumonic plague is uncommon in most epidemics, it is not true of all.  The 1994 plague in Surat, India had a large percentage of pneumonic cases and it was initially misidentified as a more common respiratory illness. The 2017 outbreak in Madagascar was mainly pneumonic and the Black Death in Bergen, Norway, in 1349, was initially pneumonic and only later changed to a mainly Bubonic type infection (presumably when Norwegian brown rats and their fleas became involved).
What about later episodes?
Could there be alternate forms of transmission of the bubonic form that we haven't previously suspected?
Rat fleas stick closer to their hosts than other fleas, and a healthy rat flea is unlikely to bite an infected human. In any case, it has been long taught that a healthy flea of any species biting an infected human would be unlikely to get infected. This is because it is thought that there isn’t enough concentration of bacteria in the blood of humans to overwhelm its initial protective mechanisms.
Rita Greer, The Great Plague
Rodents can carry 500-1,000 times more plague bacteria per unit of blood than humans who would be overwhelmed before reaching anything like this.
Humans with the septicaemic form of the plague have (by definition) a far higher amount of bacteria in the blood than the bubonic form but is it enough? Many experts would doubt it.
This seems to mean that (apart from Pneumonic plague) humans do not spread plague and this would be astounding. It would mean that, in the worst epidemics in history humans are passengers, not active participants, they are mostly along for the ride in what is essentially a plague in rats.
Questioning the exclusive role of rats
Some researchers have pointed to outbreaks of the garden variety of Plague in situations where it is thought that the rat population was low.
For rat centred spread of bubonic plague, Plague would have to be transferred to the local rat population and then spread amongst it. After that, it takes the bacteria 12–16 days to block the digestive tract of the flea and then the flea doesn’t live too long after that. 
According to recent mathematical modelling, the spread during the Black Death period was too fast for this method of transmission in several localities. The researchers suggested there must be another plague vector and suspicion has fallen on Pulex irritans often called the ‘human flea’ or ‘house flea’ which gets its name because of its irritating bite.
Pulex Irritans (the Human Flea) has a wide distribution, can live on a very wide range of hosts: birds, humans, dogs and cats, to name a few.
Whether 'human' fleas can even be a vector for plague has been hotly debated. These fleas are not susceptible to having their foregut blocked. The ones in favour of the human flea being a vector suggest that if a blocked foregut is not necessary, transfer of infection can go faster. The few cases of North American plague is transmitted from certain wild squirrels by a flea that doesn’t have its digestion blocked, and transmission is indeed quicker.
During a 2013 outbreak of plague in rural in Madagascar, researchers caught rats in traps and also fleas in 'candle' traps in village houses. 73% of the fleas were Pulex Irritans ‘human fleas’ and about 4 % of them were carrying Y.Pestis. 2/3 of these had not recently fed suggesting the fleas were infected and not just carrying infected blood in their latest meal.
None of the rats were carrying human fleas, suggesting the human fleas had most likely contracted the plague from humans. None of the other flea species including the usual ‘vectors’ had plague DNA, but their numbers were lowish. 
Can Pulex Irritans transmit Plague from humans to humans? This research needs to be confirmed, but our new suspect has been caught, not only leaving finger prints at the crime scene but also holding the murder weapon.
Don’t think to throw away the rat theories. It is still a major pathway for transmission and for entry into the human population but maybe there is a second pillar holding up the plague banner and waving it.
For pet lovers
The ‘cat’ and dog fleas are thought to be poor vectors. Cats and dogs might bring infected rat fleas indoors on their bodies where they might bite humans.
Your favourite pet can get the plague by biting an infected rodent (and eating it or being bitten by it) or they can be bitten by a rat flea. Cats are much more susceptible to the plague and usually develop enlarged submandibular nodes and sneezing, passing on the plague to their owners in the pneumonic form. Direct transmission from dogs is rare but has occurred. Dogs are often asymptomatic.
Another reason why the plague is so lethal (in case we needed another reason).
A predator species doesn’t want to be too efficient in eliminating its prey.
Similarly, an infective agent wants to infect and replicate (a lot) in its host but it wants to balance this need to replicate against the risk of an overwhelming infection killing the host. 
Ideally it should form a reservoir in the host population and maybe even have asymptomatic ‘carriers’. 
This would require a less lethal strain, forming a reserve, though from time to time more lethal strains would emerge.
At the same time as the possible evolutionary pressure for the infection not to be super-virulent, hosts develop resistance over time by the Darwinian selection.
The same thing happened with the Plague but unfortunately this process mainly benefited rodents, especially wild rodents, and not humans. Rodents are the main hosts.
It is speculative, but plague that is more virulent in humans might be more readily transmitted by human fleas. So selection may favour strains that are more deadly to humans.
Human resistance has been slow to develop and no reliable vaccine has yet been developed.
It remains endemic in Africa but in modern times it has become somewhat less of a problem with better rat, flea control, better public health and antibiotics. 

Next month's Blog: The Great Plague, major epidemics

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