Ebola, Dynamin, and the Cordon Sanitaire of Dr. Adrien Proust
2015; Wiley; Volume: 29; Issue: 1 Linguagem: Inglês
10.1096/fj.15-0101ufm
ISSN1530-6860
Autores Tópico(s)Bacillus and Francisella bacterial research
ResumoThe FASEB JournalVolume 29, Issue 1 p. 1-4 EditorialFree Access Ebola, Dynamin, and the Cordon Sanitaire of Dr. Adrien Proust Gerald Weissmann, Gerald Weissmann Editor-in-ChiefSearch for more papers by this author Gerald Weissmann, Gerald Weissmann Editor-in-ChiefSearch for more papers by this author First published: 01 January 2015 https://doi.org/10.1096/fj.15-0101ufmCitations: 1AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Dr. Adrien Proust (1834-1903) Champion of the cordon sanitaire. Photo: Atelier Nadar 1886. Image courtesy of Apic/Getty Images. Blocking traffic at the gate (1885) Sanitation and quarantine to save New York. From Harper's Weekly (Sept. 5, 1885) (28). Image from the History of Medicine (NLM). Cordon sanitaire—we call it a cordon when someone who presents any symptoms of that disease is transferred, if their condition permits, to a hospital or to an equivalent place designated by the local authorities.Dr. Adrien Proust, 1873 (1)We believe [that] these new measures (temperatures and questionnaires at [JFK]) will further protect the health of Americans, understanding that nothing we can do will get us to absolute zero risk until we end the Ebola epidemic in West Africa.Thomas R. Frieden, 2014 (2)Here we report that Ebola cytotoxicity involves a cellular trafficking pathway that is dependent upon dynamin, a GTPase that mediates transport vesicle formation.Sullivan et al., 2005 (3)To our surprise, we found that viral infections are suppressed by bisphosphonates [by] inhibiting the GTPase activity of dynamin-2.Masaike et al., 2010 (4) STOPPING TRAFFIC We have learned from the Ebola outbreak of 2014 that, to stop pandemics, we must regulate the transport of host and virus alike. Public transmission and cellular invasion depend on the unimpeded traffic of people across borders and viruses across cell membranes. Barring the traffic of people across the Atlantic from Liberia would certainly have prevented the first three cases of Ebola in the United States and that blocking the traffic of virus in human cells would have prevented thousands of cases worldwide. The Ebola epidemic in West Africa not only presents a major challenge to our public health system but also to our capacity to develop antiviral drugs. Thanks to cell and molecular biology, we already understand some of the critical pathways of virus entry and replication. We have also learned that these conduits can be blocked by inhibitors of the mechanochemical enzyme dynamin, an intracellular GTPase. Some dynamin inhibitors such as dynasore (sic) are on way to the clinic; newer ones like Dyngo (sic) are coming along (5). To everyone's surprise, bisphosphonates, drugs that are widely used to treat osteoporosis, also inhibit dynamin-dependent viral traffic (4). Thus, we have the tools available: dynamin inhibitors, vaccines, adenosine analogs, inhibitors of RNA dependent-RNA polymerase, etc. (see ref. 6). It is time to launch a major effort-such as those against yellow fever, smallpox, and polio-to bring the benchwork of pharmacology to the bedsides of Liberia. QUARANTINE AND SANITATION If drugs or vaccines have not been developed for a pathogen, there are only two time-tested ways to quell an epidemic: quarantine and sanitation. In the case of Ebola, the first step would be to stop reliance on thermometers and telephones to keep infected victims from transmitting disease. Temperatures quiver, Tylenol is available, and telephones depend on who is asking and who answers. Those protocols did not work in Dallas, Texas in the case of the first victim, Thomas Eric Duncan (7). Also fallible was the U.S. Centers for Disease Control and Prevention's (CDC) policy of voluntary self-monitoring by people exposed to active Ebola victims: ask the many airline passengers between Dallas and Cleveland. The third American Ebola victim, Amber Joy Vinson, received permission for flights between Dallas and Ohio "… because her elevated temperature of 99.5°F was below the no-fly threshold of 100.4°F. " Once it became known that Ms. Vinson had been involved in Mr. Duncan's care, Dr. Frieden of the CDC confessed that "she should not have traveled on a commercial airline"—let alone take a taxi or visit a popular bridal shop (8). In contrast, the quarantine of Mr. Duncan's immediate family seems to have worked. The CDC and White House have presented cogent arguments against a strict ban on flights from Liberia, Guinea, and Sierra Leone, arguing that this would wreck the fragile economies of the area. "Trying to seal off an entire region of the world—if that were even possible—could actually make the situation worse," said President Barack Obama (9). A ban would also curtail the free passage of sanitary supplies and aid workers. Many public health experts agree and warn that the threat of Ebola to the U.S. and Europe will not end until its exponential spread is stopped on the ground (10). They are right to worry: the early kinetics and extent of the 2014 outbreak in West Africa certainly have dwarfed all earlier ones. According to the World Health Organization (WHO), it was the worst ever, with 14,098 confirmed cases and 5160 deaths by November 12 (11). Those kinetics and that extent are the best reasons why a travel ban, with visa restrictions and overseas monitoring, should be in place until the WHO criteria for an end to the outbreak are met. These actions were taken by South Africa on August 24th, Australia on October 28th, the U.S. Army on October 29th, Canada on November 1st, and the Philippines on November 4th (11). That would be the quarantine part of the equation. What about sanitation? Well, I am afraid that all the noble efforts of the Medicins sans Frontieres or U.S. Army engineers are unlikely to produce timely changes in the sanitary culture of West Africa. Among the expected obstacles, they will be faced with unfamiliar, ritual burial practices such as those that sparked earlier Ebola outbreaks. Ebola, which is endemic in African fruit bats, first appeared in 1976 in rural Sudan and the Democratic Republic of the Congo (a.k.a. Zaire) where 284 were infected and 117 had died. By 2000, there were 425 cases and 224 deaths in Uganda. The index case in Uganda was Esther Awete, a villager who had died in her mud hut on September 17, 2000 after several days of fever and pain. Seven of her family members also died after they had ritually bathed Awete's corpse and washed their hands in a communal basin as a sign of communion with the dead (12). Ritual bathing remains common in West Africa today. Three months into the 2014 epidemic, the WHO reported that: "60% of all cases in Guinea were linked to traditional burial practices that involve touching, washing, or kissing the body" (13). Not only in Guinea, thanks to gravesite infection, Ebola remains endemic in the Democratic Republic of the Congo, with 66 cases and 49 deaths reported in 2014. In September 2014, the WHO had called for a 70-70-60 target plan, i.e., isolating 70% of suspected new cases of Ebola, a safe burial of 70% without the risk of infecting others, all within the next 60 days—and no new cases by January 1, 2015 (11)! That is an unanswered call for quarantine AND sanitation. There are other factors in play. Until the 1990s, Ebola afflicted sparsely populated areas of the continent, but in 2014, Ebola ran wild in Monrovia (Liberia), Freetown (Sierre-Leone), and Conakry (Guinea), capitals with populations of over 1 million each. These cities, which retain many areas that lack clean water and adequate sewage, have also suffered from civil war and bloody coups. In Liberia where there are still United Nations peacekeepers (sic), 14 y of civil war killed 200,000 of its citizens and "produced mad generals who led ritual sacrifices of children before going into battle, naked except for shoes and a gun." (14). Sadly, there are also public health problems at the beginning of life. Even before Ebola, the infant mortality rate stood at 69/1000 in Liberia, 73/1000 in Sierra Leone, and 91/1000 in Guinea (versus 6/1000 in the United States) (15). That is why it will be a long time before we can revamp the local sanitary conditions that permit Ebola to spread. Experts insist that, in the big picture, "the most important thing that can be done to protect Americans from Ebola is controlling Ebola in West Africa " (9) I agree but we are not in the big picture, and the virus is a global threat now. NEW YORK AND PARIS Supporters of the original CDC protocols argued that thermometers, questionnaires, and telephones are more humane than the "medieval" solution of official quarantine (10). However, a more rigorous model has been around for a while. Monrovia and Freetown in the 21st century could take lessons from 19th century New York and Paris. It took the better part of that century, but the two capitals overcame 5 lethal epidemics of "Asiatic" cholera despite polluted water, civil war, and urban grunge. In good part, this was attributed to enlightened sanitarians, who came up with solutions such as the Croton reservoir for New York and Baron Haussmann's roadways and sewage systems in Paris (16). However, sanitation alone was not the answer. The measures in New York followed the principles of the French cordon sanitaire; those showing signs of the disease were "taken to a hospital or to an equivalent place designated by the local authorities" (dans quelques hopital ou endroit désignée par les autorités locales pour en tenir lieu) (1). The places designated by local authorities included quarantine ships in the East River near Bellevue Hospital and quarters at Castle Garden, which from 1820 until 1892 was the entry point for immigrants. Inspectors washed its walks and walls with carbolic acid (see illustration by Friedrich Graetz). Ellis Island opened on January 1, 1892, equipped with larger processing hospital and quarantine facilities. That September, in response to the last major cholera outbreak in Europe, President Benjamin Harrison issued the last major quarantine order for New York: "No vessel from any foreign port carrying immigrants shall be admitted to enter any port of the United States until such vessel[s] have undergone quarantine detention of 20 days… " (17). That is Ebola-level timing. A Congressional Act followed, but soon enough when cholera was no longer a threat from overseas, the quarantine order was lifted and never to be used by an American president again. Opponents of quarantines against Ebola in 2014 consider that a visa-based travel ban on people from West Africa has racial overtones. We have heard that before in 1892 when New York was faced with both cholera and an influx of Eastern European Jews. A prominent government official complained to the New York Times that: "Europe is showing no anxiety to keep cholera away from us. Why should the United States accept her miserable paupers anyhow ?In my opinion, the President [should] ask Congress to absolutely prohibit immigration for the present" (18). Some advocates of a travel ban today may indeed have a problem with West African entry. Most of us view it simply as a modern version of the cordon sanitaire, which stopped an epidemic of cholera. DR. ADRIEN PROUST AND SUEZ The champion of the cordon sanitaire was Dr. Adrien Proust (1834–1903), the father of Marcel Proust. Six pandemics of "Asian cholera" ravaged Europe and spread to the United States in the 19th century. The disease, which originated in Bengal (India), reached the West by land and sea, its greatest hurt was wrought at times of civil or imperial war. In France, cholera reached epidemic proportions during periods of political strife in 1830-1845 and during the German siege of Paris in 1870. In 1866, Dr. Proust, chief of the clinic at the Hôpital de la Charité, represented France at an international sanitary conference at Constantinople. European and Ottoman officials mostly agreed that the disease was carried by contaminated water. Friedrich Graetz: Cholera on the bowsprit (18 July, 1883) Puck magazine, New York, NY (17). Sanitary inspectors and carbolic acid defend Castle Garden against cholera. "Water would seem, according to the observations made principally in England by Dr. Snow…to contribute, in certain circumstances, to the development of cholera in a locality" (19). Dr. Proust was referring to Dr. John Snow's take on the Bow Street pump (see cover legend). To map the itineraries of earlier epidemics, Proust trekked to Persia, Mecca, Turkey, and Egypt. Because he was able to trace the origin of each Parisian epidemic to the Orient, Proust pleaded repeatedly that vessels with disease on board be prevented from traversing the newly dug Suez canal. He maintained that: "We must absolutely close the Suez Canal, to all vessels, of whatever nationality, with cholera on board or with recent exposure" (20). It was no surprise that Ferdinand de Lesseps, president of the Suez Canal Company, objected strongly. (Does the airline industry today oppose a flight ban?) At the Academie des Sciences, de Lesseps opposed strict cordons as: "futile and inconsistent with current enlightened opinion, which now held that emanations from local miasma" were responsible for the contagious spread of disease (21). De Lesseps and Company won their argument, and sure enough, the 5th cholera pandemic of 1884 arrived in on ships that had passed through the Canal (21). Eventually, cordons sanitaires were set up as a second line of defense around Toulon and Marseille to prevent the spread of cholera to the rest of France. Cordons around Marseille were so troublesome that the English gentry transferred their winter watering holes to the Cote d'Azure; Cannes, Nice, and Villefranche became the Floridas of the next century (22). The state-enforced cordons sanitaires finally did the trick and saved Toulon and Marseille from the outbreaks of cholera. How about today? A cordon sanitaire in the Fall of 2014 has already prevented Ebola from crossing the borders of a score of African nations, whereas British Airways and Air France have already curtailed flights. Senegal closed its borders and suspended air flights, Nigerian airlines canceled flights after 11 cases of Ebola were tracked to a passenger from Liberia. As of October 22, the WHO declared these two lands free of Ebola (11). Meanwhile, in Dallas, Mr. Duncan's family is free of Ebola after 21 days of enforced quarantine, and the two nurses he infected have recovered after treatment in the most modern isolation units. And as for our safely isolated patient at Bellevue, he's discharged and no one at the hospital caught the disease. That's the sort of good news that a cordon sanitaire can bring. YOU HEARD IT HERE FIRST There is also good news from the laboratory—basic science works. Dynamin was discovered in 1989 by Howard Shpetner and Richard Vallee, then at the Worcester Foundation (now University of Massachusetts Medical School, Worcester, MA, USA) as a mechanochemical enzyme responsible for microtubule sliding in vivo (23). They soon found that it was a GTPase enzyme and that the hunt was on to connect dynamin to discrete cellular functions. Given that large and small GTPases regulate fission, fusion, and other cell properties and because regulator molecules are often regulated by other regulators (24), it soon became probable that cell/ virus interactions could be modulated by dynamin, rippling along a large/small GTPase cascade. Sure enough, dynamin seems to act not only as a regulatory GTPase in the early stages of clathrin-mediated endocytosis but also as a mechanochemical enzyme to promote pinching of macroendocytic vesicles from the cell membrane: the open door to Ebola virus (25). From the bench, we have moved closer to the clinic; dynamin inhibitors such as dynasore have already shown efficacy in early in vivo studies (26), whereas the newest dynamin inhibitors, the bisphosphonates, may already be on many a woman's medicine shelf. Masaike et al. (4) offer the hopeful claim that: "since certain bisphosphonates block endocytosis of adenovirus and a model substrate by inhibiting GTPase activity of dynamin-2… this study offers potential novel use for these drugs." That sure sounds like a prod for a timely test in the clinic. "Who would have thunk it?"—to quote Mary McCarthy (27). The opinions expressed in editorials, essays, letters to the editor, and other articles comprising the Up Front section are those of the authors and do not necessarily reflect the opinions of FASEB or its constituent societies. The FASEB Journal welcomes all points of view and many voices. We look forward to hearing these in the form of op-ed pieces and/or letters from its readers addressed to [email protected] REFERENCES 1Proust, A. (1873) Essai sur l'hygiène internationale, ses applications contre la peste, la fièvre jaune et le choléra asiatique (avec une carte indiquant la marche des épidémies de cholera [in French] ( G. Masson, ed.), p. 52, Paris 2Frieden, T. R. (2014) Enhanced Ebola Screening to Start at Five U.S. Airports and New Tracking Program for all People Entering U.S. from Ebola-affected Countries. CDC Press Release. Centers for Disease Control and Prevention. 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(2011) Ebola virus enters host cells by macropinocytosis and clathrin-mediated endocytosis. J. Infect. Dis. 204(Suppl 3), S957– S967 26Macia, E., Ehrlich, M., Massol, R., Boucrot, E., Brunner, C., and Kirchhausen, T. (2006) Dynasore, a cell-permeable inhibitor of dynamin. Dev. Cell 10, 839– 850 27McCarthy, M. (1963) The Group, p. 6, Harcourt, Brace & World, New York 28Burns, M. J., Monks, J. A. J., and Graham, C. (September 5, 1985) Harper's Weekly, Vol. 29, p. 592, Harper Brothers, New York Citing Literature Volume29, Issue1January 2015Pages 1-4 ReferencesRelatedInformation
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