Key Milestones in the History of Yellow Fever (Bryan et al., 2004) [18]
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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"41734",title:"Yellow Fever Encephalitis: An Emerging and Resurging Global Public Health Threat in a Changing Environment",doi:"10.5772/52244",slug:"yellow-fever-encephalitis-an-emerging-and-resurging-global-public-health-threat-in-a-changing-enviro",body:'Emergence and re-surgence of vector-borne diseases still constitute an important threat to human health in the 21st century, causing over a million death and considerable mortality and morbidity worldwide. Vector-borne diseases are linked to the environment by the ecology of the vectors and of their hosts, including humans. In the recent decades, climate change is a global phenomenon which has greatly influenced the emergence and resurgence of several infectious diseases such as malaria, dengue fever, plague, filariasis, trypanosomiasis, leishmaniasis and arbo-viral diseases, particularly yellow fever. Indeed, arbo-viruses will represent a threat for the coming century too. The resource constrained developing countries are the foremost sufferer and the major victims of several vector-borne diseases [1], including yellow fever.
Yellow fever (YF) is one of the great infectious scourges of humankind. It is a zoonosis indigenous to some tropical regions of South America and Africa which has caused numerous epidemics with high mortality rates throughout history [2]. Approximately 200,000 cases of YF occur annually, resulting in about 30 000 deaths; 90% of cases occur in Africa. Large epidemics, with over 100,000 cases, have been recorded repeatedly in Sub-Saharan Africa, and multiple outbreaks have occurred in the Americas. The virus has never appeared in Asia or in the Indian subcontinent [3].
YFV is endemically transmitted in forests and savannas of South America and Africa, periodically emerging from enzootic cycles to cause epidemics of hemorrhagic fever [2],with reported fatality rates ranging from 20% to 80% due to two principal syndromes: YEL-AND (yellow-fever associated neurologic disease, which includes encephalitis, myelitis or myelo-encephalitis [ADEM]), and YEL-AVD (yellow-fever associated viscerotropic disease, which usually involves multi-organ failure including liver, renal and circulatory failure) [4].
Although YF has undoubtedly been endemic in tropical Africa for thousands of years, it was only after the arrival of the European migrants in the New World at the end of the fifteenth century that this scourge emerged in the form of devastating epidemics. The term ‘vomitonegro’ was used in those days to describe clinical aspects of this pathological condition, because death was frequently preceded by black vomit or by partially digested blood. Other terms used to designate yellow fever included ‘Yellow Jack’ and ‘Safran scourge,’ with reference to the jaundice observed in many patients [5].
Griffin Hughes was the first to use the term “yellow fever” to describe the disease in his book in 1750 [6]. At different stages of human development, YF has caused untold hardship and indescribable misery among different populations in the Americas, Europe, and Africa. Hundreds of thousands of people have been affected by the disease throughout ages among which tens of thousands have died. YF brought economic disaster in its wake, constituting a stumbling block to development too [7].
YF is known for bringing on a characteristic yellow tinge to the eyes and skin, and for the terrible “black vomit” caused by bleeding into the stomach [8,9]. It was one of the most feared lethal diseases before the development of effective vaccine. Today the disease still affects as many as 200,000 persons annually in the tropical regions of Africa and South America, and poses a significant hazard to unvaccinated travellers to these areas [10]. Recent increases in the density and distribution of the urban mosquito vector, Ae. aegypti, as well as the rise in air travel has increased the risk of introduction and spread of yellow fever to North and Central America, the Caribbean and Asia [10].
In East Africa, yellow fever remains as a disease of increasing epidemic risk. The most recent yellow fever outbreak in the region was reported by the WHO in the late 2010 and included the first human cases reported in Uganda in almost 50 years [11]. Prior to this, outbreaks occurred in Sudan (2003 and 2005) and were the first reports of yellow fever from that country in approximately 50 years. These events were preceded by the first outbreak ever reported in Kenya (1992–1993), which were the first reported human cases in East Africa for close to 25 years [11].
Over the last 20 years the number of yellow fever epidemics has risen and more countries are reporting cases. Mosquito numbers and habitats are increasing. Nevertheless, in both Africa and the Americas, there is a large susceptible, unvaccinated population. Changes in the world\'s environment, such as deforestation and urbanization, have increased contact with the mosquito/virus. Widespread international travel plays an important role in spreading the disease. The priorities are vaccination of exposed populations, improved surveillance and epidemic preparedness [12]. During the 20th century yellow fever has reemerged as a cause of human suffering. The recent epidemics are clearly indicating the vulnerability and potentiality of the YF as a global public health threat in the changing environment. In this context, the present chapter becomes more significant and pertains.
The virus is endemic in tropical areas of Africa and Latin America, with a combined population of over 900 million people [13]. During the past decade, official reports of YF incidence (50-120 cases a year from South America and 200–1200 cases a year from Africa) probably underestimate the true number of cases. Many cases of jaundice and fever (a surveillance definition of yellow fever) are not assessed, unexplained deaths go unreported, symptoms suggest alternative diagnoses, and, in some countries, surveillance systems for yellow fever are not in place [14]. The case-fatality rate ranges from 20% to 50% and is partly dependent on case recognition and testing practices [15,16]. The continued presence and epidemic potential of yellow fever virus make it a global health threat. The growth of international travel to endemic areas annually has increased the number of travelers potentially exposed to the virus and consequently it has increased the risk of introduction into other new areas where competent vectors are present [10].
The cause of YF was unknown, but it was thought to be contracted either by coming into contact with “effluvia” from those stricken by the disease or with fomites such as clothing, sheets, and other articles that patients had used. Fear of contracting the contagion led people to shun their neighbours and friends and even to abandon loved ones. “It just tore society apart” [17]. Known today to be spread by infected mosquitoes, yellow fever was long believed to be a miasmatic disease originating from rotten vegetable matter and other putrefying filth, and most believed the fever to be contagious. There were many debates regarding the agent that caused YF and Carlos Findlay was the first to suggest that mosquitoes transmitted the disease [8,9]. Text box 1 indicates some of the key milestones in the history of YF [18].
The earliest description of yellow fever is found in a Mayan manuscript in 1648, but by genome sequence analysis it appears that yellow fever virus evolved from other mosquito-borne viruses about 3000 years ago [19]. Yellow fever originated in Africa and in the 1500s yellow fever virus was probably introduced into the New World via ships carrying slaves from West Africa. Epidemics soon became common in the coastal communities of South and Central America and along the southern and eastern seaboard of North America as far north as Boston. Between 1668 and 1893, there were more than 135 epidemics in the USA [17]. Large epidemics occurred throughout the 18th and 19th centuries in the Caribbean islands, the United States, Africa, Europe, West Indies, and South America.
YF is present in both the rural and urban tropical areas of 45 endemic countries in Africa and Latin America, with a potential combined population of over 900 million individuals [20]. The vast majority of cases and deaths take place in sub-Saharan Africa, where yellow fever is a major public health problem occurring in epidemic patterns. Africa also experiences periodic yet unpredictable outbreaks of urban yellow fever. Thirty-two African countries are now considered at risk of yellow fever, with a total population of 610 million people, among which more than 219 million live in urban settings [21]. The countries in Africa and the Americas to be at the risk of yellow fever is given in text box 2 [22].
\n\t\t\t\tYear\n\t\t\t | \n\t\t\t\n\t\t\t\tDescription of events\n\t\t\t | \n\t\t|
\n\t\t\t\t1648\n\t\t\t | \n\t\t\tAn epidemic of probable yellow fever erupts in the Yucatan Peninsula (Mexico) | \n\t\t|
\n\t\t\t\t1750\n\t\t\t | \n\t\t\tGriffin Hughes was the first to use the term “ yellow fever ” to describe the disease in his book | \n\t\t|
\n\t\t\t\t1793\n\t\t\t | \n\t\t\tAn epidemic in Philadelphia kills about 10% of the population and sparks debate between ‘‘contagionists’’ and ‘‘anti-contagionists.’’ | \n\t\t|
\n\t\t\t\t1802\n\t\t\t | \n\t\t\tStubbinsFfirth, a Philadelphia medical student, begins self-experiments to disprove the theory of contagion. | \n\t\t|
\n\t\t\t\t1854\n\t\t\t | \n\t\t\tLuis Daniel Beauperthuy of Venezuela suggests that a mosquito might transmit yellow fever. | \n\t\t|
\n\t\t\t\t1881\n\t\t\t | \n\t\t\tCarlos J. Finlay of Havana publishes his hypothesis that a specific mosquito (Cubex cubensis now Aedes aegypti) might transmit yellow fever. | \n\t\t|
\n\t\t\t\t1880s \n\t\t\t | \n\t\t\tYellow fever in Panama kills tens of thousands of French workers, causing Ferdinand DeLesseps to abandon his attempt to build a canal across the isthmus. | \n\t\t|
\n\t\t\t\t1901\n\t\t\t | \n\t\t\tThe Reed Commission publishes its definitive proof of the mosquito hypothesis based on the data obtained at Camp Lazear. | \n\t\t|
\n\t\t\t\t1902\n\t\t\t | \n\t\t\tWilliam Crawford Gorgas supervises on the eradication of yellow fever from Havana by controlling Ae. aegypti. | \n\t\t|
\n\t\t\t\t1916\n\t\t\t | \n\t\t\tThe Rockefeller Foundation begins its commitment to eradicate yellow fever. | \n\t\t|
\n\t\t\t\t1925\n\t\t\t | \n\t\t\tThe Rockefeller Foundation opens a laboratory in Yaba, Nigeria, to investigate the etiology of yellow fever. | \n\t\t|
\n\t\t\t\t1927\n\t\t\t | \n\t\t\tThe causative agent of YF disease, YFV, was first isolated from a Ghanaian patient named Asibi | \n\t\t|
\n\t\t\t\t1930\n\t\t\t | \n\t\t\tMax Theiler demonstrates that white mice are susceptible to yellow fever by intracerebral inoculation, which leads to a ‘‘mouse protection test’’ for seroepidemiologic studies and to an effective vaccine. | \n\t\t|
\n\t\t\t\t1933\n\t\t\t | \n\t\t\tFred L. Soper and colleagues report an outbreak of yellow fever in a rural area of Brazil in which Ae. aegypti was not present, suggesting other vectors. | \n\t\t|
\n\t\t\t\t1937\n\t\t\t | \n\t\t\tLarge-scale immunizations with the 17-D yellow fever vaccine are begun. | \n\t\t|
\n\t\t\t\t1940s\n\t\t\t | \n\t\t\tDue to mass vaccination campaigns and efforts to remove Ae. aegypti breeding sites, urban YF was dramatically controlled in Africa, particularly in French speaking West African countries | \n\t\t|
\n\t\t\t\t1951\n\t\t\t | \n\t\t\tTheiler receives the Nobel Prize for his work that led to the discovery of the 17D vaccine. | \n\t\t|
\n\t\t\t\t2002\n\t\t\t | \n\t\t\tThe World Health Organization estimates that yellow fever affects each year up to 200,000 persons with up to 30,000 deaths. | \n\t\t
Key Milestones in the History of Yellow Fever (Bryan et al., 2004) [18]
\n\t\t\t\tAfrica\n\t\t\t | \n\t\t\t\n\t\t |
West Africa | \n\t\t\tBenin, Burkina Faso, Cape Verde, Coˆ te d’Ivoire, Equatorial Guinea, Gambia, Ghana, Guinea, Guinea-Bissau, Liberia, Mali, Mauritania, Niger, Nigeria, Sao Tome and Principe, Senegal, Sierra Leone, Togo | \n\t\t
Central Africa | \n\t\t\tAngola, Burundi, Cameroon, Central African Republic, Chad, Democratic Republic of the Congo, Gabon, Rwanda | \n\t\t
East Africa | \n\t\t\tEthiopia, Kenya, Somalia, Sudan, Tanzania, Uganda | \n\t\t
\n\t\t\t\tAmerica\n\t\t\t | \n\t\t\t\n\t\t |
Central America | \n\t\t\tPanama | \n\t\t
South America | \n\t\t\tArgentina, Bolivia, Brazil, Colombia, Ecuador, Guyana, French Guyana, Paraguay, Peru, Suriname, Trinidad and Tobago, Venezuela | \n\t\t
Countries in Africa and the Americas at the risk of yellow fever
The yellow fever endemic countries in the tropical region of Africa and America are shown in the map (Figure 1) [23]. YF is endemic in ten South and Central American countries and in several Caribbean islands. Bolivia, Brazil, Colombia, Ecuador, and Peru and Venezuela are considered to be at greatest risk. Although the disease usually causes only sporadic cases and small outbreaks, nearly all the major urban centers in the American tropics have been reinfested with Ae. aegypti and most urban dwellers are vulnerable because of the low immunization coverage. Latin America is now at greater risk of urban epidemics than at any time in the past 50 years [21].
Yellow fever endemic countries in the tropical regions of Africa and America
YF has never been reported from Asia, but, should it be accidentally imported, the potential for outbreaks, as the appropriate mosquito vector is present over there [21]. The lack of YFV in Asia is not clearly understood, although a number of hypotheses have been put forward [24]. The mosquito vector Ae. aegypti is prevalent in Asia and Pacific countries and has been important in the rapid emergence of dengue as a major public health problem in the twentieth century [25]. Laboratory studies indicate that Asian strains of Ae. aegypti can transmit YFV but are less competent than strains from the Americas. Demographic factors, including the remote location of sylvatic YF transmission and the cross-protective immunity provided by prior exposure to dengue and other flaviviruses, likely play a role in the lack of YF in Asia [26].
At the beginning of the 20th century, a large number of yellow fever epidemics were recorded in both African and American cities, and these occurred against a background of annual cases. Table 1 and 2 lists an overview on the historical outbreaks in both tropical Africa and America by year and countries. Yellow fever epidemics are re-emerging in Africa and America, and the occurrence of repeated rural outbreaks increases the risk for major urban epidemics. The first disease outbreak that can reliably be regarded as YF was documented in 1648 and occurred in the Yucatan, Mexico and Guadeloupe [27].
\n\t\t\t\tYear\n\t\t\t | \n\t\t\t\n\t\t\t\tCountries\n\t\t\t | \n\t\t\t\n\t\t\t\tName of City\n\t\t\t | \n\t\t\t\n\t\t\t\tCases\n\t\t\t | \n\t\t\t\n\t\t\t\tDeaths\n\t\t\t | \n\t\t
\n\t\t\t\t1668\n\t\t\t | \n\t\t\tUnited States America | \n\t\t\tNew York and Philadelphia | \n\t\t\tNA | \n\t\t\tNA | \n\t\t
\n\t\t\t\t1793\n\t\t\t | \n\t\t\tUnited States America | \n\t\t\tNA | \n\t\t\tNA | \n\t\t\tNA | \n\t\t
\n\t\t\t\tBetween 1668 and 1870 nearly 15 epidemics\n\t\t\t | \n\t\t\tUnited States America | \n\t\t\tNew York | \n\t\t\tNA | \n\t\t\tIn 1798, 1 500 people died | \n\t\t
\n\t\t\t\tbetween 1668 and 1867 30 epidemic in 1793\n\t\t\t | \n\t\t\tUnited States America | \n\t\t\tPhiladelphia | \n\t\t\tNA | \n\t\t\t3500 | \n\t\t
\n\t\t\t\t1793 outbreak\n\t\t\t | \n\t\t\tUnited States America | \n\t\t\tPhiladelphia | \n\t\t\tNA | \n\t\t\t4000 | \n\t\t
\n\t\t\t\t1853\n\t\t\t | \n\t\t\tUnited States America | \n\t\t\tNew Orleans | \n\t\t\tNA | \n\t\t\t7849 | \n\t\t
\n\t\t\t\t1854\n\t\t\t | \n\t\t\tUnited States America | \n\t\t\tCharleston | \n\t\t\tNA | \n\t\t\t682 persons | \n\t\t
\n\t\t\t\t1878\n\t\t\t | \n\t\t\tUnited States America | \n\t\t\tMississippi Valley | \n\t\t\tNA | \n\t\t\t13,000 people | \n\t\t
\n\t\t\t\t1795 outbreak\n\t\t\t | \n\t\t\tWest Indies | \n\t\t\tEuropean troops stationed there | \n\t\t\tNA | \n\t\t\t3 1,000 people died | \n\t\t
\n\t\t\t\t1905\n\t\t\t | \n\t\t\tUnited States America | \n\t\t\tNew Orleans | \n\t\t\t4000 | \n\t\t\t423 | \n\t\t
\n\t\t\t\t1647\n\t\t\t | \n\t\t\t\n\t\t\t | Barbados | \n\t\t\tNA | \n\t\t\t6000 | \n\t\t
\n\t\t\t\t1802\n\t\t\t | \n\t\t\tHaiti | \n\t\t\tNA | \n\t\t\tNA | \n\t\t\t29000 | \n\t\t
\n\t\t\t\t1878\n\t\t\t | \n\t\t\tUnited States America | \n\t\t\tOver 100 American towns | \n\t\t\tNA | \n\t\t\t20000 | \n\t\t
\n\t\t\t\t1942\n\t\t\t | \n\t\t\tBrazil | \n\t\t\tNA | \n\t\t\tNA | \n\t\t\tNA | \n\t\t
\n\t\t\t\t1981-1982\n\t\t\t | \n\t\t\tBolivia | \n\t\t\tNA | \n\t\t\tNA | \n\t\t\tNA | \n\t\t
\n\t\t\t\t2003\n\t\t\t | \n\t\t\tColombia | \n\t\t\tStates of Cesar, Magdalena and La Guajira | \n\t\t\t28 | \n\t\t\t11 | \n\t\t
The history of Yellow fever outbreaks in subtropical regions of America
In the 18th and 19th centuries, YF was a huge public health problem until mosquito control measures and production of an effective vaccine brought the epidemics under control in the 20th century. Yet as we enter the 21st century this virus is once again a significant public health problem [15,26,28] and is classified as a reemerging disease. Urban YF has not been reported from the Americas since 1954, but jungle yellow fever transmitted by Haemagogus vectors increasingly affects forest dwellers in Bolivia, Brazil, Columbia, Ecuador, and Peru, and periodically causes small outbreaks [15, 29,30]. The reinvasion of South America by Ae. aegypti after relaxation of the eradication programme in the 1970s, and presence of Ae. aegypti in cities near areas in which sylvatic yellow fever is endemic, poses a threat of urbanisation of yellow-fever transmission [25,29]. Following several decades of relative calmness, YF reappeared in Africa in the 1980s, endangering populations not only in the so-called endemic countries but in the rest of the world too [31]. The resurgence of YF is also closely connected with changes in the modern world and with the interaction of various economic, climatic, social and political factors [32].
YF has been subjected to partial control for decades, but there are signs that case numbers are now increasing globally, with the risk of local epidemic outbreaks [33]. The agent of YF, yellow fever virus, can cause devastating epidemics of potentially fatal, hemorrhagic disease. We rely on mass vaccination campaigns to prevent and control these outbreaks. However, the risk of major YF epidemics, especially in densely populated, poor urban settings, both in Africa and South America, has greatly increased due to: (1) reinvasion of urban settings by the mosquito vector of YF, Ae. aegypti; (2) rapid urbanization, particularly in parts of Africa, with populations shifting from rural to predominantly urban; and (3) waning immunization coverage. Consequently, YF is considered an emerging, or reemerging disease of considerable importance [22].
\n\t\t\t\tYear\n\t\t\t | \n\t\t\t\n\t\t\t\tCountries\n\t\t\t | \n\t\t\t\n\t\t\t\tNumber of cases\n\t\t\t | \n\t\t\t\n\t\t\t\tYear\n\t\t\t | \n\t\t\t\n\t\t\t\tCountries\n\t\t\t | \n\t\t\t\n\t\t\t\tNumber of cases\n\t\t\t | \n\t\t
\n\t\t\t\t1912\n\t\t\t | \n\t\t\tZaire | \n\t\t\tNA | \n\t\t\t\n\t\t\t\t1994\n\t\t\t | \n\t\t\tGabon | \n\t\t\t28 | \n\t\t
\n\t\t\t\t1917\n\t\t\t | \n\t\t\tZaire | \n\t\t\tNA | \n\t\t\t\n\t\t\t\t1994\n\t\t\t | \n\t\t\tGhana | \n\t\t\t79 | \n\t\t
\n\t\t\t\t1927-1928\n\t\t\t | \n\t\t\tZaire | \n\t\t\tNA | \n\t\t\t\n\t\t\t\t1994\n\t\t\t | \n\t\t\tKenya | \n\t\t\t7 | \n\t\t
\n\t\t\t\t1936\n\t\t\t | \n\t\t\tSudan, Uganda, Kenya | \n\t\t\tNA | \n\t\t\t\n\t\t\t\t1994\n\t\t\t | \n\t\t\tNigeria | \n\t\t\t1227 | \n\t\t
\n\t\t\t\t1940\n\t\t\t | \n\t\t\tSudan, Uganda, Kenya | \n\t\t\tNA | \n\t\t\t\n\t\t\t\t1995\n\t\t\t | \n\t\t\tGabon | \n\t\t\t16 | \n\t\t
\n\t\t\t\t1958\n\t\t\t | \n\t\t\tZaire | \n\t\t\tNA | \n\t\t\t\n\t\t\t\t1995\n\t\t\t | \n\t\t\tLiberia | \n\t\t\t360 | \n\t\t
\n\t\t\t\t1959\n\t\t\t | \n\t\t\tSudan | \n\t\t\tNA | \n\t\t\t\n\t\t\t\t1995\n\t\t\t | \n\t\t\tSenegal | \n\t\t\t79 | \n\t\t
\n\t\t\t\t1960-1962\n\t\t\t | \n\t\t\tEthiopia | \n\t\t\t100,000 | \n\t\t\t\n\t\t\t\t1995\n\t\t\t | \n\t\t\tKenya | \n\t\t\t3 | \n\t\t
\n\t\t\t\t1965\n\t\t\t | \n\t\t\tSenegal | \n\t\t\t20,000 | \n\t\t\t\n\t\t\t\t1995\n\t\t\t | \n\t\t\tSierra Leone | \n\t\t\t1 | \n\t\t
\n\t\t\t\t1966\n\t\t\t | \n\t\t\tEthiopia, Sudan | \n\t\t\t10,000 | \n\t\t\t\n\t\t\t\t1996\n\t\t\t | \n\t\t\tBenin | \n\t\t\t120 | \n\t\t
\n\t\t\t\t1969\n\t\t\t | \n\t\t\tNigeria | \n\t\t\tNA | \n\t\t\t\n\t\t\t\t1996\n\t\t\t | \n\t\t\tGhana | \n\t\t\t27 | \n\t\t
\n\t\t\t\t1971\n\t\t\t | \n\t\t\tAngola | \n\t\t\tNA | \n\t\t\t\n\t\t\t\t1996\n\t\t\t | \n\t\t\tSenegal | \n\t\t\t128 | \n\t\t
\n\t\t\t\t1972\n\t\t\t | \n\t\t\tZaire | \n\t\t\tNA | \n\t\t\t\n\t\t\t\t1997\n\t\t\t | \n\t\t\tBenin | \n\t\t\t18 | \n\t\t
\n\t\t\t\t1978\n\t\t\t | \n\t\t\tGambia | \n\t\t\t8400 | \n\t\t\t\n\t\t\t\t1997\n\t\t\t | \n\t\t\tIvory Coast | \n\t\t\t11 | \n\t\t
\n\t\t\t\t1983\n\t\t\t | \n\t\t\tUpper Volta | \n\t\t\tNA | \n\t\t\t\n\t\t\t\t1997\n\t\t\t | \n\t\t\tGhana | \n\t\t\t6 | \n\t\t
\n\t\t\t\t1988\n\t\t\t | \n\t\t\tAngola | \n\t\t\tNA | \n\t\t\t\n\t\t\t\t1997\n\t\t\t | \n\t\t\tNigeria | \n\t\t\t7 | \n\t\t
\n\t\t\t\t1992-1993\n\t\t\t | \n\t\t\tKenya | \n\t\t\tNA | \n\t\t\t\n\t\t\t\t1997\n\t\t\t | \n\t\t\tLiberia | \n\t\t\t1 | \n\t\t
\n\t\t\t\tEpidemics between 1986 and 1994\n\t\t\t | \n\t\t\tNigeria | \n\t\t\tApproximately 120,000 | \n\t\t\t\n\t\t\t\t1998\n\t\t\t | \n\t\t\tBurkina Faso | \n\t\t\t2 | \n\t\t
\n\t\t\t\t1990\n\t\t\t | \n\t\t\tCameroon | \n\t\t\t20,000 | \n\t\t\t\n\t\t\t\t2000\n\t\t\t | \n\t\t\tNigeria | \n\t\t\t2 | \n\t\t
\n\t\t\t\t1992\n\t\t\t | \n\t\t\tKenya | \n\t\t\tNA | \n\t\t\t\n\t\t\t\t2000\n\t\t\t | \n\t\t\tLiberia | \n\t\t\t102 | \n\t\t
\n\t\t\t\t1993\n\t\t\t | \n\t\t\tGhana | \n\t\t\t39 | \n\t\t\t\n\t\t\t\t2000\n\t\t\t | \n\t\t\tGuinea | \n\t\t\t512 | \n\t\t
\n\t\t\t\t1993\n\t\t\t | \n\t\t\tKenya | \n\t\t\t27 | \n\t\t\t\n\t\t\t\t2001\n\t\t\t | \n\t\t\tIvory Coast | \n\t\t\t203 | \n\t\t
\n\t\t\t\t1993\n\t\t\t | \n\t\t\tNigeria | \n\t\t\t152 | \n\t\t\t\n\t\t\t\t2001\n\t\t\t | \n\t\t\tGuinea | \n\t\t\t18 | \n\t\t
\n\t\t\t\t1994\n\t\t\t | \n\t\t\tCameroon | \n\t\t\t10 | \n\t\t\t\n\t\t\t\t2005\n\t\t\t | \n\t\t\tSudan | \n\t\t\t491 | \n\t\t
The history of Yellow fever outbreaks in the subtropical regions of Africa
It is one of the key determinant in terms emergence and resurgence of many vector-borne diseases particularly YF. With an annual growth rate of nearly 4%, Africa’s cities are the fastest expanding in the world. Not only are more and more people living in the cities but the number of cities is also increasing. Whereas today 62.1% of Africa’s population lives in rural areas, it is predicted that by 2020 this proportion will be reversed, i.e. that 63% of the continent’s population will be urban dwellers. Between now and 2015, it is estimated that the number of cities with more than 1 million inhabitants will increase from 43 to 70 in Africa [34]. On the edge of modern cities, shanty towns with no access to basic sanitation (running water and waste disposal) are also developing rapidly. Domestic water containers and all manner of refuse littering the streets (aluminium and tin cans, old tyres, etc.) favor the multiplication of breeding sites for mosquito larvae [35].
Climate change affects the spread of vector borne diseases both directly and indirectly. Global warming and increased rainfall contribute to the abundance and distribution of vectors like mosquitoes. Current evidence suggests that inter-annual and inter-decadal climate variability have a direct influence on the epidemiology of vector-borne diseases [36]. It is estimated that average global temperatures will have risen by 1.0-3.5oC by 2100 [37], increasing the likelihood of many vector-borne diseases [36]. If the water temperature rises, the larvae take a shorter time to mature [38] and consequently there is a greater capacity to produce more offspring during the transmission period.
The extrinsic incubation period of dengue and yellow fever viruses is also dependent on temperature. Within a wide range of temperature, the warmer the ambient temperature, the shorter the incubation period from the time the mosquito imbibes the infective blood until the mosquito is able to transmit by bite. The implication is that with warmer temperatures not only would there be a wider distribution of Ae. aegypti and faster mosquito metamorphosis, but also the viruses of dengue and yellow fever would have a shorter extrinsic incubation period and thus would cycle more rapidly within the mosquito. A more rapid cycle would increase the speed of epidemic spread [39].
Kelley Lee (2000) [40] has defined globalization as ‘the process of closer interaction of human activity across a range of spheres, including the economic, social, political and cultural, experienced along three dimensions: spatial, temporal and cognitive’. The recent emergence and resurgence of vector-borne diseases are the result of human activities-transportation of goods and people-and will continue with increasing globalization of trade [41]. The increasing phenomenon of globalization has been observed to alter the YF disease pattern.
Every year, about 9 million people from Asia, Europe, and North America travel to countries where yellow fever is endemic; the number of travellers who actually visit areas within these countries where transmission of the virus occurs might exceed 3 million in the coming years [42]. In Africa yellow fever was mainly a problem of the sub-Saharan countries of West Africa, but reached as far east as central Sudan and Kenya [43-46]. A large number of outbreaks were reported in eastern Mexico and other Central American countries. At this time, YF was an epidemic disease mainly of port cities [35].
West Africa is witnessing significant migratory flows owing to rural exodus, movements of religious groups such as the Mourides in Senegal, cross-border movements of seasonal workers and nomadic pastoral communities, trade routes stretching from the Sahel to the coast of the Gulf of Guinea, the phenomenon of new urban dwellers returning regularly to their rural communities of origin, and migration by populations fleeing armed conflicts. These human movements increase the risk of contamination of non-immune persons travelling in areas where contaminated vectors persist and, conversely, favour the introduction of the disease into previously YF free zones [47].
YF outbreaks are common in Africa despite the current knowledge of the disease transmission and the availability of a vaccine. In Africa, YF cases are not uniformly distributed throughout the endemic area; rather, more cases are reported in West Africa compared to East and Central Africa. Genetic differences between genotypes of YF in Africa probably contribute to the observed distribution of YF outbreaks. Genetic and behavioral variation in mosquito vectors may also play a major role in the distribution of YF outbreaks. The other factors also contribute to the epidemiology of YF, including host genetic background, climate, vaccination coverage, vertebrate hosts and movement of vertebrate hosts [48].
Yellow fever virus is transmitted principally by insects (mosquitoes), but ticks (Amblyomma variegatum) may play a secondary and minor role in Africa. It was not until 1901 that yellow fever transmission to humans was associated with the blood-feeding by the Ae. aegypti mosquito (Figure 2), which was a major breakthrough in understanding this dreadful disease. Dispatched to Cuba by the United States government to investigate the cause of YF, Walter Reed and colleagues confirmed that the primary mode of YF transmission to humans was the Ae. aegypti mosquito (Figure 2) and the in ground-breaking virologic studies demonstrated that the disease was caused by an agent that could be filtered from the blood of infected individuals [49]. The reservoirof yellow fever virus is the susceptible vector mosquito species that remains infected throughout its life and can transmit the virus transovarially. Yellow fever can persist as a zoonosis in the tropical areas of Africa and America, with nonhuman primates responsible for maintaining the infection. Man and monkey play the role of amplifiers of the amount of virus available for the infection of mosquitos [50].
Aedes aegypti, the primary disease vector for yellow fever (Photo by Muhammad Mahdi Kharim, published under the GNU free documentation licences)
Ever since the causative agent of YF disease YFV, was first isolated in 1927 from a Ghanaian patient named Asibi [50], the Asibi YFV strain is still widely used by the scientists of today. YFV is the prototype member of the family Flaviviridae(from the Latin flavus, meaning yellow), and genus Flavivirus, which get their name from the Latin word for yellow (flavus). The genome is a single-stranded, positive-sense RNA, 10,500 - 11,000 nucleotides in length. The genus Flavivirus contains approximately 70 viruses, and the major flavivirus diseases are yellow fever (YF), dengue, West Nile, Japanese encephalitis, and tick-borne encephalitis [51]. Unlike other mosquito-borne flaviviruses, YFV has a tropism for the liver and causes a viscerotropic disease whereas many other mosquito-borne flaviviruses have a tropism for the brain, or in the case of the DEN viruses they target cells of reticuloendothelial origin [52].
It was one of the earliest viruses to be identified and linked to human disease. Although substantial variation exists among strains, they can be grouped into monophyletic geographical variants, called topotypes. African isolates are usually grouped into two topotypes, associated with East and West Africa [53,54], although some studies have argued for up to five [55]. Two more have been identified from South America, although one has not been recovered since 1974, suggesting that it may be extinct in the wild. There is no evidence for a difference in virulence between the topotypes [56]. YF activity often occurs in areas after increases in temperature and rainfall that will favor increased biodiversity, including increased numbers of animals and arthropods while reduced rainfall limits mosquito vector density [49]. It has been known for over 50 years that increased temperatures are associated with enhanced transmission of YF virus [56] due to shortened extrinsic incubation period and increased biting by mosquitoes of vertebrate hosts [49].
The virus is maintained in endemic areas of Africa and South America by enzootic transmission between mosquitoes and monkeys, and obviously the epidemiology of the disease reflects the geographical distribution of the mosquito vectors [57].
The enzootic transmission cycle involves tree-hole-breeding mosquitoes such as Aemagogus janthinomys(South America) and Ae. africanus(Africa), and nonhuman primates. Infection of mosquitoes begins after ingestion of blood containing a threshold concentration of virus (~3.5 log 10 ml¯1), resulting in infection of the midgut epithelium. The virus is released from the midgut into the hemolymph and spreads to other tissues, notably the reproductive tract and salivary glands. A period of 7-10 days is required between ingestion of virus and virus secretion in saliva (the extrinsic incubation period), after which the female mosquito is capable of transmitting virus to a susceptible host.
Vertical transmission of virus occurs from the female mosquito to her progeny and from congenitally infected males to females during copulation. Virus in the egg stage provides a mechanism for virus survival over the dry season when adult mosquito activity and horizontal transmission abate. The virus is maintained over the dry season by vertical transmission in mosquitoes. Ova containing virus survive in dry tree-holes and hatch infectious progeny mosquitoes when the rains resume [58].
Yellow Fever Transmision cycles in Africa and South America
In Africa, three transmission cycles can be distinguished: the sylvatic, urban, and savannah cycles. In South America, only sylvatic and urban cycles have been identified (Figure 3). In all the three cycles, yellow fever virus is transmitted between primates by diurnally active tree hole-breeding mosquitoes. Neither the virus nor the clinical disease differs in these three cycles, but identifying the type of transmission cycle is important for disease control. In all of these cycles, endemic and epidemic disease patterns can occur [59]. Sylvatic yellow fever (YF) in South America is maintained in an epizootic cycle between non-human primates and Haemagogus and Sabethes mosquitoes, tree-hole breeding species that reside in the forest canopy. Humans are infected incidentally in the sylvatic cycle when they inhabit or work in the forest where infected mosquitoes are present [60].
In the ‘‘Jungle’’ or ‘‘Sylvatic’’ cycle, the virus is transmitted among monkeys by tree-hole breeding mosquitoes. Humans are infected incidentally when entering the area (e.g., to work as foresters) and have what is termed ‘‘jungle yellow fever’’. The main vector in Africa is Aedes africanus, while in South America it is Haemagogus species. Other mosquito species involved in transmission include Ae. africanus, Ae. furcifer, Ae. vittatus, Ae. luteocephalus, Ae. opok, Ae. metallicus, and Ae. simpsoni in Africa, and Sabetheschloropterus in South America. The primate species acting as vertebrate hosts of the virus also differ by geographic area.
The ‘‘Urban’’ cycle involves transmission of YF virus between humans by Ae. aegypti, a domestic vector that breeds close to human habitation in water, and scrap containers including used tires in urban areas or dry savannah areas. In this situation, the disease is known as ‘‘urban yellow fever’’ [49]. YF is transmitted in urban cycles between humans and the container-breeding, anthropophilic mosquito Aedes aegypti [15]. In Africa, a third cycle is recognized, the intermediate or savannah cycle, where humans in the moist savannah regions come into contact with the jungle cycle. This has been referred to as the ‘‘Zone of Emergence.’’ Although YF is considered to be a mosquito-borne disease, Amblyommavariegatum ticks have been shown to be naturally infected with the virus in central Africa [61]. The significance of this observation in the ecology of YF virus has yet to be determined.
Urban cycle epidemics develop from anthroponotic, also known as human-to-human, transmission in which humans serve as the sole host reservoir of the peridomestic Ae. aegypti mosquito vector. Urban epidemics occur when anicteric but viremic persons who are not yet severely ill, travel from jungles and savannas to cities where they infect local Ae. aegypti mosquitoes, a species that is abundant in urban areas and in areas where humans store water. When YF is identified in any setting, the likelihood that it resulted from human-to-human transmission or its possible introduction into an urban setting must be rapidly assessed to determine the need for emergency vaccination [62]. The intrinsic incubation period in human beings is between two and six days. The extrinsic incubation period in a mosquito varies from four to 18 days (average 12 days), with the temperature and humidity. Once the mosquito becomes infective, it remains so for the rest of its life [63].
YF is the original viral haemorrhagic fever (VHF), a pansystemic viral sepsis with viraemia, fever, prostration, hepatic, renal, and myocardial injury, haemorrhage, shock, and high lethality. Patients with yellow fever suffer with a terrifying and untreatable a clinical disease as yellow fever is responsible for 1000-fold more illness and death than Ebola. Yellow fever stands apart from Ebola and other VHFs in its severity of hepatic injury and the universal appearance of jaundice [10]. It is difficult to distinguish YF\' clinically from many other tropical diseases and often impossible when the condition is mild or atypical. The clinical symptoms associated with the early stages of YF infection are indistinguishable from those of malaria, and where the two diseases coexist, YF should not be ruled out even in the absence of jaundice or the finding of malaria parasites in a blood smear [64,65]. The clinical disease varies from non-specific abortive illness to fatal haemorrhagic fever [66]. Disease onset is typically abrupt, with fever, chills, malaise, headache, lower back pain, generalised myalgia, nausea, and dizziness. On physical examination the patient is febrile and appears acutely ill, with congestion of the conjunctivae and face and a relative bradycardia with respect to the height of fever (Faget’s sign). The average fever is 39o C and lasts for 3.3 days.
Clinical diagnosis of yellow fever is possible when the pathognomonic features of biphasic/triphasic acute illness and typical clinical features occur in unvaccinated individuals with a compatible exposure history. Unfortunately, these features are present only in a minority of patients [67]. Laboratory confirmation of YF is pivotal to diagnosis, but unfortunately requires highly trained laboratory staff with access to specialized equipment and materials.
Laboratory diagnosis of YF is made by detection of either virus or virus antigen or genome (by enzymelinkedimmunosorbent assay (ELISA), polymerase chain reaction (PCR), or inoculation virus into suckling mice, mosquitoes, or cell cultures), or by serology (immunoglobulin M capture ELISA), though cross-reactions with other flaviviruses complicate serologic methods of diagnosis. Postmortem examination of the liver reveals pathognomonic features of YF, including mid-zonal necrosis, and definitive diagnosis can be made by immunohistochemical staining of tissues (liver, heart, kidneys) for yellow fever antigen. It is important to note that liver biopsy should never be used for diagnosis during YF illness because of the risk for fatal hemorrhage at the biopsy site [67].
In the absence of specific therapy, treatment of YF is chiefly supportive. Because most YF cases occur in areas lacking basic hospital facilities and where patients do not have access to modern intensive care. In the early stages of the disease, therapy should focus on controlling the fever and vomiting, relieving the headache and abdominal pains, and correcting the dehydration. During the hepatorenal phase, suitable therapy based on careful patient monitoring should be administered to control the bleeding and manifestations associated with hepatorenal damage. Appropriate treatment to control malaria and secondary bacterial infections should be administered when necessary [64,65].
Because no antiviral treatment exists for the disease, prevention through use of personal protection measures and vaccination is crucial to lower disease risk and mortality [14]. A number of approaches have been taken to control YF. Historically, the development of live vaccines was used to control the disease in Africa, whereas mosquito vector control was used in the Americas. Following the demonstration that YFV is transmitted by Ae. aegypti came the realization that it should be possible to control the disease by controlling mosquito populations [26]. The re-emergence of yellow fever in Africa and South America during the past decade tempers previous optimism that this disease as a public health problem could be eliminated during the twentieth century [15]. Vaccination and eradication of Ae. aegypti are the only effective strategies to reduce YF morbidity and mortality in the affected areas.
Yellow fever vaccine is given for two reasons: to protect travellers visiting areas with the risk of yellow fever virus transmission and to prevent the international spread by minimizing the risk of importation and translocation of the virus by viraemictravellers [14]. Following the successful isolation of YFV in 1927 by American (strain Asibi) and French (strain French viscerotropic virus) workers, researchers placed great effort on the development of vaccines. The development of two live vaccines in the 1930s represents a milestone in the control of the disease. Strain Asibi was passaged through chicken tissue to develop the 17D vaccine strain, whereas strain French viscerotropic virus was passaged through mouse brain to develop the French neurotropic vaccine (FNV). Both vaccines are highly efficacious and they dramatically reduced the number of YF cases in Africa. Unfortunately, the FNV caused cases of postvaccinal neurotropic disease in vaccinees and was discontinued in 1971, whereas 17D is still used today throughout the world [26].
Although immunity from vaccination probably lasts for a lifetime [68,69], a 10 year interval between vaccinations is stipulated in the International Health Regulations (2005) for individuals travelling to countries with a yellow fever vaccination entry requirement. The International Certificate of Vaccination or Prophylaxis is a traveler’s official documentation and it becomes valid 10 days after vaccination and remains so for 10 years [36]. Re-immunization is required every 10 years to maintain a valid international vaccination certificate. The World Health Organization recommends vaccination of children at 9 months old, concomitant with measles vaccination, because of better cost/benefit analysis than campaign vaccinations to control outbreaks [70]. It is recommended that the yellow fever vaccine be administered at 12 months of age. In the case of outbreaks, it can be administered as early as 6 months of age [71]. Yellow fever vaccine is a live vaccine, so theoretically it should not be given to pregnant women or to immunosuppressed individuals. A single fatal adverse reaction (encephalitis) has been reported in an immunosuppressed individual with HIV/AIDS.
Vector control is defined as measures of any kind directed against a vector of disease and intended to limit its ability to transmit the disease [72]. In yellow fever control specifically in certain circumstances, mosquito control is vital until vaccination takes effect.
The risk of yellow fever transmission in urban areas can be reduced by eliminating potential mosquito breeding sites and applying insecticides to water where they develop in their immature stages [13]. Indeed, source reduction is one of the key components in the vector control programme since the target is exceptionally specific unlike adult control [73]. Vector-control strategies that were once successful for elimination of yellow fever from many regions have faltered, leading to reemergence of the disease[3]. Application of spray insecticides to kill adult mosquitoes during urban epidemics, combined with emergency vaccination campaigns, can reduce or halt yellow fever transmission and the "buying time" for vaccinated populations to build immunity [13].
Historically, mosquito control campaigns successfully eliminated Ae. aegypti, the urban yellow fever vector, from most mainland countries of central and South America. However, this mosquito species has re-colonized urban areas in the region and poses a renewed risk of urban yellow fever. Mosquito control programmes targeting wild mosquitoes in forested areas are not practical for preventing jungle (or sylvatic) yellow fever transmission [13]. The period between about 1950 and the 1970s was one of the complacency about the control of YF, probably arising from the feeling that YF vaccination had solved the problem. Ae. aegypti control was reduced and overall disease record keeping appears to have diminished. For the period 1960–2005, only 110 yellow fever points were recorded in Africa and 171 in South America. In both regions, these records more or less fall within the same areas of risk shown for the first half of the last century, although there is a noticeable lack of new records in Central America and proportionately more cases within the Amazon basin [33].
Ae. aegypti, has adapted their peak biting activities in the early evening and early morning, when their potential hosts are less protected. Mosquito repellents have a unique role under these conditions. Easily accessible, safe and effective mosquito repellents provide a valuable supplement to IRS and ITN use, and in areas with day-biting, exophagic vectors, this may be the only option for reducing the level of disease transmission [74]. The core principle of repellents usage is that they are extremely useful and helpful whenever and wherever other personal protection measures are impossible or impracticable [75]. Insect repellents are exceptionally helpful to the travelers, who visit for a short-span of time in the disease endemic areas. The main advantage is that the repellents are relatively cheap, highly effective and can be applied as a short-term measure [76].
A laboratory study was carried out to evaluate the relative efficacy of N-N-diethylm-toluamide (DEET) and N,N-diethyl-phenylacetamide (DEPA)-treated wristbands against three major vector mosquitoes. Overall, both DEET and DEPA have shown various degrees of repellency impact against all three vector mosquitoes. DEPA treated wristbands did not show any significant differences in terms of reduction in human landing rate and the mean complete protection time against An. stephensi and Ae. aegypti were between 1.5 and 2.0 mg/cm2 [77]. A study revealed the repellent efficacy of dimethyl-phthalate (DMP) treated wristband against Ae. aegypti under the laboratory conditions. It is estimated that 74.4 and 86.5% of reduction of man landing rates were obtained against Ae. aegypti at concentrations of 1.5 and 2.0 mg/cm2 respectively [1]. These studies results suggest that repellent-treated fabric strips could serve as a means of potential personal protection expedient to avoid insect’s annoyance and to reduce vector-borne disease transmission.
However, generally synthetic repellents have several limitations, including reduced efficacy owing to sweating, unpleasant odor, relatively expensive and can cause allergic reactions [72]. Plants have been used since ancient times to repel/kill blood-sucking insects in the human history and even now, in many parts of the world, people use plant substances to drive-away the mosquitoes and other blood-sucking insects [78]. Currently repellents of plant origin have been receiving massive attention due to their environmental and user friendly nature [79].
It is unlikely that vector control strategies alone will result in the elimination of yellow fever; such strategies must be combined with effective vaccination programs. Besides, in YF endemic countries, people particularly travelers should take precautions to avoid mosquito bites to reduce the risk of yellow fever. Besides, using insect repellents, people must use permethrin-impregnated clothing, and bed nets and staying in the screened room could be advisable.
YF has played a central role in the history of infectious diseases. It was the first disease to be demonstrated to be transmitted by an arthropod, one of the first diseases to be shown to be caused by a virus, and one of the first infectious agents to be controlled by the development of a live vaccine [80]. Indeed, the challenges and dangers posed by yellow fever remain formidable. It is mainly contributed by the global warming, land use changes, uncontrolled population growth, unchecked urbanization, rural - urban migration, international trade, conflict and civil disruption. Although the tools for diagnosis, vector control, vaccine and surveillance are available, their implementation is extremely poor or inadequate in many of the resource-constrained YF endemic countries. In addition, the global-warming concomitant effect immensely contributed to the high reproduction rate and the capacity of insect vectors to establish and to adapt to new environmental conditions.
Certainly, the present scrutiny clearly suggests that the yellow fever encephalitis is emerging and resurging as a global public health threat in a changing environment. It contributes to remain as a disease of increasing epidemic risk. Therefore, the following issues such as high population density, development of peri-urban areas with rural interfaces, urban construction in forest areas, inconsistent vector control programme, spread of new pathogens, inadequate coverage and short-supply of yellow fever vaccine, must be addressed effectively for the betterment of humankind, eventually to build a yellow fever free world in the near future.
I would like to thank Mrs. Melita Prakash for her sincere assistance in editing the manuscript. My last but not the least heartfelt thanks go to my colleagues of our Department of Environmental Health Science, College Public Health and Medicine, Jimma University, Jimma, Ethiopia, for their kind support and cooperation.
Antibiotic resistance most commonly evolves in bacteria either through mutation of a target site protein, through the acquisition of an antibiotic-resistant gene that confers resistance through efflux or inactivation of the antibiotic, or through synthesis of a new target protein that is insensitive to the antibiotic [1]. An extensive body of knowledge has been gained from studies of antibiotic resistance in human pathogens and in animal agriculture. The ability of bacterial pathogens to acquire antibiotic-resistant genes and to assemble them into blocks of transferable DNA encoding multiple antibiotic-resistant genes has resulted in significant issues that affect successful treatment interventions targeting some specific human infections. The current global antibiotic resistance crisis in bacterial populations has been fuelled by basic processes in microbial ecology and population dynamics, engendering a rapid evolutionary response to the global deployment of antibiotics by humans in the millions of kilograms per year. What was not anticipated when antibiotics were discovered and introduced into clinical medicine is that antibiotic-resistant genes pre-existed in bacterial populations [2, 3, 4]. Furthermore, the extent to which antibiotic-resistant genes could be transferred between bacteria, and even between phylogenetically distinct bacteria, was not understood 70 years ago but is becoming more apparent through a number of elegant studies identifying the microbial antibiotic resistome. The collection of all known antibiotic-resistant genes in the full-microbial pan-genome is defined as the antibiotic resistome [5].
\nEffective management of bacterial plant diseases is difficult and is exacerbated by factors such as the large size of bacterial pathogen populations on susceptible plant hosts and the few available bactericides. In the absence of durable and robust host disease resistance, antibiotics have represented the best option for bacterial disease control in many pathosystems because these materials provide the most efficacious means of reducing bacterial population size and limiting disease outbreaks. Although many new types of antibiotics were rapidly tested and then deployed in animal agriculture starting in the 1950s, antibiotic use for plant disease control was tempered by several factors, including lack of efficacy at lower doses, phytotoxicity problems at higher doses, and expense compared to other existing methods of disease control. Thus, although penicillin, streptomycin, aureomycin, chloramphenicol, and oxytetracycline were tested for plant disease control in the late 1940s [6, 7], only streptomycin and oxytetracycline were ultimately deployed in plant agriculture and only in specific disease pathosystems. Streptomycin is the main antibiotic currently in use for plant disease control around the world, targeting pathogens such as Erwinia amylovora, which causes fire blight of apple and pear; Pseudomonas syringae, which causes flower and fruit infection of apple and pear trees; and Xanthomonas campestris, which causes bacterial spot of tomato and pepper [8]. Oxytetracycline has been used as the primary antibiotic in specific disease control situations, including the control of Xanthomonas arboricola pv. pruni, the causal agent of bacterial spot of peach and nectarine [8]. In addition, oxytetracycline has been used as a secondary antibiotic for fire blight management in the United States, most prominently in situations in which streptomycin resistance has become a problem [9, 10].
\nThe problem of antibiotic resistance is not limited to the Indian subcontinent only, but is a global problem. To date, no known method is available to reverse antibiotic resistance in bacteria. The discovery and development of the antibiotic penicillin during the 1900s gave a certain hope to medical science, but this antibiotic soon became ineffective against most of the susceptible bacteria. The antibiotic resistance in bacteria is generally a natural phenomenon for adaptation to antimicrobial agents. Once bacteria become resistant to some antibiotic, they pass on this characteristic to their progeny through horizontal or vertical transfer. The indiscriminate and irrational use of antibiotics these days has led to the evolution of new resistant strains of bacteria that are somewhat more lethal than the parent strain. More recently, in 2016, a Section 18 emergency exemption was granted by the US Environmental Protection Agency for the use of streptomycin and oxytetracycline on citrus trees in Florida for management of citrus Huanglongbing (HLB) disease [11, 12, 13]. Regarding other antibiotics, gentamicin has been used in Mexico for fire blight control and in Chile, Mexico, and Central American countries for vegetable disease control, while oxolinic acid (OA) has been used only in Israel for fire blight management [14, 15]. Lastly, kasugamycin is used in Japan and other Asian countries to control the fungal disease rice blast and bacterial seedling diseases of rice [16] and has recently been registered for use in the United States and Canada for managing fire blight [17]. Concerns regarding the use of antibiotics in plant disease control and potential impacts on human health have led to the banning of antibiotic use by the European Union. However, streptomycin is still utilized for fire blight management in Austria, Germany, and Switzerland under strict control parameters.
\nThe lack of effective bactericide alternatives in several plant disease systems has resulted in a decade-long dependence or overdependence on streptomycin. As streptomycin has been used the longest, over the largest geographic area, and for treatment of the largest variety of crops, streptomycin resistance is relatively widespread among plant-pathogenic bacteria. Although the first streptomycin-resistant (SmR) plant-pathogenic bacteria detected were strains of E. amylovora harboring a chromosomal resistance mutation, the majority of SmR plant pathogens encode the transmissible SmR transposon Tn5393 [8]. Tn5393 is a Tn3-type transposon originally isolated from E. amylovora that harbors strAB, a tandem resistance gene pair that confers streptomycin resistance through covalent modification of the streptomycin molecule [18]. The Tn5393 transposon is composed of genes required for the transposition process (tnpA and tnpR), a central site that contains outwardly directed promoters for expression of both tnpA and tnpR as well as the strAB SmR genes. Expression of the strAB genes from Tn5393 in E. amylovora is driven by a promoter present in the 3 prime end of the insertion sequence IS1133 that is inserted directly upstream of the strA gene [19]. Two closely related variants of Tn5393 have also been found in plant pathogens: Tn5393a, an element that does not contain IS1133, has been detected in P. syringae and in a group of E. amylovora strains from California exhibiting a moderate level of resistance, and Tn5393b, an element that does not contain IS1133 but instead contains an insertion of IS6100 within the tnpR gene, has been characterized in X. campestris [19, 20].
\nThere are two other reports of additional genetic mechanisms of streptomycin resistance in plant pathogens; these include the occurrence of the small, nonconjugative but mobilizable broad-host-range plasmid RSF1010 in some strains of E. amylovora isolated in California [21]. This observation carries further significance because RSF1010 has been distributed globally among a number of bacterial genera and also occurs in some human-pathogenic bacteria [22]. A recent report detailing an analysis of streptomycin-resistant X. oryzae subsp. oryzae from China indicated that four strains harbored the aadA1 gene associated with class 1 integron sequences [23]. This observation is significant because of the importance of integrons in both the transfer of antibiotic resistance in human and animal pathogens and the accumulation of antibiotic resistance genes within one multiresistance element. To date, streptomycin resistance mediated by Tn5393 or the closely related variants has been reported in E. amylovora, P. syringae, and X. campestris isolated from North and South America and Asia [19, 20, 24, 25, 26, 27, 28, 29, 30]. The location of essentially the same genetic element in different genera of plant pathogens isolated from distinct crop hosts and from different continents is confirmatory evidence of the role of horizontal gene transfer (HGT) in the dissemination of antibiotic resistance in these pathosystems.
\nThe source of Tn5393 to the plant pathogens was likely not from the antibiotic preparations themselves as a study of 18 available agricultural streptomycin formulations revealed no contamination with the strA SmR gene [31]. Instead, the acquisition of Tn5393 by bacterial plant pathogens was likely from commensal co-occurring epiphytic bacteria via HGT. For example, Tn5393 was thought to have been acquired by E. amylovora on the plasmid pEa34 from Pantoea agglomerans, a common orchard epiphyte [18]. The transfer event most likely occurred on the apple flower stigma, a surface where E. amylovora grows to high population densities and where Pantoea agglomerans can also grow. Pseudomonas syringae and X. campestris pv. vesicatoria both have epiphytic phases where the pathogens grow on leaf surfaces, providing opportunities for HGT with other epiphytes. It should be noted that high-level streptomycin resistance, conferred by a spontaneous mutation within the rpsL gene that encodes the ribosomal target protein for streptomycin, does occur in some populations of E. amylovora, particularly within populations from the western United States as well as in a small number of strains isolated in Michigan and New Zealand [32, 33]. The minimal inhibitory concentration (MIC) of streptomycin in these highly resistant spontaneous mutants is greater than 4096 μg/mL [32]. In contrast, SmR strains of E. amylovora harboring Tn5393 exhibit MICs of streptomycin ranging from 512 to 1024 μg/mL [32]. Streptomycin solutions used for fire blight management are typically applied at 100 μg/mL; thus, it is unclear whether the increased level of resistance exhibited by the spontaneous mutants provides a survival advantage in streptomycin-treated orchards.
\nTetracycline resistance has been reported in a few plant-pathogenic bacteria, including P. syringae [34, 35] and Agrobacterium tumefaciens [36]. Other studies have reported on sensitivity; for example, in one study, 138 strains of E. amylovora from the Pacific Northwest, USA, were all determined to be sensitive to oxytetracycline [37]. Although there are few reports of resistance, multiple tetracycline resistance genes homologous to tetA and tetM are present within the genomes of many different plant-pathogenic bacteria. Efflux pump proteins that belong to the same protein family as TetA have been identified in Ralstonia solanacearum; Erwinia piriflorinigrans; multiple Xanthomonas species, including Xanthomonas citri, Xanthomonas phaseoli, Xanthomonas perforans, and X. campestris; multiple Pseudomonas species, including P. syringae, Pseudomonas aeruginosa, and nonpathogenic Pseudomonas putida and Pseudomonas fluorescens. However, even though putative tetracycline-resistant proteins have been annotated in the NCBI database for plant-pathogenic bacteria such as Erwinia, Pseudomonas, Xanthomonas, Agrobacterium, and Ralstonia, their function in tetracycline resistance remains to be characterized.
\nThere are a few reports documenting resistance to other antibiotics used in plant disease management. OA was introduced in 1997 for fire blight management in Israel as a replacement for streptomycin, and OA resistance in E. amylovora was first detected in 1999 [38] and expanded in range by 2001 [39]. However, populations of OA-resistant E. amylovora fluctuated, with OA-resistant strains becoming undetectable in orchards where they previously occurred. Laboratory analyses of OA-resistant strains suggested that these strains were reduced in fitness compared to OA-sensitive strains [40]. Analysis of OA-resistant strains of Burkholderia glumae also showed that the strains were reduced in fitness, as these strains could not survive in rice paddy fields [41]. Kasugamycin was discovered in Japan and has been used since the 1960s in Asia for the control of rice blast caused by the fungus Magnaporthe grisea and for the control of bacterial grain and seedling rots of rice. This antibiotic has also been used to control diseases of sugar beet, kiwi, and Japanese apricot in at least 30 countries [42]. More recently, kasugamycin has been utilized for management of the blossom blight phase of fire blight disease in Canada and the United States. Resistance to kasugamycin was reported for two bacterial rice pathogens in Japan, Acidovorax avenae subsp. avenae and Burkholderia glumae [43, 44]. Kasugamycin resistance in A. avenae subsp. avenae and B. glumae was conferred by a novel aac(2)-IIa acetyltransferase gene located within an IncP genomic island and likely acquired by HGT [45]. A promoter mutation that resulted in a fourfold increase in expression of the aac(2)-IIa gene was found to confer an increased level of kasugamycin resistance in strain 83 of A. avenae subsp. avenae [46]. Kasugamycin resistance has not been reported in E. amylovora; one study assessing the potential for spontaneous resistance revealed that a two-step mutational process was required and that spontaneous kasugamycin resistant mutants were substantially reduced in fitness [17].
\nAll of the antibiotics applied to trees in orchard systems using conventional air blast spraying systems does not reach the desired target; thus, the effects of antibiotic usage are potentially more complex than simply studying effects on the target pathogen and commensals co-located in the target plant habitat. Antibiotics reaching the target sites in the tree canopy impact the phyllosphere microbiome and flower microbiomes if applied during the bloom phase. Insects feeding within the tree canopy could also ingest the antibiotic, which could impact the insect gut microbiota. A portion of the antibiotic spray applied to trees will not reach the target because of spray drift or could be lost by runoff during spraying or runoff owing to rain events. It has been estimated that as much as 44–71% of spray solutions applied by air blast sprayers is lost into the environment [47]. Whether it hits the target or not, once the antibiotic solution has been released into the environment, the material is negatively affected by environmental parameters, including rainfall, sunlight (visible and ultraviolet radiation), and temperature, and other specific aspects of the plant leaf environment that may affect adsorption. For example, oxytetracycline residues are lost relatively rapidly from peach leaf surfaces because of weather parameters [48]. Any antibiotic lost from the tree target by spray drift may land on other plant surfaces, such as the leaves of grasses or weeds, and thus impact the microbes inhabiting the phyllosphere of those plants. There is also the possibility of drift offsite to nontarget plants, and insect or animal may feed on the nontarget plants and potentially consume the antibiotic, which could impact the gut microflora of these animals. We are aware of one study in which the percentage of streptomycin-resistant E. coli isolates from feces of sheep feeding in a pasture that was sprayed with streptomycin was shown to increase (from 14.7 to 39.9% compared to 15.8 to 22.3% in a control group) [49]. However, this study did not simulate actual conditions in commercial orchards as the streptomycin solution was sprayed directly onto the pasture grass and sheep were grazed in the pasture for 12 h immediately following application. Neither of these situations occurs in commercial orchards.
\nTwo studies have been published examining the effect of antibiotic application in apple orchards on phyllosphere bacteria. In one study using both culture-based and culture-independent approaches, Yashiro and McManus [50] examined phyllosphere bacteria from apple orchards that either had received streptomycin applications in spring for fire blight management for up to 10 previous years or had not been sprayed. The percentage of culturable isolate resistant to streptomycin was actually larger from the non-sprayed orchards. An examination of community structure using 16S rRNA clone libraries indicated that streptomycin treatment did not have long-term effects on the diversity or phylogenetic composition of the phyllosphere bacterial community in the examined apple orchards [50]. A separate cultural study evaluated the effect of weekly applications of streptomycin (for 0, 3, 5, and 10 weeks) beginning at 80% bloom on specific components of the phyllosphere community. Testing of orchard epiphytes for streptomycin resistance indicated that 76.2, 94.5, 95.5, and 98.5% of the bacterial isolates were resistant to streptomycin on trees receiving 0, 3, 5, and 10 applications within one season, respectively [51]. Further microbiome studies have also been conducted examining the effect of antibiotic usage on soil microbiomes in apple orchards. For example, Shade et al. [52] determined that streptomycin application to apple trees did not result in any observable difference in soil bacterial communities (soil collected beneath trees 8–9 days after streptomycin application). The authors concluded that application of the antibiotic had minimal impact on nontarget bacterial communities [52]. A second microbiome study of apple orchard soil collected 14 days after streptomycin application also failed to detect any influence of the antibiotic on the soil bacterial community [53].
\nThe microbiome studies detailed above have provided information that show limited impacts of antibiotics on the selection of antibiotic resistance at a period of time after application. However, there are no published studies to date assessing the resistome of crop plants and in particular the resistome of crop plants that have been treated with antibiotics. Interestingly, the application of struvite (MgNH4PO4·6H2O), which has been used as a plant fertilizer, alters the antibiotic resistome in the soil, rhizosphere, and phyllosphere [54]. This might have resulted from the fact that struvite usually contains ARGs, antibiotic-resistant bacteria, and antibiotic residues [50]. The need for knowledge of the antibiotic resistome in plant agricultural systems and especially in plant agricultural systems in which antibiotics are applied is critically important because we need to understand whether the use of antibiotics in plant agriculture has the potential to select ARGs that could impact human health. This issue regarding potential impacts to human health is highly significant, with current implications for the use of antibiotics in animal agriculture [55, 56]. Identification of particular ARGs, and the organisms harboring these genes, is important for risk assessments of pathogen acquisition of resistance based on close phylogenetic relationships with coinhabiting antibiotic-resistant commensals. If ARGs of importance in clinical medicine are identified in the resistome of plants sprayed with antibiotics, it is critical to determine whether their frequency and/or bacterial host range changes based on antibiotic exposure.
\nOne of the gaps involved in the understanding of the host-plant-environment interaction is the attributes involved with respect to the change in climatic conditions. Changes brought about by the pathogen populations to the host are influenced by cultural practices, control methods, introduction of new cultivars or varieties, and climatic variability in equal measure. A majority of these studies are often hindered due to the difficulty in obtaining the information or evidence with respect to the presence of the pathogen throughout the said period, genetic composition and its associated changes before and after interaction with the host, climatic requirements for the host and pathogen during the said period and arrive at a convincing trend without background noise with respect to the disease pattern.
\nSimilar to the pathogen-human interaction, the challenge and attack by pathogenic organisms are halted by the defense mechanisms of the plants. This mechanism is often trespassed by the evolution and emergence of newly faced pathogens that have evolved in response to evolution or agricultural practices and colonization strategies in native communities with no prior evolutionary history [57, 58, 59]. It is well-known that the ecosystem, frequency, and evolution of both host and pathogens are largely dependent on catastrophic outbreaks that have a direct involvement of the human population. Added to this is the development of a new species, migration of humans, speciation, susceptibility of the plants, divergence, and climate change [58]. With a positive association between the emergence of new pathogens and extinction of crop production being rendered by many researchers, understanding and identification of emerging pathogens is a necessary strategy to counter them [60, 61].
\nUnderstanding the emergence of new pathogens has largely been a challenge for scientists as the host-pathogen interaction is a complex process. Global distribution and diversity of plant pathogens is also dependent on trade, human migration, plant ecosystem, and distribution of plant-based products. An additional indirect way to gauge pathogens and their associated effects is the elucidation of migration pathways [62]. The ever-increasing investment by the researchers in analyzing genome sequences has revealed another world of improvement in understanding the adaptability of pathogens to plant disease [63, 64, 65], and any changes in pattern of pathogenicity may thus arise. Horizontal gene transfer and interspecific hybridization have been the two mechanisms that have been comprehensively reviewed [58, 63, 66, 67, 68, 69]. Along with strategies such as population genomics study for development of improved disease management, awareness of agricultural heterogeneity and management or restriction of movement of plant materials aids have also been integrated. Further a cumulative effort by plant epidemiologists, ecologists, pathologists, and academic researchers facilitates successful management of emerging phytopathogens.
\nIn addition to a plethora of published GE strategies, ongoing research, and the wide expansion of genetic resources, conceivable applications are gaining momentum [70] that invests prospective for future generations. The dynamics of the adaptation of pathogen toward the host can be invested by GE strategies due to its selective efficacy against a group or particular target pathogens. Such a targeted advantage minimizes health concerns at the consumers’ end with no risk of nontarget biota in an agrarian ecosystem. Some of the processes that occur naturally have also been undertaken in GE processes (Table 1). Although the futuristic potential of GE strategies with controlled disease conditions in the subsequent host generations is questionable in the present day, it is demonstrated that GE strategies that were initiated as a proof of concept are now well-established and have been marketed as commercially viable varieties.
\nPlant species | \nDisease | \nPathogen species | \nPathogen class | \nGene product | \nReference | \n
---|---|---|---|---|---|
Arabidopsis | \nCrown gall disease | \n\nAgrobacterium tumefaciens\n | \nBacteria | \nArabinogalactan protein | \n[78, 79] | \n
Crown gall disease | \n\nAgrobacterium tumefaciens\n | \nBacteria | \nMannan synthase | \n||
Root-knot nematode | \n\nMeloidogyne incognita\n | \nNematode | \nKelch repeat protein | \n[80, 81] | \n|
Powdery mildew | \n\nErysiphe orontii\n | \nFungus | \nReceptor-like kinase | \n[82] | \n|
Root-cyst nematode | \n\nHeterodera schachtii\n | \nNematode | \nEthylene response | \n[83, 84] | \n|
Bacterial speck | \n\nPseudomonas syringae\n | \nBiotrophic bacteria | \nLectin receptor kinase | \n[22] | \n|
Gray mold/rot; leaf spot | \n\nAlternaria brassicicola; Botrytis cinerea\n | \nNecrotropic fungus | \nExpansin | \n[85] | \n|
Powdery mildew | \n\nGolovinomyces orontii\n | \nBiotrophic fungus | \nMembrane-attached protein | \n[86] | \n|
Downy Mildew | \n\nHyaloperonospora arabidopsidis\n | \nBiotrophic oomycete | \nADP ribosylation factor—GTPase activating factor | \n[87] | \n|
Bacterial wilt | \n\nRalstonia solanacearum\n | \nBiotrophic bacteria | \nMAPkinase phosphatase | \n[88] | \n|
Aphid | \n\nMyzus persicae\n | \nInsects | \nFatty acid desaturase | \n[89] | \n|
Maize | \nSouthern corn leaf blight | \n\nBipolaris maydis/Cochliobolus heterostrophus\n | \nNecrotrophic fungus | \nMitochondrial transmembrane protein | \n[90] | \n
Powdery mildew | \n\nBlumeria graminis\n | \nBiotrophic fungus | \nLong-chain aldehyde synthesis | \n[91] | \n|
Tomato | \nGray mold/rot | \n\nBotrytis cinerea\n | \nNecrotrophic fungus | \nPolygalacturonase and expansin | \n[92] | \n
Soft rot, gray mold/rot | \n\nBotrytis cinerea, Erwinia chrysanthemi\n | \nFungus, bacteria | \nABA aldehyde oxidase | \n[93] | \n|
Powdery mildew | \n\nLeveillula taurica\n | \nBiotrophic fungus | \nMembrane-anchored protein | \n[94] | \n|
Aphid | \n\nMacrosiphum euphorbiae\n | \nInsects | \nFatty acid desaturase | \n[95, 96] | \n|
Fusarium wilt | \n\nFusarium oxysporum\n | \nHemibiotrophic fungus | \nLipid transfer protein | \n[97] | \n|
Rice | \nBacterial blight | \n\nXanthomonas oryzae\n | \nBacteria | \nMAPKKK | \n[98] | \n
Blight rot | \n\nBurkholderia glumae\n | \nBacteria | \nMAP kinase | \n[99] | \n|
Rice blast | \n\nMagnaporthe oryzae\n | \nHemibiotrophic fungus | \nTranscription factor WRKY | \n[100, 101] | \n|
Leaf blight | \n\nXanthomonas oryzae\n | \nBacteria | \nStearoyl-ACP desaturase | \n[102] | \n
Genes and their contributions to the plant-pathogen interaction studies.
Similar to a human system, plants also trigger defense molecules on recognizing particular molecules of invading pathogens generally referred to as pathogen-associated molecular patterns (PAMPs; [71, 72, 73]) that illicit a PAMP-triggered immunity. Although PAMP receptor molecules differ among plant species, genes that encode PAMP receptor can be transformed into other crops for triggering immunity [73]. Such a method of transformation does not introduce a novel defense mechanism but rather introduces a receptor that helps the transformed plant recognize infection making it independently counter the infection by its natural immune system [74, 75, 76, 77].
\nAn intracellular receptor protein (R-protein) is produced as a mechanism of effector-triggered susceptibility which is banked on by a model of disease resistance [72, 103]. This protein is specifically detected in the presence or when an activity of a pathogen effectors is triggered resulting in effector-triggered defense [103]. However, these effectors may modify or change the defense response in the host in response to a new effector produced by the pathogen. With this production of specific R genes with respect to the pathogen effector, pools of resistance genes evolved can be made useful in breeding crops for disease resistance by producing cisgenics [104]. Exceptional efforts by conventional introgression of cisgenes undertaken in crops such as apple, banana, grape, and potato have established it to be labor intensive and time consuming [73, 104]. GE strategies offer a major advantage not only by making it easier and faster but also evading linkage drag [50, 74]. Further introgression of R genes can be made feasible between unrelated plant species among monocots and dicots [77, 105, 106, 107, 108]. The tendency of the pathogen to overcome the resistance rendered by R genes can be circumvented by mining R genes from unrelated species by integrating GE strategies and breeding [109, 110].
\nThe activity of defense can be boosted by targeting molecules such as reactive oxygen species, pathogenesis-related genes involved in defense regulation, signaling, and associated processes activating acquired resistance. Such measures were profited to a great extent in enhancing resistance to diseases such as citrus greening and pathogens such as Rhizoctonia solani and Magnaporthe oryzae that utilizes the plant’s own natural immune system without the introduction of new or novel metabolic pathways [111, 112].
\nSome important genes that facilitate normal physiology in plants have been observed to be involved in facilitating pathogen colonization and infection. Changes induced in such susceptibility genes is an efficient strategy for disease resistance [113]. Disarming susceptibility genes may alter the pathosystems and many host factors that contribute to compatibility between the pathogen and host. Gaining a new function to replace the lost host factor is not a likely by the pathogen to overcome the activity of a disarmed susceptibility gene; therefore, this strategy does not leave any exogenous DNA [113].
\nRNA interference is elicited in plants to silence genes that render pathogenicity by using genetic constructs with identical sequence of dsRNA. Such efforts directly trigger posttranscriptional gene silencing of the natural disease process. Such a process of silencing does not generate a biochemical pathway or produce a novel protein. Integrating the need of the hour with the potential of the strategy of RNA silencing proved profitable for the papaya industry in Hawaii [114, 115]. Such applications are observed in cases where severe strains of the virus can be reduced in case of an infection by a mild strain. Implementing a natural phenomenon for cross-protection as a means to manage disease conditions has practical drawbacks. These drawbacks were controlled by feeding insects with dsRNA constructs that can trigger RNAi [116, 117].
\nClustered regularly interspaced short palindromic repeats has been identified to be a prokaryotic defense system that combines with its associated proteins (Cas) to render an endonuclease activity that cuts the invading DNA at a particular target of interest. This specificity is determined by the sequence of DNA that matches the sequence of the RNA guide strand associated with the Cas protein. Some studies have engineered a Cas9/gRNA that targets the replicating DNA of Gemini virus that leads to agrarian crisis in tropical and subtropical climates [118, 119, 120]. Significant resistance to host can be achieved against a DNA virus by a targeted sequence-specific engineered complex of Cas9/gRNA, although the results are meant to be reproducible [121]. Long-term utilization of this strategy against a variety of genetic elements that hamper the host such as viruses can be successfully targeted [122, 123, 124, 125, 126].
\nGenome editing, brought about by Agrobacterium-mediated transformation or biolistic methods, gives way to a wide range of possibilities for genetic changes. Targeted modifications, specific mutagenesis, and /or modest changes can be brought about by targeting existing genes in live cells. By using CRISPR/Cas9, it is possible to create a non-transgenic gene edit that can be introgressed by conventional breeding and can yield a change that cannot be distinguished from a mutation [127]. Another application of CRISPR is that the genome editing is HDR-based that allows editing a gene from the crop’s natural pool giving rise to cisgenic lines that can achieve outcomes stabilized by conventional breeding. HDR-based genome editing strategies also helps add a specific gene from an evolutionary distant organism therefore making the regulatory scrutiny mandatory similar to that of transgenics [128, 129]. Various research groups have validated CRISPR/Cas9 techniques to be straightforward, low cost, and efficient, but the accessibility of the applications of genome editing is largely dependant on democratizing genome editing, nonprofit organizations, and governmental regulations.
\nWhile recognizing the important benefits GE technologies offer, larger considerations merit attention, especially questions of public acceptability and of whether there are any long-term ecological risks different from those posed by conventional breeding. In considering such issues, it is important to remember that, not only do diverse GE strategies exist, but diverse GE manipulations are possible, ranging from very modest, targeted mutagenesis, through cisgenics and intragenics, to insertion of transgenes from other crops, from other (non-crop) plants, and from evolutionarily distant organisms. Thus, in considering socioeconomic and cultural perspectives of GE, it is important to bear in mind this diversity of strategies and applications: GE crops can differ markedly from one another. A useful GE construct may target one or a few pathogens of particular importance, but other breeding techniques still is important for tackling disease problems not targeted by available GE traits. Thus, GE should be understood, not as the best approach to addressing sustainability challenges, but as a suite of tools that capitalizes on the knowledge that biologists gain through our ongoing study of Nature. GE simply expands the breeding “toolbox,” providing options to consider on a case-by-case basis for enhancing the sustainability of crop disease management.
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