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The classics never get old: Why are scientists studying plague in the 21st century?

The mere mention of plague usually evokes the imagery of medieval villages ravaged by the disease, piles of corpses accumulating day after day on the streets, thousands of people abandoning their hometowns to escape this “divine punishment”, dubious treatments administered by doctors wearing beak-like masks… But what if I told you that plague still continues to claim victims almost every year to this day?


One should never rush to conclusions, especially without proper statistical analysis. But let me make an exception this time. If I were to bring up that my PhD research topic was plague, 99,9% of my interlocutors would answer “I thought that it only existed during the Middle Ages”, or something of the sort. This is not only the case when discussing with non-biologists, but also when chatting with scientists; in fact, I had a similar thought when I first came across the lab where I would later end up carrying out my doctoral research.

Plague is an extremely virulent infectious disease caused by a species of bacteria known as Yersinia pestis, which has been responsible for three major historic pandemics. Although the infamous Black Death during the 14th century is known by virtually anyone, the current status of this potentially fatal disease is hidden to most. Some people rightly point out that they don’t remember having heard about any recent plague cases on the news; a few others are aware of the existence of some plague vaccines back in the days. It is at this moment that I usually get the incredibly frequent question, i.e., “Why should scientists continue studying plague?”. To answer this fundamental question, I decided to split the issue “into as many parts as possible, and as many as were required to solve them in the best way”, as the good old Descartes suggested almost 400 years ago.

Are there cases of plague now?

Yes. The outbreak of more than 2,000 cases that took place in Madagascar in 2017 is indeed a powerful reminder that plague is not eradicated (1). Together with the Democratic Republic of the Congo, Madagascar reports the highest number of annual cases worldwide (the annual incidence is about 200 to 700 cases per year) whereas in other endemic countries, these remain rather sporadic (2). Fortunately, despite being one the deadliest diseases known to man, not all cases end with the patient’s death. This is explained by the fact that the recommended antibiotic treatment is usually effective against Y. pestis.

Given that the incidence is rather low compared to other infectious diseases, will plague someday be eradicated?

This is very unlikely. The reason for this is that plague is mainly a zoonotic disease; in other words, an infectious disease that can be transmitted from animals to humans. Briefly, the bacterium is maintained in animal reservoirs (the number of reservoir species is estimated to be greater than 300, including many rodents) and transmitted by vectors (around 80 vector species, mostly fleas) (3). When bitten by infected fleas, humans get infected, developing the most frequent form of the disease, i.e., bubonic plague. For some of you, the previous description of the plague cycle in nature might sound familiar. Indeed, it is in the very first pages of Camus’ well-known book “The Plague” that the French writer narrates how thousands of rats were found dead just before plague spread to the inhabitants of the Algerian city of Oran. The role of fleas is also found in the story: people were recommended extreme cleanliness and expected to call the municipal dispensaries if they suspected contact with fleas.

Going back to the question, the vast diversity of species that can serve as animal reservoirs plus the great extent in terms of their geographical distribution (all inhabited continents except Australia) makes it very difficult to imagine that the plague bacillus will completely disappear from the face of the earth in the near future.

But even if plague can’t be eradicated, isn’t it curable with modern antibiotic treatments? Why should we continue plague research in the 21st century?

Let’s begin with a few considerations.


Today, there is no completely safe and effective vaccine for plague available. Although some vaccines do exist, these are not marketed in Europe nor in the United States due to safety concerns, and they only provide short-term immunity.


Fortunately, most Y. pestis strains isolated from clinical cases are sensitive to first antibiotic choices for treatment. Yet, a huge public health concern is that as antibiotic resistance continues to rise, this may no longer be the case in the future. As a matter of fact, in the 1990s two clinical strains of Y. pestis harboring one or multiple antibiotic resistances (including several drugs recommended for therapy and prophylaxis against plague) (4), were independently isolated for the first time. So we cannot exclude the possibility that resistant bacteria can be even more frequent in the near future.


It is important to insist not only on the extreme virulence displayed by the plague bacillus, as mentioned above, but also on the very short time span between the first onset of symptoms and the advanced stages of the disease. This time span is only a few days, and if the treatment is not initiated promptly the progression of the disease may become irreversible (resulting in the death of the patient in 40 to 100% of the cases) (5). Occasionally, plague causes pneumonia and becomes transmittable via aerosols, a twist allowing both higher contagiousness and faster clinical damage leading to even higher mortality. These characteristics pose a major public health problem since the treatment of plague requires a particularly fast and accurate diagnosis, which is sometimes impaired in low-income regions due to a lack of proper infrastructure and medical resources. Apart from the number of victims, plague outbreaks can deeply affect economies – as we observed recently with the Covid-19 pandemic – thus having a negative indirect impact on the rest of the population.


One might think that the risk of contracting plague is only limited to certain regions in the world, and that avoiding them could be enough to prevent the risk of infection. However, the frontiers of the current endemic areas are far from rigid, especially because climate change is reshaping ecosystems, so the possibility of an expansion of the endemic zones can’t be dismissed. Also associated with climate change is an expected increase in the number of climate refugees and a deterioration in housing conditions. Plague is indeed a poverty-related disease since inadequate housing and increased contact with wild rodents increase the probability of infection.


Something that should always be kept in mind as well is that plague could potentially be used as a bioterrorist weapon. This is far from being just a far-fetched story and is in fact well supported by historical evidence (6). In light of this, the plague bacillus is currently classified in many countries, such as the United States and France, as a biological agent that poses a risk to national security.


As Camus phrased it: “The plague bacillus never dies or disappears for good”

This is what I’ve been trying to get across: Plague should remain a disease of the past and for this, we must study it in the present. Although current plague incidence may be considered as rather low, diverse factors (including climate change) could make the number of cases skyrocket. Moreover, even though several effective antibiotics are available today, the rise of multidrug-resistant Y. pestis strains would be a serious problem. But even if this did not occur, there’s still much work to do regarding the development of rapid, accurate detection methods and vaccines. Vaccination would be indeed of particular help in the worst-case scenario of bioterrorism.

Letting plague take us by surprise would be dangerous. Thankfully, some researchers are still on guard against one of mankind’s old, but still vigorous, nemeses.


References


1. Randremanana, R. et al. (2019) Epidemiological characteristics of an urban plague epidemic in Madagascar, August-November, 2017: an outbreak report. Lancet Infect Dis. DOI:https://doi.org/10.1016/S1473-3099(18)30730-8


2. Bertherat, E. (2019) Plague around the world in 2019. Weekly Epidemiological Record. https://apps.who.int/iris/handle/10665/325482


3. Dubyanskiy, V. M. & Yeszhanov, A. B. (2016) Ecology of Yersinia pestis and the epidemiology of plague. Advances in Experimental Medicine and Biology. DOI: 10.1007/978-94-024-0890-4_5


4. Galimand, M. et al. (1997) Multidrug resistance in Yersinia pestis mediated by a transferable plasmid. The New England Journal of Medicine. DOI: 10.1056/NEJM199709043371004


5. Dennis, D. T. et al. (1999) Plague Manual: Epidemiology, Distribution, Surveillance and Control. World Health Organization (WHO).


6. Inglesby T. et al. (2000) Plague as a biological weapon. JAMA. DOI: 10.1001/jama.283.17.2281


This article was specialist edited by Dr. Christian Demeure and copy edited by Dr. Cassandra Koh.


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