Plague: The first pandemic disease

Ann G. Matthysse, Professor of Biology from The University of North Carolina at Chapel Hill, writes in detail about plague, the first pandemic disease including comment on bacteria

Before 2019, if you asked people about pandemic diseases the two most likely to be mentioned were plague (the black death) and influenza. Plague still remains in the memory of the Western world as the dreaded disease which killed a large portion of the population in medieval Europe. Images of people dying with large swollen black lymph nodes, flagellants marching through the streets, and plague doctors in strange clothes with large beak-shaped masks come to the mind of many of those of us who studied European history.

General information about the plague and the bacterium that causes it

Plague is caused by a bacterium, currently called Yersinia pestis. It is named for Alexandre Yersin who discovered it as the cause of plague in China in the 1890s during the third pandemic. The bacterium has also been known as Pasteurella pestis or Francisella pestis. There are two other members of the bacterial genus Yersinia which cause disease in humans, Y. pseudotuberculosis and Y. enterocolitica. Both of these bacteria cause an enterocolitis (gastrointestinal tract infection) which is generally limited and not life-threatening. However, despite the very different diseases caused by these three species of Yersinia, they share many virulence factors and genes in common. This allows Y. pseudotuberculosis to be used as a substitute for Y. pestis in laboratory experiments in some circumstances. Plague is primarily a disease of rodents, transmitted from animal to animal by fleas. When a rodent dies of plague, its associated fleas look for another rodent host. If the fleas cannot readily find another rodent to act as a host, then the fleas may jump onto whatever mammal is nearby. If this is a human, the result may be an individual with bubonic plague.

Transmission, bacterial virulence factors and disease symptoms

When the bacteria are ingested by the flea as a result of feeding on an infected rodent, the bacteria grow in the flea gut and form a biofilm there in the region of the connection between the oesophagus and the mid-gut. This biofilm blocks the gut, so that when the flea bites a new host it cannot feed until it regurgitates the mass of bacteria blocking this site so that it can take in a new meal. The regurgitated bacteria then enter the dermis from the bite and disseminate through the lymph to the lymph nodes. There is a bottleneck at the exit from the dermis into the lymph, and only a fraction of the injected bacteria actually enter the lymph. Thus, not all laboratory dermal injections or all natural flea bites result in infection and disease. The bacteria are not motile and apparently are simply carried by the flow of the lymph [1]. In the lymph node, the bacteria may be phagocytosed by neutrophils or macrophages. However, the bacterial virulence factors include genes whose expression is upregulated at 37° (human, but not flea body temperature). The products of some of these genes prevent phagocytosis. Others result in the synthesis of a type 3 secretion system (T3SS) which is a syringe-like structure that extends from the bacterial cytoplasm across the bacterial cell membrane, cell wall, and outer membrane to contact the host cell membrane. Various proteins can then be injected into the host cell without ever being exposed to the outside milieux. These effector proteins include various toxins and enzymes as well as proteins that cause rearrangements of the host cell cytoskeleton. They alter host cell signaling pathways and cause cell death (apoptosis) [2].

As the bacteria grow in the lymph nodes which drain the site of initial entry at the flea bite, the nodes swell and many cells die resulting in the accumulation of blood and fluid which results in the swollen black lymph nodes which are referred to as buboes. These are most often found in the nodes in the armpit and the groin but can occur anywhere in the body. From the lymph nodes, the bacteria make their way into the bloodstream, resulting in a circulating bacteremia. If the bacteria enter the lung pneumonic plague results. The bacteria can then be transmitted directly from one person to another.

Origin and evolution of the plague

It is the presence of the bacteria in the blood and thus in the pulp of the teeth and the bone marrow, which has allowed the isolation of bacterial DNA from ancient burials and the study of the evolution of plague. The closest living relative of Yersinia pestis is Y. pseudotuberculosis. These species share most of their genome in common, and it is estimated that Y. pestis diverged from Y. pseudotuberculosis as recently as about 6,000 years ago [3]. Y. pseudotuberculosis is a generalist pathogen transmitted by the oral-faecal route in many animals. One of the critical developments in the evolution of Y. pestis from Y. pseudotuberculosis appears to have been the acquisition of the ability of Y. pestis to be transmitted by fleas and other arthropods. The bacteria acquired two new plasmids. These are small extra-chromosomal DNA elements that are often readily transmissible from one bacterium to another, even to an entirely different bacterial species. One of these plasmids carries a gene (ymt which encodes a phospholipase D) which allows the survival of gram-negative bacteria in the gut of the flea. The other gene changes which allow growth in the flea are gene losses; many of these gene losses are responsible for the growth of the biofilm in the flea gut. The earliest isolates of Y. pestis have been sequenced from bronze age burials in Asia [4].

Plagues and pandemics

The first recorded pandemic of plague is the plague of Justinian in the 6th to 8th centuries. DNA from the bacterium causing this pandemic has been isolated from teeth from a burial in Germany. The bacterium is related to that which caused the second pandemic (14th-18th century) and the third pandemic (19th century to the present). Each of these pandemics resulted in a high rate of mortality (perhaps as much as 30-50% of the population in some cases) [5]. Even in the modern era with the aid of antibiotics, plague still has a high mortality, due in part to the rapid progression of the disease so that unless the diagnosis is prompt and treatment begins immediately, it may be impossible to save the patient.

The cause(s) of the start and end of each of these pandemics are unclear. They probably include complex ecological interactions between climate, fleas, rodents, and human populations.

References

1. Gonzalez, R.J., et al., Dissemination of a highly virulent pathogen: tracking the early events that define infection. PLoS Pathog, 2015. 11(1): p. e1004587.
2. Atkinson, S. and P. Williams, Yersinia virulence factors – a sophisticated arsenal for combating host defences. F1000Res, 2016. 5.
3. Demeure, C., et al., Yersinia pestis and plague: an updated view on evolution, virulence determinants, immune subversion, vaccination and diagnostics. Microbes Infect, 2019. 21(5-6): p. 202-212.

4. Hinnebusch, B.J., I. Chouikha, and Y.C. Sun, Ecological Opportunity, Evolution, and the Emergence of Flea-Borne Plague. Infect Immun, 2016. 84(7): p. 1932-40.
5. Slack, Paul, Plague A Very Short Introduction. Oxford University Press. Oxford, Great Britain. 2012.

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