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A Single Gene Shaped the Deadly History of Plague
This came in on one of my news feeds: A Single Gene Shaped the Deadly History of Plague
The subtitle:
A gene in plague bacteria adjusted virulence and infection duration, shaping pandemics and eventual extinction.
I'll reference and briefly excerpt the full scientific paper below, which was published in Science.
Excerpts of the news article:
Scientists have documented the way a single gene in the bacterium that causes bubonic plague, Yersinia pestis, allowed it to survive hundreds of years by adjusting its virulence and the length of time it took to kill its victims, but these forms of plague ultimately died out.
A study by researchers at McMaster University and France’s Institut Pasteur, published today in the journal Science, addresses some fundamental questions related to pandemics: how do they enter human populations, cause immense sickness, and evolve different levels of virulence to persist in populations?
The Black Death remains the single deadliest pandemic in recorded human history, killing an estimated 30 to 50 per cent of the populations of Europe, Western Asia and Africa as it moved through those regions. Appearing in the 14th century, it re-emerged in waves over more than 500 years, persisting until 1840.
The Black Death was caused by the same bacteria which caused Plague of Justinian, the first plague pandemic which had broken out in the mid-500s. The third plague pandemic began in China in 1855 and continues today. Its deadly effects are now more controlled by antibiotics but are still felt in regions like Madagascar and the Democratic Republic of Congo, where cases are regularly reported...
... An extensive genetic analysis revealed that its copy number, or total number of pla genes found in the bacterium, had decreased in later outbreaks of the disease, which in turn decreased its mortality by 20 per cent and increased the length of its infection, meaning the hosts lived longer before they died...
... “The reduction of pla may reflect the changing size and density of rodent and human populations,” explains Poinar. “It’s important to remember that plague was an epidemic of rats, which were the drivers of epidemics and pandemics. Humans were accidental victims.”
Black rats in cities likely acted as “amplification hosts” due to their high numbers and proximity to humans. Because black rats are highly susceptible to Y. pestis, the pathogen needed rat populations to stay high enough to supply new hosts for Y. pestis to persist and allow the pandemic cycle to continue.
However, the pla-reduced strains eventually went extinct, likely reflecting another shift in the host-pathogen relationship within their environment...
A study by researchers at McMaster University and France’s Institut Pasteur, published today in the journal Science, addresses some fundamental questions related to pandemics: how do they enter human populations, cause immense sickness, and evolve different levels of virulence to persist in populations?
The Black Death remains the single deadliest pandemic in recorded human history, killing an estimated 30 to 50 per cent of the populations of Europe, Western Asia and Africa as it moved through those regions. Appearing in the 14th century, it re-emerged in waves over more than 500 years, persisting until 1840.
The Black Death was caused by the same bacteria which caused Plague of Justinian, the first plague pandemic which had broken out in the mid-500s. The third plague pandemic began in China in 1855 and continues today. Its deadly effects are now more controlled by antibiotics but are still felt in regions like Madagascar and the Democratic Republic of Congo, where cases are regularly reported...
... An extensive genetic analysis revealed that its copy number, or total number of pla genes found in the bacterium, had decreased in later outbreaks of the disease, which in turn decreased its mortality by 20 per cent and increased the length of its infection, meaning the hosts lived longer before they died...
... “The reduction of pla may reflect the changing size and density of rodent and human populations,” explains Poinar. “It’s important to remember that plague was an epidemic of rats, which were the drivers of epidemics and pandemics. Humans were accidental victims.”
Black rats in cities likely acted as “amplification hosts” due to their high numbers and proximity to humans. Because black rats are highly susceptible to Y. pestis, the pathogen needed rat populations to stay high enough to supply new hosts for Y. pestis to persist and allow the pandemic cycle to continue.
However, the pla-reduced strains eventually went extinct, likely reflecting another shift in the host-pathogen relationship within their environment...
Ah...the rats.
I recently remarked on the difficulty of translation, and my efforts, during the Covid plague beginning in 2019 (and exacerbated by the same functional idiots now running the Government, only worse this time) on my abandoned effort to translate Camus' La Peste, (The Plague) into English. My son picked up something very cool in Canada. I did get to the part about the rats:
The French:
...C'est à peu près à cette époque en tout cas que nos concitoyens commencèrent à s'inquiéter. Car, à partir du 18, les usines et les entrepôts dégorgèrent, en effet, des centaines de cadavres de rats. Dans quelques cas, on fut obligé d'achever les bêtes, dont l'agonie était trop longue. Mais, depuis les quartiers extérieurs jusqu'au centre de la ville, partout où le docteur Rieux venait à passer, partout où nos concitoyens se rassemblaient, les rats attendaient en tas, dans les poubelles, ou en longues files, dans les ruisseaux. La presse du soir s'empara de l'affaire, dès ce jour-là, et demanda si la municipalité, oui ou non, se proposait d'agir et quelles mesures d'urgence elle avait envisagées pour garantir ses administrés de cette invasion répugnante. La municipalité ne s'était rien proposé et n'avait rien envisagé du tout mais commença par se réunir en conseil pour délibérer. L'ordre fut donné au service de dératisation de collecter les rats morts, tous les matins, à l'aube. La collecte finie, deux voitures du service devaient porter les bêtes à l'usine d'incinération des ordures, afin de les brûler.
Mais dans les jours qui suivirent, la situation s'aggrava. Le nombre des rongeurs ramassés allait croissant et la récolte était tous les matins plus abondante. Dès le quatrième jour, les rats commencèrent à sortir pour mourir en groupes. Des réduits, des sous-sols, des caves, des égouts, ils montaient en longues files titubantes pour venir vaciller à la lumière, tourner sur eux-mêmes et mourir près des humains. La nuit, dans les couloirs ou les ruelles, on entendait distinctement leurs petits cris d'agonie. Le matin, dans les faubourgs, on les trouvait étalés à même le ruisseau, une petite fleur de sang sur le museau pointu, les uns gonflés et putrides, les autres raidis et les moustaches encore dressées. Dans la ville même, on les rencontrait par petits tas, sur les paliers ou dans les cours. Ils venaient aussi mourir isolément dans les halls administratifs, dans les préaux d'école, à la terrasse des cafés, quelquefois. Nos concitoyens stupéfaits les découvraient aux endroits les plus fréquentés de la ville. La place d'Armes, les boulevards, la promenade du Front-de-Mer, de loin en loin, étaient souillés. Nettoyée à l'aube de ses bêtes mortes, la ville les retrouvait peu à peu, de plus en plus nombreuses, pendant la journée. Sur les trottoirs, il arrivait aussi à plus d'un promeneur nocturne de sentir sous son pied la masse élastique d'un cadavre encore frais. On eût dit que la terre même où étaient plantées nos maisons se purgeait de son chargement d'humeurs, qu'elle laissait monter à la surface des furoncles et des sanies qui, jusqu'ici, la travaillaient intérieurement. Qu'on envisage seulement la stupéfaction de notre petite ville, si tranquille jusque-là, et bouleversée en quelques jours, comme un homme bien portant dont le sang épais se mettrait tout d'un coup en révolution !...
Mais dans les jours qui suivirent, la situation s'aggrava. Le nombre des rongeurs ramassés allait croissant et la récolte était tous les matins plus abondante. Dès le quatrième jour, les rats commencèrent à sortir pour mourir en groupes. Des réduits, des sous-sols, des caves, des égouts, ils montaient en longues files titubantes pour venir vaciller à la lumière, tourner sur eux-mêmes et mourir près des humains. La nuit, dans les couloirs ou les ruelles, on entendait distinctement leurs petits cris d'agonie. Le matin, dans les faubourgs, on les trouvait étalés à même le ruisseau, une petite fleur de sang sur le museau pointu, les uns gonflés et putrides, les autres raidis et les moustaches encore dressées. Dans la ville même, on les rencontrait par petits tas, sur les paliers ou dans les cours. Ils venaient aussi mourir isolément dans les halls administratifs, dans les préaux d'école, à la terrasse des cafés, quelquefois. Nos concitoyens stupéfaits les découvraient aux endroits les plus fréquentés de la ville. La place d'Armes, les boulevards, la promenade du Front-de-Mer, de loin en loin, étaient souillés. Nettoyée à l'aube de ses bêtes mortes, la ville les retrouvait peu à peu, de plus en plus nombreuses, pendant la journée. Sur les trottoirs, il arrivait aussi à plus d'un promeneur nocturne de sentir sous son pied la masse élastique d'un cadavre encore frais. On eût dit que la terre même où étaient plantées nos maisons se purgeait de son chargement d'humeurs, qu'elle laissait monter à la surface des furoncles et des sanies qui, jusqu'ici, la travaillaient intérieurement. Qu'on envisage seulement la stupéfaction de notre petite ville, si tranquille jusque-là, et bouleversée en quelques jours, comme un homme bien portant dont le sang épais se mettrait tout d'un coup en révolution !...
My translation:
It was a just around this period, in any case, that our citizens began to be disquieted. This was because, beginning on the 18th, the factories and the warehouses were beginning to disgorge, in effect, hundreds of rat corpses. In some cases we were required to finish them off, since their agony was very long. From the outer regions of the city to the city center, wherever Dr. Rieux went, wherever our citizens gathered, piles of rats were waiting, or else lined the gutters. The press seized on the affair on that day, asking whether or not the authorities had a plan of action and what urgent measures would be taken to protect our citizens from this repugnant invasion. The authorities had nothing to offer, and nothing planned, but began meeting in council to deliberate. An order was given to the extermination service to collect the dead rats each morning at dawn. When the collection finished, two service vehicles were to transport them to the incineration plant in order to burn them.
But in the days that followed, the situation worsened. The number of rodents picked up was increasing and every morning the harvest was more abundant. On the fourth day, the rats began to come out to die in groups. From below, from basements, from cellars, from sewers they rose, stumbling in long lines to waver in the light, wobbling, turning on themselves and dying close to people. In the night, in the alleys or in corridors, one could hear their distinct cries of agony. In the morning, in the suburbs, one found them spread among themselves in the gutters, a small bloom of blood on their snouts, some swollen and putrid, others stiff and with their whiskers still erect. In the city, one encountered them in small heaps on the landings or in courtyards. They also came alone to die in administrative halls, on the terraces of cafes, sometimes in school yards. Our stupefied citizens found them in the busiest places. The Army square, the boulevards, the boardwalk by the sea, now and then were fouled. Cleaned at dawn of the dead animals, the city found them again in larger and larger numbers during the day. On the sidewalks, more than once an evening pedestrian would feel the squishing mass of a fresh dead corpse beneath his feet. One could say that the very ground where our houses stood was purged of its charge of the putrescence allowed to rise to the surface in boils and pus, where heretofore, it had worked internally. One should imagine the shock to our little city, so peaceful until then, convulsed in a few days, like a man in good health whose blood took to coagulating in total revolt...
But in the days that followed, the situation worsened. The number of rodents picked up was increasing and every morning the harvest was more abundant. On the fourth day, the rats began to come out to die in groups. From below, from basements, from cellars, from sewers they rose, stumbling in long lines to waver in the light, wobbling, turning on themselves and dying close to people. In the night, in the alleys or in corridors, one could hear their distinct cries of agony. In the morning, in the suburbs, one found them spread among themselves in the gutters, a small bloom of blood on their snouts, some swollen and putrid, others stiff and with their whiskers still erect. In the city, one encountered them in small heaps on the landings or in courtyards. They also came alone to die in administrative halls, on the terraces of cafes, sometimes in school yards. Our stupefied citizens found them in the busiest places. The Army square, the boulevards, the boardwalk by the sea, now and then were fouled. Cleaned at dawn of the dead animals, the city found them again in larger and larger numbers during the day. On the sidewalks, more than once an evening pedestrian would feel the squishing mass of a fresh dead corpse beneath his feet. One could say that the very ground where our houses stood was purged of its charge of the putrescence allowed to rise to the surface in boils and pus, where heretofore, it had worked internally. One should imagine the shock to our little city, so peaceful until then, convulsed in a few days, like a man in good health whose blood took to coagulating in total revolt...
Sounds like Washington...doesn't it?
Of course, we have infectious rats in our halls of government, a sure to be deadly plague of them.
The full scientific publication to which the news item refers is here: Ravneet Kaur Sidhu et al., Attenuation of virulence in Yersinia pestis across three plague pandemics. Science 388, eadt3880 (2025).
Some text from the full article:
Yersinia pestis is a zoonotic pathogenic bacterium that naturally resides in rodents and their fleas—the vectors that transmit it to humans—causing outbreaks of high mortality. Spillover events from wild rodents to both peridomestic rodents and humans have resulted in three well-described plague pandemics: the Plague of Justinian, the herald wave (541 to 544) of the first pandemic, which lasted from 541 to 750 CE (1, 2); the Black Death (1346 to 1353) (3), the initial phase of the second pandemic, which lasted from 1346 CE until 1840 CE; and the third pandemic that began in China in 1855 CE, which spread worldwide and continues today (4). Although there is genetic evidence of plague infections over much longer timescales (i.e., Bronze Age and Late Neolithic), their mode of transmission and infectiousness are unknown (5, 6).
The Black Death, the single greatest mortality event in recorded human history, stretched across Europe, Western Asia, and Africa, with estimated overall mortality at ~30 to more than 50% of affected European populations (3). It was followed by centuries of nearly decennial reoccurrences throughout Eurasia (3, 7). Many of these subsequent epidemics had lower mortality, potentially because of a confluence of factors, including virulence attenuation of Y. pestis (8, 9), the evolution of protective immune variants in humans (10), the die-off of reservoir hosts (11), changes to interregional trade routes and human behavior (12), and/or the synergistic interactions between them (13). Both the first and second pandemic strains of Y. pestis emerged from rodent reservoirs. However, whereas the first pandemic left no circulating descendants (2), Y. pestis strains from the second pandemic form two major clades: one that was ancestral to all contemporary third-pandemic strains and another that resulted in centuries-long reemergences of plague across Europe and went extinct by the early 19th century (14). Interestingly, the extinction of the first pandemic lineage and one of the two clades of the second pandemic occurred after the depletion of a ~2100–base pair (bp) region containing the pla gene and neighboring genes encoding a hypothetical protein and a transcriptional regulator (15). This depletion, which represents a reduction in pla gene dosage but is not a complete deletion, occurred a century or so into each pandemic (15, 16). The pla gene encodes a virulence factor, and its depletion has been hypothesized to reflect a virulence-transmission trade-off (16), in which natural selection for increased transmission (i.e., reproductive success) resulted in a reduction in Y. pestis virulence (8, 9).
Y. pestis has several virulence factors that allow for cellular adhesion, evasion of host immune responses, and proliferation of the bacterium within host tissues, particularly lymph nodes (17). The pla gene, which is carried by the high–copy number plasmid (pPCP1) (18), encodes Pla, an outer membrane protease that is crucial for the development of bubonic and pneumonic forms of plague (19–21). This protease has been hypothesized to interact with several host proteins, including plasminogen, which it converts to plasmin; this enables the lysis of fibrin clots, which is believed to help Y. pestis disseminate from the site of injection (i.e., skin) to a lymph node. There, the bacteria can replicate before spreading throughout the body (19, 22, 23). With Pla inactivation, there is up to a 1 million–fold increase in the median lethal dose (LD50) of bacteria in rodents when inoculated subcutaneously or intradermally (19, 20). Y. pestis strains lacking the entire pPCP1 plasmid do persist in some sylvatic rodents (i.e., Y. pestis subspecies microtus bv. caucasica) but rarely cause epizootics or human disease (24, 25)...
The Black Death, the single greatest mortality event in recorded human history, stretched across Europe, Western Asia, and Africa, with estimated overall mortality at ~30 to more than 50% of affected European populations (3). It was followed by centuries of nearly decennial reoccurrences throughout Eurasia (3, 7). Many of these subsequent epidemics had lower mortality, potentially because of a confluence of factors, including virulence attenuation of Y. pestis (8, 9), the evolution of protective immune variants in humans (10), the die-off of reservoir hosts (11), changes to interregional trade routes and human behavior (12), and/or the synergistic interactions between them (13). Both the first and second pandemic strains of Y. pestis emerged from rodent reservoirs. However, whereas the first pandemic left no circulating descendants (2), Y. pestis strains from the second pandemic form two major clades: one that was ancestral to all contemporary third-pandemic strains and another that resulted in centuries-long reemergences of plague across Europe and went extinct by the early 19th century (14). Interestingly, the extinction of the first pandemic lineage and one of the two clades of the second pandemic occurred after the depletion of a ~2100–base pair (bp) region containing the pla gene and neighboring genes encoding a hypothetical protein and a transcriptional regulator (15). This depletion, which represents a reduction in pla gene dosage but is not a complete deletion, occurred a century or so into each pandemic (15, 16). The pla gene encodes a virulence factor, and its depletion has been hypothesized to reflect a virulence-transmission trade-off (16), in which natural selection for increased transmission (i.e., reproductive success) resulted in a reduction in Y. pestis virulence (8, 9).
Y. pestis has several virulence factors that allow for cellular adhesion, evasion of host immune responses, and proliferation of the bacterium within host tissues, particularly lymph nodes (17). The pla gene, which is carried by the high–copy number plasmid (pPCP1) (18), encodes Pla, an outer membrane protease that is crucial for the development of bubonic and pneumonic forms of plague (19–21). This protease has been hypothesized to interact with several host proteins, including plasminogen, which it converts to plasmin; this enables the lysis of fibrin clots, which is believed to help Y. pestis disseminate from the site of injection (i.e., skin) to a lymph node. There, the bacteria can replicate before spreading throughout the body (19, 22, 23). With Pla inactivation, there is up to a 1 million–fold increase in the median lethal dose (LD50) of bacteria in rodents when inoculated subcutaneously or intradermally (19, 20). Y. pestis strains lacking the entire pPCP1 plasmid do persist in some sylvatic rodents (i.e., Y. pestis subspecies microtus bv. caucasica) but rarely cause epizootics or human disease (24, 25)...
The authors worked with archeological tissue specimens utilized in previous work. The medieval samples came from Danish victims. Modern samples seem to have come from Vietnam.
A figure from the text:
The caption:
Fig. 1. Depletion of the plasminogen activator (pla) virulence factor gene in three plague pandemics.
(A to C) Linear regression of pla versus pst depth, histogram of samples present at different gene depth ratios, and a maximum likelihood (ML) phylogeny highlighting the evolutionary relationships of pla-reduced and pla-WT strains across all three plague pandemics. In all panels, pla-reduced strains are blue, and pla-WT strains are green; in (C), pla-intermediate strain IP1643H is denoted by a darker blue (data S1). Only samples with more than 10X pPCP1 coverage were used for the histogram and linear regression (n = 17 first pandemic, n = 74 second pandemic, n = 1994 third pandemic). In the ML trees, samples with less than 10X pPCP1 coverage are shown in gray, and nodes with more than 95% bootstrap support are indicated with asterisks. Presence and absence of GBRs, in addition to the pla/pst gene depth ratio, was considered before tips on the phylogeny were colored. Samples without GBRs were identified as pla-WT. Only ancient samples with >70% coverage at a read depth of 3X were used in the phylogenetic analysis (n = 16 first pandemic, n = 55 second pandemic). The complete phylogenetic tree, representing most Y. pestis diversity (27), is present in supplementary materials (fig. S5 and data S4 to S5); the subtrees shown in each panel have been extracted from the full tree to show the lineages corresponding to the three pandemics only (0.ANT4, 1.PRE, 1.ORI). Shown in (A) are data for the first plague pandemic. In the phylogenetic tree, the sweep of pla-reduced samples is highlighted in blue. Shown in (B) are data for the second plague pandemic. The sweep of pla-reduced samples is highlighted in blue in the phylogenetic tree, and samples corresponding to pestis secunda and ancestral to third-pandemic strains are highlighted in pink. Yellow stars indicate samples used for de novo assembly. Shown in (C) are data for the third plague pandemic, with pla-WT, pla-intermediate, and pla-reduced strains from Vietnam and their hosts (human and black rat) indicated.
(A to C) Linear regression of pla versus pst depth, histogram of samples present at different gene depth ratios, and a maximum likelihood (ML) phylogeny highlighting the evolutionary relationships of pla-reduced and pla-WT strains across all three plague pandemics. In all panels, pla-reduced strains are blue, and pla-WT strains are green; in (C), pla-intermediate strain IP1643H is denoted by a darker blue (data S1). Only samples with more than 10X pPCP1 coverage were used for the histogram and linear regression (n = 17 first pandemic, n = 74 second pandemic, n = 1994 third pandemic). In the ML trees, samples with less than 10X pPCP1 coverage are shown in gray, and nodes with more than 95% bootstrap support are indicated with asterisks. Presence and absence of GBRs, in addition to the pla/pst gene depth ratio, was considered before tips on the phylogeny were colored. Samples without GBRs were identified as pla-WT. Only ancient samples with >70% coverage at a read depth of 3X were used in the phylogenetic analysis (n = 16 first pandemic, n = 55 second pandemic). The complete phylogenetic tree, representing most Y. pestis diversity (27), is present in supplementary materials (fig. S5 and data S4 to S5); the subtrees shown in each panel have been extracted from the full tree to show the lineages corresponding to the three pandemics only (0.ANT4, 1.PRE, 1.ORI). Shown in (A) are data for the first plague pandemic. In the phylogenetic tree, the sweep of pla-reduced samples is highlighted in blue. Shown in (B) are data for the second plague pandemic. The sweep of pla-reduced samples is highlighted in blue in the phylogenetic tree, and samples corresponding to pestis secunda and ancestral to third-pandemic strains are highlighted in pink. Yellow stars indicate samples used for de novo assembly. Shown in (C) are data for the third plague pandemic, with pla-WT, pla-intermediate, and pla-reduced strains from Vietnam and their hosts (human and black rat) indicated.
Well, that's interesting. I don't know if there's a cure for the pestilence in our government, the rats seem not to be dying. These people seem not to evolve into less virulence; they are more virulent in this second plague than ever.
That's another thing though.
From La Peste:
A Oran comme ailleurs, faute de temps et de réflexion, on est bien obligé de s'aimer sans le savoir.
The Plague:
"In Oran, as elsewhere, one is compelled, by a lack of time and of reflection, to love one another without knowing it."
Have a nice weekend.
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