The Great Plague of Sevvile Peer Reviewed Articles

What caused the Black Expiry?

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1. C J Duncan,
2. Due south Scott

1. School of Biological Sciences, University of Liverpool, Liverpool, U.k.

1. Correspondence to:
 Professor C J Duncan
 School of Biological Sciences, Academy of Liverpool, Life Sciences Building, Liverpool L69 7ZB, Uk; sscottliverpool.air-conditioning.u.k.

Abstruse

For the whole of the 20th century it was believed that the Black Death and all the plagues of Europe (1347–1670) were epidemics of bubonic plague. This review presents testify that this view is incorrect and that the disease was a viral haemorrhagic fever, characterised by a long incubation period of 32 days, which allowed information technology to be spread widely fifty-fifty with the express transport of the Centre Ages. It is suggested that haemorrhagic plague emerged from its animal host in Federal democratic republic of ethiopia and struck repeatedly at European/Asian civilisations, before appearing as the Black Death. The CCR5-Δ32 mutation confers protection confronting HIV-one in an average of 10% of the people of European origin today. It is suggested that all the Δccr5 alleles originated from a single mutation event that occurred before 1000 bc and the subsequent epidemics of haemorrhagic plague gently forced up its frequency to 5×ten^−v at the time of the Blackness Death. Epidemics of haemorrhagic plague over the adjacent three centuries so steadily raised the frequency in Europe (simply non elsewhere) to present day values.

• plague epidemics
• viral haemorrhagic fever
• CCR5-Δ32 mutation
• emergent diseases

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• plague epidemics
• viral haemorrhagic fever
• CCR5-Δ32 mutation
• emergent diseases

Immediately on its arrival in 1347 in the port of Messina in Sicily the Great Pestilence (or Black Death as it was named in 1823 considering of the blackness blotches acquired by subcutaneous haemorrhages that appeared on the skin of victims) was recognised every bit a straight infectious disease. Michael of Piazza, a Franciscan friar who wrote 10 years after the Blackness Death had arrived, said "The infection spread to anybody who had whatsoever intercourse with the disease".^one Indeed, they believed (incorrectly) that priests who heard the confessions of the dying "were immediately overcome by death, so that some even remained in the rooms of the dying."¹ Case mortality was 100%. They realised that prophylactic lay in fleeing just this, very effectively, served but to spread the infection.

The Black Death moved as a wave northwards through Europe at an average speed of about 4 km per mean solar day and reached the Arctic Circle by 1350, remarkable progress in the days of very limited ways of send.^{2– iv} Fifty-fifty more than impressively: it had earlier appeared in Asia Small-scale and the Crimea and moved south through Antioch; information technology was nowadays in the Levant and spread along the due north African coastlands and to Mecca in Kingdom of saudi arabia, covering, in all, some seven 1000000 foursquare km. When it had burnt itself out, 40% of the population of Europe had been killed. This outbreak was a pandemic on a scale never earlier experienced (or since).

Only this unknown disease had not disappeared completely and at that place were epidemics scattered through Europe during the 1350s.^five Thereafter, the plague was permanently established in France with epidemics every year that cycled circular the main trading routes. From in that location, infected travellers carried the disease by route and river across the continental landmass and by sea to United kingdom and Ireland. But all these peripheral epidemics died out completely and were restarted past fresh infectives coming from the focus in French republic.⁴

The epidemics progressively increased in spread, frequency, and ferocity (fig i) with a pronounced ascension afterward 1550 because transport improved and the population of the towns steadily grew (that is, at that place was a greater number of susceptibles). Contemporary accounts, pattern of spread, and mortality all ostend that the aforementioned pathogen was responsible for all the plagues, including the offset strike of the Blackness Death.

PUBLIC HEALTH MEASURES

Even in the 14th century the health authorities in northern Italy had established the importance of a 40 twenty-four hour period quarantine period, which became the gold standard for continental Europe for the side by side 300 years. The forty mean solar day quarantine was non adopted in England until the 16th century and fifty-fifty so information technology was changed to 30 days only to find that this was completely ineffective, whereupon this regulation was rapidly rescinded.

The complete success of the quarantine period confirms that the plague was a straight communicable diseases and information technology also shows that information technology had a long incubation flow. Towns in France gradually realised that the danger lay in the arrival of an infected traveller who may well take come up from a considerable distance. Entry was denied if they had come from a town that had suffered an epidemic. Subsequently, in addition to inspecting travellers on arrival, the authorities too required proof that all the towns through which they had journeyed were completely free of plague.

One time an epidemic had erupted, those displaying symptoms were removed to emergency archaic isolation hospitals called pest (an abbreviation of pestilence) houses, which were hurriedly erected outside the town. Once a plague example had been identified, the family unit was locked upward in the house, the well known cross was daubed on the door, and a watchman was appointed to stand guard. These measures were less successful in containing an epidemic considering, as shown below, victims were more infectious earlier the appearance of the symptoms.

Despite but sketchy medical knowledge at the fourth dimension, the epidemiology of the plague was fully understood at least by the middle of the 17th century. Daniel Defoe⁶ had perspicaciously noted that, in the Bang-up Plague of London in 1665, "because of its infectious nature, the disease may be spread past apparently salubrious people who harbour the illness only have not withal exhibited the symptoms. Such a person was in fact a poisoner, a walking destroyer perhaps for a week or a fortnight before his death, who might have ruined those that he would accept hazarded his life to save… breathing decease upon them, even perhaps his tender kissing and embracings of his ain children."

Clearly, they recognised that victims were infectious before the symptoms appeared, the lengthy duration of the incubation period, the necessity of a 40 day quarantine, and the dangers of droplet infection. Just in that location were many features of the epidemics that were mystifying and they also clung to their beliefs in divine intervention, transmission via contaminated habiliment and bedding, movements of the planets, and poisonous miasmas.

YERSINIA PESTIS AND BUBONIC PLAGUE

Even before 1347, bubonic plague had been grumbling along for centuries in Asia with occasional severe epidemics. Only from the mid-19th century the disease gathered momentum and erupted in Canton and Hong Kong in 1894, Calcutta in 1895, and Bombay in 1896 and the pandemic of the 20th century had begun. Steamships carried infected rats and fleas from the infested warehouses of the Chinese ports to many of the warmer parts of the world, wherever suitable rodent hosts could be found. Simply endemic bubonic plague never became established in Europe, despite numerous introductions in the 20th century.

The complex aetiology and biology of bubonic plague was elucidated by Yersin^vii and the Plague Committee of India⁸: it is a disease of wild rodents in which the bacterial pathogen, Yersinia pestis, is spread past infected fleas. Occasionally today it is transmitted to humans from peridomestic rats and there are some 1600 cases a twelvemonth.⁹ The characteristic (but not specific) symptom of bubonic plague in humans is the appearance of the bubo.

However, once Yersin had announced his seminal results, it was realised that victims of haemorrhagic plague as well sometimes presented with swollen lymph glands. It was, manifestly, immediately assumed that the Blackness Decease was caused past bubonic plague. Nobody compared the two diseases objectively and for the whole of the 20th century this view, based solely on the appearance of one symptom, was universally accepted without question.

THE Biological science OF BUBONIC PLAGUE

To be able to abnegate unequivocally the belief that Yersinia pestis was the pathogen of the Blackness Death it is necessary to understand fully the complicated biology of bubonic plague. The key lies in the difference between susceptible and resistant rodent species. Susceptible species, similar rats, die from the infection and an outbreak of homo bubonic plague was often presaged by the advent of hundreds of dead rats. Apparently, no outbreak can be maintained for whatsoever length of fourth dimension and bubonic plague cannot go endemic where all the local species are susceptible. In central Colorado an isolated colony of prairie dogs (Cynomys gunnisoni) was wiped out when Yersinia pestis was introduced.¹⁰

In Siberia and Mongolia, for example, susliks and tarabagans are susceptible and subject to recurrent, brusque term outbreaks that might eventually eliminate the plague focus through lack of hosts; but the local gerbils and voles are more resistant to Y pestis and then they tin can serve to maintain the endemic state in the surface area because they practice not die from an infection.^x

In warm climates, rodents brood throughout the twelvemonth and may produce up to nine litters. In this way, the density of a population of rodents living under favourable conditions increases rapidly and outbreaks of bubonic plague can occur at any time of year. The turnover of a rodent population in a subtropical area can exist very high: equally fast every bit they brood, infections (including Yersinia) and predators act to reduce their numbers. This process generates regular cycles in the population of rodents and prevents the institution of a stable, plague resistant population. Therefore, any focus of bubonic plague in rodents in subtropical climates is in a continual state of population flux.

The spread of bubonic plague through a rodent population is critically dependent on active fleas. At least 30 species of flea take been proved to be vectors and, as more than 200 species of rodent can carry plague, the host-vector permutations in the Asian subcontinent are formidable and the population dynamics complex.^{3, x}

Flea reproduction is strongly dependent on environmental and other factors: temperature and humidity greatly touch on both egg laying and the development of the larvae. Temperatures betwixt xviii°C and 27°C and a relative humidity of 70% are platonic, whereas temperatures below 7°C are deleterious to all developmental stages except the adult. The fleas, the rats, the resistant rodents, and the susceptible rodents each need specific conditions for the successful completion of their life wheel and the overall maintenance of their populations. All are potentially capable of prodigious reproduction. These life cycles and the environmental requirements for reproduction have to intermesh successfully if an infection of Yersinia pestis is to be established in rodents. The dynamics of bubonic plague are complicated but rodents usually keep within their abode range and the illness spreads only slowly through the countryside.^{3, 10}

SPREAD OF BUBONIC PLAGUE TO HUMANS

If an infected wild rodent strays most man habitations and then shares its fleas with rats living around the settlement, Yersinia can spread from rodent to rat, and from rat to human. The rat is just an intermediary and is not a reservoir of bubonic plague: its office is to die and then pass on the infection. A number of dead rats will usually exist found during an outbreak of bubonic plague in humans: in a minor village perhaps just a few; in a large Southward African township peradventure many barrow loads.

At that place are several other means in which Yersinia pestis can spread from a focus amid local rodents to humans: when humans become out and invade an surface area where the rodents are infected—for example when hunting or picnicking—they may catch bubonic plague direct from the fleas living on the wild rodents.¹⁰

MANIFESTATIONS OF BUBONIC PLAGUE IN HUMANS

Patients with bubonic plague, who have been bitten by an infected flea, are not normally infectious to other people and tin be nursed in open wards. Notably, the incubation catamenia is typically two to half dozen days after exposure and the characteristic symptom is the bubo. Typically the onset is sudden with chills and rigors and a rise of temperature to 38.8°C–39.iv°C. The patient has a astringent, splitting headache and often pains in the limbs, the back, and abdomen. They become confused, restless, irritable or apathetic, their speech slurred, and they may vomit. Inside a day or two the person is prostrate with all the symptoms of daze. Virtually patients die between the third and sixth mean solar day: if they are alive on the seventh day they may struggle through to recovery.¹⁰

Still, in almost 5% of the cases of bubonic plague the Yersinia reaches the lungs and the patient coughs out the bacteria in the sputum, which may be inhaled past anyone in close contact who then gets pneumonic plague. The victim dies between the third and sixth day and, without medical handling, pneumonic plague is invariably fatal.¹⁰

Pneumonic plague cannot occur in the absence of the bubonic form, not can it persist independently. While pneumonic plague increased the mortality locally in an epidemic focus, it was rarely responsible for spreading Yersinia pestis over whatsoever distance—mortally sick people were unable to move very far in the few days before decease. Furthermore, transmissibility of pneumonic plague is depression: the boilerplate number of secondary cases per primary example (R _o) based on by outbreaks was only 1.3.^xi

MANIFESTATIONS OF HAEMORRHAGIC PLAGUE

We believe that the Black Death was caused by a affliction that was completely unlike from bubonic plague and, to avoid confusion, have named it haemorrhagic plague. Case mortality was 100% and the disease was directly infectious. In the Plague of Athens, victims were stricken suddenly with severe headaches, inflamed eyes, and bleeding in their mouths and throats. The next symptoms were coughing, sneezing, and chest pains followed past stomach cramps, intensive vomiting and diarrhoea, and unquenchable thirst. The skin was flushed, livid, and cleaved with small blisters and open sores. The patients burned with fever and then extreme that they could not tolerate being covered, choosing rather to go naked. Their desire was to cast themselves into cold water, and many of those who were unsupervised did throw themselves into public cisterns, consumed equally they were past unceasing thirst. Many became delirious.³ In the Black Decease, prolonged bleeding from the nose and vomiting blood was regarded as a fatal prognostic.¹ Some of the primeval signs were blisters (the "blains") or carbuncles on the skin and these were followed by the buboes. Gui de Chauliac, physician to the Papal Court at Avignon during the Blackness Death, saw clearly that the buboes were by no means an invariable symptom and that the mortality was of two types. I died from the get-go in 3 days. The second presented with apostumes and carbuncles on the external parts, principally on the armpits and groin and, from this, the victim died in v days.² But the well-nigh feared signs were the haemorrhagic spots (God'southward tokens), which varied in size and colour and could occur anywhere, although the neck, breast, back, and thighs were the nearly common site. Necropsies showed general necrosis of the internal organs.

WHY YERSINIA PESTIS WAS Non RESPONSIBLE FOR THE PLAGUES OF EUROPE

The following is a brief summary of the evidence:

1. There were 2 accurate plague epidemics in Iceland in the 15th century that persisted through the freezing conditions of winter.¹² No rats were present on the isle and the weather were inimical for flea activity.³

2. The brown rat (Rattus norwegicus) did not arrive in Europe until sixty years after the plagues had disappeared.³ The black rat (Rattus rattus) was absent in rural England^xiii; no rat species were available to spread the illness throughout the country.

3. There are no resistant rodents present in Europe (and never were), which are essential for the establishment of focus of bubonic plague.^{3, x}

4. The plagues were confined to Europe where the CCR5-Δ32 mutation is at present plant, whereas bubonic plague, which was not a serious disease until the late 19th century, was bars to Asia where CCR5-Δ32 is absent^{4, xiv} (see below).

5. The case mortality in haemorrhagic plague was 100% and the total mortality recorded in an epidemic was very much greater (ordinarily at to the lowest degree 10-fold) than that in an outbreak of bubonic plague: humans tin can be infected with Yersinia pestis without suffering from the disease and there are clinical forms (pestis minor) where in that location is no danger of dying. In victims who present with fever and the bubo, between 30% and 50% die if not treated.¹⁰ This level of mortality is insufficient to force up the CCR5-Δ32 mutation to present twenty-four hour period levels.¹⁵

6. Flea reproduction was impossible in the climatic conditions of northern Europe.³

7. The Black Death spread remarkably rapidly—from Sicily to the Chill Circle in less than three years and covered vast areas of Europe. Many of the subsequent epidemics jumped over 300 km. This is in complete dissimilarity with an epidemic of bubonic plague that moves very slowly^{4, 14}; the black rat has a dwelling house range of 100 metres and rarely strays outside it.¹⁶

8. The bacterium Yersinia does not utilize the CCR5 receptor.¹⁷

9. The 40 twenty-four hour period quarantine for the plague was rigorously established and completely successful for 300 years. It corresponds with the long incubation flow that has been established for the plagues of Europe.⁴ Quarantine measures are not applicable to bubonic plague.^{four, 14}

10. The plagues were recognised as a directly infectious affliction and it was established that information technology was not prophylactic to come inside four metres of an infected person.⁴

11. Both normal and CCR5 scarce mice accept been infected with Yersinia pestis only there were no differences betwixt the two groups in either bacterial growth or survival time.¹⁷

12. The report that DNA specific for Y pestis was amplified from 16th and 18th century human teeth believed to be from French plague victims¹⁸ and 14th century French Blackness Death victims¹⁹ has not been confirmed and the results accept been ascribed to contamination.^xx

PROFILE OF AN EPIDEMIC OF HAEMORRHAGIC PLAGUE

A full scale plague epidemic developed only in a town in a higher place a sure minimum size. Bloodshed was low in villages. Figure 2 illustrates the profile of a typical epidemic that began in the spring. Information technology follows the pattern of a person to person infection, only is characterised by its slow generation and its long elapsing of eight or 9 months. The epidemic falls into iii stages:

1. Rising. Bloodshed rises exponentially, dependent on the transmission rate. Once the epidemic has killed a proportion of the population, the manual charge per unit starts to fall and, concomitantly, the mortality charge per unit decreases because there are fewer susceptibles around to infect.

2. Plateau. When the manual rate  = i, the mortality charge per unit remains static.

3. Decaying. In one case the pool of remaining susceptibles is depleted beneath a critical level, the transmission rate falls to <one and, inevitably, the epidemic fizzles out.

REED AND FROST MODELLING

The unpublished mathematical model of the epidemics of directly infectious diseases adult past Reed and Frost²¹ may exist summarised equally follows. In a closed population of size N inside which people intermingle fairly uniformly, it is assumed that, in a certain period of time t, every person volition have about the aforementioned number of contacts with other individuals, Thousand. If t is made equal to the serial generation time, the individuals infected during 1 catamenia volition then be infectious during the side by side.

The probability of an adequate contact between any two given individuals during time t will be

and

will be the probability of any given person avoiding adequate contact with whatever other given person during fourth dimension t.

Thus, the population is at any time, t, composed of cases, C_t , and susceptibles, S_t , and the probability of whatsoever given person fugitive contact with whatever of the cases will be q and, with all the C_t cases, volition exist

And the probability of any given person having at least i adequate contact with whatsoever of the cases will exist

In the next time period (t+1), the number of contacts between cases and susceptibles is given by

Reckoner modelling of Reed and Frost dynamics shows that the duration of an epidemic is strongly dependent on the series generation time of the disease.^four The epidemic at Newcastle (fig 2) suggests a long serial generation fourth dimension of 22 days and a low R_o of 3.

These conclusions are illustrated in effigy 3, which shows the results of modelling epidemics of influenza (incubation period  = 2–three days) and a hypothetical plague (incubation menses  = 32 days), with R_o standardised at iii. Due north = 1200.

Determination OF THE CHARACTERISTICS OF THE Affliction

From the Elizabethan menstruum vicars and parish clerks were required to marking the registers of plague burials with a "P" or "Pest". Detailed analysis of some 100 plague epidemics recorded in parish registers, coupled with family reconstitution enabled the tracing of the lines of infection both within and between households and the determination of the vital characteristics of the pathogen^four:

1. An epidemic was oftentimes specifically recorded as being started by a visiting stranger or past a resident returning from a visit to a place where the plague was raging.

2. There was a considerable delay, oft more than 15 days, between the death of the primary case and the first secondary case.

3. Transmission was much easier within, rather than between, households.

4. Transmission was much more difficult in the colder months and probably incommunicable out of doors in the depth of winter.

5. Iv metres was established as a safe distance of separation out of doors.

6. From April to Oct, R_o  = 3 to four, but with a range of 1 to more than twenty, depending on circumstances.

7. The characteristic symptom was the appearance of haemorrhagic spots.

By the following of the lines of infection, especially in the early and late stages of an epidemic, it is possible to make up one's mind the following:

• Latent menses  = 12 days (occasionally 10 days)

• Infectious menstruation before symptoms  = 20–22 days

• Incubation period  = 32 days

• Period of symptoms  = five to half dozen days (range  = 2–15 days). Victim probably less infectious during this time.

• Total infectious period  = 25–27 days

• Total time from point of infection to death  = 37–38 days, in agreement with the 40 day quarantine instituted in the 14th century.

It was the very long incubation flow that, even in the days of very express send, immune travellers and traders to spread the plague widely throughout Europe and beyond the sea to England, Ireland, and Iceland.

RESISTANCE

During the Blackness Death in 1348 at that place was evidence of a few people who were resistant to the disease. For example, a monk who was the sole survivor in a monastic community, having nursed and buried his beau inmates. By the 17th century, inspection of the burials registers of London suggests that the pct of the resident population showing resistance had risen considerably, with the greatest mortality amongst naive immigrant apprentices and maidservants from the provinces.⁴

Current studies in molecular biology throw light on this phenomenon. The transmembrane CCR5 chemokine receptor is used by HIV strains to enter cells of the immune system.^{22– 24} The CCR5-Δ32 deletion prevents the expression of the receptor and provides nearly consummate resistance to HIV-1 infection in homozygous people and partial resistance in the heterozygous state.^{25– 29} The average frequency of the CCR5-Δ32 deletion allele is estimated at 10% in European populations, only is virtually absent among native sub-Sahara African, Asian, and American Indian populations^{25, 29– 31}—that is, the CCR5-Δ32 mutation is plant today simply in the area that was in one case ravaged by plague. The historic period of the CCR5-Δ32 bearing haplotype has been computed to be about 700 years onetime (but with a broad range of 275–1875 years) and it has been suggested that it was driven upwards to the present solar day frequencies of 5% to 15% by a historic, strongly selective event, probably an enormous bloodshed mediated past a widespread epidemic of a pathogen that, like HIV-1, utilised CCR5 for entry into lymphoid cells.³⁰ The Black Decease is an excellent candidate for such a catastrophic result³⁰ just this single pandemic would have raised the frequency of the mutation from the estimated value of 5×10^−v to only, at about, 10^−iv. Rather, we propose that the virus of haemorrhagic plague used the CCR5 receptor as a means of entry and that the continuous epidemics for the post-obit 300 years acted as a strong selection pressure level that drove upward the frequency of the mutation to present 24-hour interval values in Europe of 10⁻¹. Recent inquiry has shown that Yersinia pestis, the bacterium of bubonic plague, cannot enter via the CCR5 receptor.¹⁷

NATURE OF THE PATHOGEN

There is no known disease today that presents with the symptoms of haemorrhagic plague. The studies with the CCR-5 receptor propose that the pathogen was viral and the symptoms and necropsy reports of haemorrhagic plague are closest to those of Ebola and Marburg, specially the necrosis of the internal organs and the haemorrhagic manifestations,³² suggesting that the pathogen may have been a filovirus. "Filoviruses are the prototypical emerging pathogens: they cause a haemorrhagic disease of high instance-fatality associated with explosive outbreaks due to person-to-person manual, have no known treatment, occur unpredictably, and have an unknown reservoir".³² Nosotros suggest, therefore, that the plagues were an emergent haemorrhagic fever, probably caused by a filovirus.

Central references

• Scott S, Duncan CJ. Biological science of plagues. Cambridge: Cambridge University Press, 2001.

• Twigg G. The Black Decease: a biological reappraisal. London: Batsford Academic, 1984.

• Karlsson G. Plague without rats: the case of fifteenth century Iceland. Journal of Medieval History 1996;22:263–84.

• Gilbert MTP, Cuccui J, White West, et al. Absence of Yersinia pestis-specific Dna in human teeth from five European excavations of putative plague victims. Microbiology 2004;150:341–54.

• Libert F, Cochaux P, Beckman G, et al. The delta CCR5 mutation conferring protection against HIV-1 in Caucasian populations has a single and recent origin in Northeastern Europe. Hum Mol Genet 1998;7:399–406.

ORIGINS OF HAEMORRHAGIC PLAGUE

Nosotros advise that haemorrhagic plague first emerged in Federal democratic republic of ethiopia, the cradle of man evolution; information technology is in this area that humans have been in longest association with animals. A number of Arabic sources take traced plague back to at that place and the disease was carried downward the Nile Valley by caravan traffic³³ to Sudan and Egypt and Due north Africa. We can trace desultory epidemics of haemorrhagic plague that occurred widely over the eastern Mediterranean surface area during a very long fourth dimension span, from the primeval writings. Presumably, the plague was agile in the Nile valley, albeit unrecorded, well before these times. Box ane summarises the written show for the historical sequence of epidemics.

Box i Epidemics of haemorrhagic plague in history

1. Haemorrhagic fevers in the Nile valley in Pharaonic Egypt, 1500–1350 bc.

2. Viral haemorrhagic fevers were reported in aboriginal Mesopotamia "If … his epigastrium [has] a piercing pain, blood flows endlessly [from his rima oris], his arms are continually weak, depression continually falls upon him [and] his optics are suffused with claret [it is] 'Hand of Marduk'; he will exist worried and die.' (Mesopotamian diagnostic handbook circa 721–453 bc).³⁶

3. Plague of Athens 430–427 bc. Originated in Ethiopia. The description of the symptoms given by Thucydides correspond closely with those of haemorrhagic plague.^{37, 38}

4. Plague of Justinian advertisement541–ii; continued sporadically until advert700. Originated in Ethiopia. The clarification of the symptoms given by Procopius correspond closely with those of haemorrhagic plague.³⁹

5. Plagues of Islam ad627 to 744.³³

6. Haemorrhagic plague in Asia pocket-size and the Levant (the plague focus), 1345–48.^{2, xl}

7. Haemorrhagic plagues of Europe, 1347–1670.

8. Epidemics of haemorrhagic plague in Denmark and Sweden, 1710–xi.⁴¹

9. Sporadic epidemics in Poland through the 18th century.⁴¹

ORIGIN OF THE CCR5-Δ32 MUTATION

It is generally agreed that nearly, if not all, Δccr5 alleles originate from a single mutation event that is estimated to have taken place either 3500 (400–13 000) or 1400 (375–3675) years agone.³¹ We come across from box 1 that this critical mutation could readily have occurred within this predicted time scale, and grumbling and desultory epidemics during a flow of over 2000 years could have gently forced up the mutation to the estimated frequency of 5×10⁻⁵ by the time of the Black Expiry. Traces of the CCR5-Δ32 mutation have been found in Bronze Age skeletons taken from a cave at Liechenstein dating from 900 bc.³⁴

REFERENCES

1. ↵

   Michael of Piazza. Bibliotheca scriptorium qui res in Sicilia gestas retulere one:562.

2. ↵

   Zeigler P . The Black Decease. Harmondsworth, England: Penguin, 1982.

3. ↵

   Twigg G . The Black Expiry: a biological reappraisal. London: Batsford Academic, 1984.

4. ↵

   Scott Southward, Duncan CJ. Biology of plagues. Cambridge: Cambridge University Printing, 2001.

5. ↵

   Biraben JN. Les Hommes, et la Peste en France et dans les Pays Européens et Méditerranéens. Tome I. La pest dans l'histoire. Paris: Mouton and Ècole des Hautes Ètudes en Sciences Sociales, 1975.

6. ↵

   Defoe D . Diary of a plague year. London: Lowest's Library, 1722.

7. ↵

   Yersin, A-E-J. La peste bubonique á Hong Kong. Annales de l'Institut Pasteur 1894;viii:662–vii.

8. ↵

   Plague Research Commission. The epidemiological observations made by the Commission in Bombay City. Journal of Hygiene 1907;7:724–98.

9. ↵

   Titball RW, Leary SEC. Plague. BMJ 1998;54:625–33.

10. ↵

    Christie AB. Infectious diseases: epidemiology and clinical practice. 3rd ed. Edinburgh: Churchill Livingstone, 1969.

11. ↵

    Gani R, Leach South. Epidemiologic determinants for modelling pneumonic plague outbreaks. Emerging Infectious Diseases 2004;10:608–fourteen.

12. ↵

    Karlsson G . Plague without rats: the case of fifteenth century Iceland. Journal of Medieval History 1996;22:263–84.

13. ↵

    Twigg G . The Black Death: a problem of population-broad infection. Local Population Studies 2003;71:40–52.

14. ↵

    Scott Southward, Duncan CJ. Return of the Blackness Decease. Chichester: Wiley, 2004.

15. ↵

    Galvani AP, Slatkin M. Evaluating plague and smallpox as historical selective pressures for the CCR5-Δ32 HIV-resistance allele. Proc Natl Acad Sci USA 2003;100:15276–9.

16. ↵

    Southern HN, ed. The handbook of British mammals. Oxford: Blackwell Scientific, 1964.

17. ↵

    Mecsas J, Franklin G, Kuziel WA, et al. CCR5 mutation and plague protection. Nature 2004;427:606.

18. ↵

    Drancourt Thou, Aboudharam Grand, Signoli M, et al. Detection of 400-yr-old Yersinia pestis Dna in human dental pulp: an arroyo to the diagnosis of ancient septicaemia. Proc Natl Acad Sci USA 1998;95:12637–twoscore.

19. ↵

    Raoult D, Aboudharam M, Crubezy E, et al. Molecular identification past "suicide PCR" of Yersinia pestis as the agent of medieval black death. Proc Natl Acad Sci USA 2000;97:12800–3.

20. ↵

    Gilbert MTP, Cuccui J, White Due west, et al. Absenteeism of Yersinia pestis-specific DNA in human teeth from five European excavations of putative plague victims. Microbiology 2004;150:341–54.

21. ↵

    Maia J de OC. Some mathematical developments on the epidemic theory formulated by Reed and Frost. Hum Biol 1952;24:167–200.

22. ↵

    Alkhatib G, Combadiere C, Broder CC, et al. CCCKR5: a RANTES, MIP-1α, MIP-1β receptor as a fusion cofactor for macrophage-tropic HIV-ane. Science 1996;272:1955–8.

23. Deng H, Liu R, Ellmeier W, et al. Identification of a major co-receptor for main isolates of HIV-1. Nature 1996;381:661–6.

24. ↵

    Dragic T, Litwin V, Allaway GP, et al. HIV-ane entry into CD4+ cells is mediated past the chemokine receptor CC-CKR5. Nature 1996;381:667–73.

25. ↵

    Dean M, Carrington M, Winkler C, et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Scientific discipline 1996;273:1856–62.

26. Huang Y, Paxton WA, Wolinsky SM, et al. The part of a mutant CCR5 allele in HIV-i transmission and affliction progression. Nat Med 1996;2:1240–3.

27. Michael NL, Chang K, Louie LG, et al. The office of viral phenotype and CCR-5 gene defects in HIV-i transmission and illness progression. Nat Med 1997;iii:338–40.

28. O'Brien T, Winkler C, Dean Chiliad, et al. HIV-1 infection in a man homozygous for CCR5-Δ32. Lancet 1997;349:1219.

29. ↵

    Samson M, Libert F, Doranz BJ, et al. Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-v chemokine receptor gene. Nature 1996;382:722–five.

30. ↵

    Stephens JC, Reich DE, Goldstein DB, et al. Dating the origin of the CCR5-Δ32 AIDS-resistance allele by the coalescence of haplotypes. Am J Hum Genet 1998;62:1507–15.

31. ↵

    Libert F, Cochaux P, Beckman Thousand, et al. The delta CCR5 mutation conferring protection against HIV-1 in Caucasian populations has a unmarried and recent origin in Northeastern Europe. Hum Mol Genet 1998;seven:399–406.

32. ↵

    Khan AS, Sanchez A, Pflieger AK. Filoviral haemorrhagic fevers. Br Med Bull 1998;54:675–92.

33. ↵

    Dols MW. The Black Death in the Middle Eastward. Princeton: Princeton University Press, 1977.

34. ↵

    Hummel S, Schmidt D, Kremeyer B, et al. Detection of the Δ32ccr5 HIV resistance gene in Bronze Historic period skeletons. International briefing on ancient DNA, Academy of Queensland, Australia, Jul 2004.

35. Panagiotakopulu E . Pharaonic Egypt and the origins of plague. J Biogeogr 2004;31:269–75.

36. ↵

    Coleman M, Scurlock J. Viral hemorrhagic fevers in ancient Mesopotamia. Trop Med Int Health 1997;two:603–half-dozen.

37. ↵

    Folio DL. Thucydides' description of the bully plague. Classical Quarterly 1953;47:97–119.

38. ↵

    Olson PE, Hames CS, Benenson AS, et al. The Thucydides syndrome: Ebola déjà vu (or Ebola reemergent?). Emerging Infectious Diseases 1996;2:155–6.

39. ↵

    Russell JC. That earlier plague. Demography 1968;5:174–84.

40. ↵

    Wheelis M . Biological warfare at the 1346 siege of Caffa. Emerging Infectious Diseases 2002;8:971–5.

41. ↵

    Christensen P . "In these perilous times": plague and plague policies in Early on Modern Denmark. Med Hist 2003;47:413–50.

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