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Infectious diseases accompanied humanity throughout its existence and shaped history more profoundly than probably any other single biological factor. The epidemic from 165 to 180 BCE, referred to as the Antonine plague, or plague of Galen, is said to have caused 2,000 deaths per day and was considered the most decisive event in Roman history. The second bubonic plague pandemic from 14th-century Europe, also known as the black death, thought to be the deadliest pandemic in history, resulted in an estimated 50 million deaths and the loss of one third of the population in Europe and the Middle East. Smallpox caused 3.5 million deaths during a 1520 to 1521 outbreak, and the 1918 to 1919 Spanish flu claimed 50 to 100 million lives worldwide. Some investigators proposed that the extinction of the Neanderthals approximately 30,000 years ago was caused by a transmissible spongiform encephalopathy, resembling kuru and “mad cow disease.”
While infectious diseases existed in the hunter-andgatherer populations, many pathogens currently infecting humans have emerged with the development of agriculture. Evolution of the benign Yersinia pseudotuberculosis into the pathogen Yersinia pestis from 1,500 to 20,000 years ago, shortly before the first known pandemics of human plague, coincided with the development of agriculture that provided an abundant food supply for rodent hosts.
Several emerging, reemerging, and deliberately emerging infectious diseases have marked the past decades. Since 1976, over 40 emerging infectious diseases were reported by the World Health Organization, and recent predictions estimate that from 10 to 40 new viruses will emerge by 2020. Certain infectious diseases, once presumed eradicated, have reemerged while others, historically confined to specific geographical areas, are surfacing in new locations. This was facilitated by a complex interplay of biological, social, political, and economical factors that include microbial evolution and adaptation, global ecosystem changes, human behavior, poverty, war, extremism, and intent to harm.
Ecosystem perturbations resulting from human activities often have far-reaching effects. The 1998 emergence of malaria in the Bure district in northwestern Ethiopia, a region that has not been affected for decades despite the presence of the disease in other locations in the country, coincided with the replacement of more traditional crops with maize in this area. Maize pollen represents an important nutrient for the larvae of Anopheles arabiensis, the main mosquito vector for malaria in the country, and larval mosquitoes were shown to develop more rapidly and produce larger adults in villages where maize pollen is more abundant. Restricting the plantation of maize in the immediate vicinity of homes or using genetically modified plants were proposed as important measures to control malaria.
Certain human interventions, despite intending to limit an outbreak, may have unpredictable effects. Yersinia pestis, the etiologic agent of plague responsible for several pandemics throughout history, is spread among rats, which constitute the main reservoir, and from rats to other species, including humans, by fleas. Campaigns to eradicate rats were often followed by human outbreaks. This was explained, in part, by the fact that decreasing rat populations required infected fleas to find other organisms to survive, and thus, they more often bit and infected humans. More recently, human interventions, such as deforestation and urbanization, together with the growth of cropland that provides abundant food resources for rodents in deforested areas, changed the interaction between rodent and human populations and facilitated new plague outbreaks.
Certain infectious diseases come from the most unusual sources. For example, discarded vehicle tires provide a habitat for several mosquito species. Female mosquitoes lay their eggs inside moist tires, and the accumulating rainwater allows the larvae to hatch and subsequently develop into adult mosquitoes. The used-tire trade, a very profitable business, was linked to the worldwide spread of Aedes albopictus, a mosquito that represents a vector for at least 22 viruses and from its southeastern Asian origin has spread to North America, Europe, Africa, and South America. A study that examined over 4,700 used tires collected from roadside locations in Vietnam reported that over half of them contained water and 34% of those harbored mosquitoes, the majority of which were vectors for the dengue virus.
One of the most significant risk factors for infectious disease is the use of unsafe injections. Approximately 1.3 million deaths annually are attributed to hepatitis B and C and HIV that are transmitted by unsafe injections administered globally. In a study examining health care injections that did not include the ones performed as part of illegal drug use, Y. J. F. Hutin and collaborators estimated that in 2000, approximately 6.7 billion injections administered in several locations worldwide were unsafe. In addition, many investigators pointed out that a large percentage of injections performed worldwide are unnecessary. To understand the effect of unsafe injections, it is important to remember that the 1976 Ebola virus outbreak from Zaire, which infected 318 individuals and caused 218 deaths, was linked to unsafe injections and traced back to a patient who received injectable medication for fever.
Human infectious diseases are increasingly caused by zoonotic pathogens. These are pathogens that normally infect animals but occasionally acquire the ability to cross species barriers and cause disease in the human population. A recent review estimated that of 1,407 infectious agents that infect humans, 58% are zoonotic. Several conditions have to be fulfilled to initiate a zoonotic outbreak in humans and usually combinations of factors are required, of which crossing the species barrier is only one requirement. HIV crossed several times from animals to humans before it emerged as a pandemic. Human T-cell leukemia viruses (HTLV 1–4) emerged from their counterparts infecting nonhuman primates, and foamy viruses from the same family repeatedly entered the human population. Ample evidence reveals that these viruses were transmitted during hunting and butchering that are part of a vast bush meat market in several African countries. As part of these practices, it is estimated that over 500 million wild animals are caught annually in the Congo basin, ape populations in Gabon declined by more than half between 1983 and 2000, and several species in western Africa have disappeared or are on the verge of extinction. N. D. Wolfe and collaborators termed this repeated transmission from animals to humans viral chatter and proposed that at high rates it can increase the diversity of viruses that cross species, facilitating the emergence of strains adapted to humans. For HIV, we know that viral entry into the human population was decisive but not sufficient. Other factors, including the sharing of contaminated needles, human trafficking, commercial sexual work, powerlessness among atrisk women in many countries and cultures worldwide, misinformation, risky sexual behavior, and the expansion of global mobility all made important contributions to the worldwide emergence of the pandemic and provide important lessons for future pathogens.
Human-induced land changes represent a major force driving the emergence of infectious diseases. Deforestation, which has been increasing over the 20th century and annually affects 2% to 3% of the forests worldwide, caused some of the major transformations in the global ecosystem. Within half a century, tropical forests have shrunk by half, a loss of approximately 9 million km2, and several pathogens were linked to landscape changes.
Lyme disease, a bacterial infection caused by Borrelia burgdorferi, is the most common vector-borne disease in North America and is transmitted by ticks of the family Ixodidae. The white-footed mouse, Peromyscus leucopus, is the main natural reservoir for the bacterium. Several deforested areas have seen changes in the species composition: While certain species cannot survive, the white-footed mouse, which has a broad habitat tolerance, is not affected to the same extent, and its relative abundance increases. The “dilution effect model,” proposed by R. S. Ostfeld and F. Keesing, predicts that high species diversity dilutes the natural reservoir and reduces the infection prevalence of ticks. Any factor that decreases the representation of the white-footed mice, relative to other hosts in the community, would reduce the proportion of ticks that are infected. Therefore, one mechanism to reduce the prevalence of the infection is to reduce the relative abundance of white-footed mice. This can be accomplished by increasing the number of alternative hosts, which often are incompetent reservoirs. In support of this model, extensive evidence indicates that reducing the composition and biodiversity of host communities increases the risk of human exposure to several vector-borne diseases. For example, L. J. Dizney and L. A. Ruedas (2009) revealed that in several forest areas in and around Portland, Oregon, the prevalence of sin nombre virus infection in deer mice (Peromyscus maniculatus), which constitute the main reservoir for this frequently fatal pathogen, drastically increases in areas with low mammalian species diversity.
Deforestation was associated with increases in malaria incidence in Africa, Asia, and Latin America. Several studies conducted in Kenya reveal higher outdoor and indoor temperatures in deforested areas, which together with other factors led to the increased vectorial capacity of mosquitoes, shorter development times of the parasite Plasmodium falciparum, and increased risk for human infection. The biting rates of Anopheles darlingi, the most important malarial vector in the South American Amazon basin, were more than 200-fold higher in sites experiencing extensive deforestation.
A Nipah virus outbreak that occurred in Malaysia between September 1998 and April 1999 was intimately linked to deforestation. In September 1998, several individuals associated with pig farming in Perak state developed acute encephalitis with a high mortality rate, around 38.5%. This was preceded by respiratory infection outbreaks among pigs within the same area. The infection spread to several states and to Singapore where it infected abattoir workers who handled pigs imported from the affected regions in Malaysia. The Singapore outbreak ended when pig importation stopped, and the outbreak in Malaysia subsided when infection control measures, including the culling of a million pigs, were adopted. Fruit bats of the Pteroid species represent the natural reservoir of the Nipah virus, and several factors were proposed to have contributed to the outbreak. This included massive deforestations from 1997 to 1998, which destroyed the natural habitat of fruit bats that, lacking their food supply, migrated from forests to fruit orchards. Pigs living around those orchards ingested bat saliva from partially eaten fruit infected with the Nipah virus, and the virus spread to domestic pigs and ultimately to humans.
Deforestation is just one of many environmental disturbances with a profound impact on infectious diseases. Other human activities, including agriculture and irrigation, significantly change the ecosystem. In 1985, a barrage was constructed at Diama to prevent seawater from entering the Senegal River and to make the river more suitable for irrigation. However, this changed water salinity and pH, which became more permissive for the growth of freshwater snails, the natural host of Schistosoma mansoni, a parasite that caused massive schistosomiasis outbreaks among people in the area. In the Thar Desert in northwestern India, malaria outbreaks were linked to mismanaged canal-based irrigation related to agriculture. And in Ethiopia, the incidence of malaria in children living within 3 km from dams was shown to be 7 times higher compared with children living from 8 to 10 km away.
Kuru and Creutzfeld-Jakob Disease
In 1957, scientists studying the Foré people living in Papua New Guinea described, for the first time, a fatal progressive “neurodegenerative condition” called kuru, which from the local dialect translates as “trembling with fear.” Several pieces of evidence, including geographical clustering, distribution in age and sex groups, and local rituals to dispose of the deceased, revealed that this initially mysterious condition was transmitted by endocannibalism, also termed transumption, a practice in which the body of the deceased was consumed by relatives as a sign of affection and an expression of grief.
In some villages, kuru became the predominant cause of death among women. One of the early observations was that the disease mostly occurred in women and children: Men represented only 2% of the diseased while women represented 60%, and the remaining were children. This was explained by the endocannbalistic rituals in which women and children were the ones to consume the internal organs, including the brain, which contained the most infectious agents, while men never consumed these parts.
The main pathogenic feature of kuru is that, unlike in many other infectious diseases, the transmissible agent is an infectious protein called prion, which was isolated from the brain tissue of the diseased individuals and was shown to cause disease in experimental animals. The prion hypothesis proposes that the protein can exist under two forms, a noninfectious one, PrPC, which is encoded by the host and can spontaneously be converted into an infectious form, PrPSc, a highly aggregated detergent-insoluble form that was extracted from affected brains. Once the infectious form is produced, it can transform noninfectious molecules into the pathogenic form. It is thought that PrPC constantly undergoes minor conformational changes, and one or a few of the misfolded prion protein forms can associate and generate seed PrPSc structures, which leads to the autocatalytic formation of more PrPSc.
Examining the PRNP locus that encodes the prion protein revealed a polymorphism at position 129, which can encode either methionine (M) or valine (V). Individuals can be homozygous for either allele if they carry both chromosomal copies encoding the same amino acid (MM or VV) or heterozygous if each chromosome encodes a different amino acid at this position (MV). A study that examined Foré women older than 50 years, who repeatedly participated in endocannibalistic behaviors, revealed a drastic overrepresentation of the frequency of heterozygotes (MV) in this group as compared to other populations, indicating that being heterozygous provides resistance to the disease and a clear survival advantage. This polymorphism has a powerful influence both on kuru susceptibility and incubation time. It is proposed that the practice of endocannibalism could have represented a selective force to eliminate homozygotes and select for heterozygotes, which were more resistant to the disease. One hypothesis is that the worldwide distribution of this polymorphism could very likely be the result of a constant exposure in our evolutionary past to animals that were constantly a source of prion disease or represent a testimony of endocannibalism in ancient populations. The polymorphism at position 129 results in one amino acid change (M versus V) in the protein and is thought to make protein-protein interactions more difficult between proteins that harbor this discrete change than between homozygous proteins, which aggregate more easily, explaining the selective advantage of heterozygous individuals.
More recently, in March 1996, another prion, causing the variant Creutzfeld-Jakob disease (vCJD), attracted worldwide interest when it was reported that the progressive spongiform encephalopathy outbreak, discovered in cattle several years before, had spread to 10 humans. About 210 clinical cases were reported by late 2008, but due to the long and variable incubation, it is unclear how many people were infected. Importantly, all individuals who developed the disease are homozygous for methionine at position 129 of PRNP, which is one of the genetic susceptibility factors described. This human epidemic occurred in the wake of the bovine spongiform encephalopathy, or “mad cow disease,” that started to be reported a few years earlier in the United Kingdom. In 1986, a previously unrecognized progressive neurological condition was reported in cattle in the United Kingdom, with spongiform lesions appearing in the brain of the affected animals. Early during the outbreak, which is thought to eventually have infected 2 million cows, epidemiological investigations revealed that cases were reported from throughout the country, indicating the likelihood of a common-source epidemic rather than one that is propagated. The cause was proposed to be the meat-andbone meal, a dietary supplement that was prepared from carcasses of sheep affected by scrapie and fed to cattle. Scrapie, a fatal neurodegenerative disease caused by a prion, has been recognized in sheep for about 250 years. This supplement was fed to dairy herds more often than to beef herds, and dairy herds exhibited a much higher incidence of the clinical manifestations during the “mad cow disease” outbreak. Feed manufacturers in the United Kingdom started introducing the meat-and-bone meal in the diet of diary calves in the 1970s, a practice that was less prevalent or nonexistent in other countries. One step during the manufacturing process involved treatment with an organic solvent at 70 °C for 8 hours to extract fat. In the early 1980s, as many manufacturing plants reduced the use of organic solvents in this process, the fat content of the meat and bone meal increased significantly and is thought to have allowed prions, which are resistant to heat but can be inactivated by lipid solvents to maintain their infectivity. It is believed that prions have always been present in the meat-and-bone meal, but were inactivated by the solvent treatment step, and changes in the manufacturing process made inactivation less effective, allowing it to cause disease. A ban on ruminant protein supplements, introduced in the United Kingdom in July 1988, led to the decline of the outbreak and confirmed the origin of the outbreak.
HIV and HTLV
For certain infectious diseases, it became clear that a multitude of factors facilitated the emergence and worldwide spread of these pathogens, and the HIV/AIDS pandemic provides an important example. Since 1981, HIV has caused an estimated 25 million deaths worldwide and was most recently implicated in 2.7 million new infections annually, becoming probably the most studied virus in history. Over 15% of the adult population is infected in Zambia, and as a result of the pandemic, life expectancy in Botswana decreased from 59 years in 1990 to around 44 years in 2003.
The mortality caused by the HIV/AIDS pandemic profoundly affected all aspects of biomedical and social sciences and even required that the validity of certain approaches that have classically been used in population studies be revisited. For example, since the infection often affects couples, mortality rates, usually determined from the number of deaths reported within a household, could be underestimated due to the disappearance of entire households, opening the need for implementing new demographic tools.
Two HIV types are currently known, and they differ in biology, epidemiology, transmission, and clinical progression of the disease. HIV-1 is distributed worldwide and responsible for the majority of disease, whereas HIV-2 is found mostly in Africa and India and is transmitted less efficiently. Extensive evidence, including molecular phylogenetic analyses, supports the view that HIV emerged from simian immunodeficiency viruses (SIV), their counterparts found in several species of nonhuman primates. HIV-1 originated from SIVCPZ, a virus that infects chimpanzees (Pan troglodytes troglodytes) in western Central Africa and was introduced into the human population on at least three separate occasions, giving rise to the three phylogenetically distinct HIV-1 lineages, M, N, and O, present in the human population. HIV-2 was shown to have originated from SIVSM, which infects sooty mangabeys (Cercocebus torquatus atys) and entered the human population on at least four different occasions. Most recently, a new HIV-1 strain, closely related to a virus that infects wild-living gorillas, SIVgor, was described in a Cameroon woman and proposed to be designated group P. Chimpanzees and sooty mangabeys are hunted for food and kept as pets. Exposure to infected animal blood and tissues during hunting and butchering, animal bites, and the consumption of uncooked, contaminated meat were all proposed to have facilitated the cross-species transmission of the virus and its emergence in humans.
Cross-species transmission explains the origins of HIV but was not sufficient to establish a pandemic. HIV existed in humans for several decades before it emerged worldwide. Testing plasma samples collected in 1959 revealed that a male member of the Bantu tribe, who lived in Kinshasa, the Democratic Republic of the Congo, had antiHIV antibodies, and the polymerase chain reaction subsequently amplified a fragment of the viral genome, confirming the infection. Phylogenetic analyses, using viral DNA isolated from a paraffin-embedded lymph node biopsy, originating from a patient in 1960 in Kinshasa, indicated that HIV could have infected humans between the late 19th century and the early 20th century. A constellation of additional factors was instrumental for the global spread of the virus. Some of them such as the high HIV mutation and recombination rates, compounded by its fast replication, are inherent to the biology of virus and make it one of the fastest evolving pathogens currently known. Most important, a complex interplay of cultural, social, economical, and political factors was instrumental in facilitating and fueling the pandemic. One of these factors, the high prevalence of other sexually transmitted diseases, particularly ulcerative ones, increased susceptibility to infection and continues to play an important role in HIV transmission worldwide. For example, gonorrhea and herpes infections both increase HIV transmission. Resistance to using condoms is often rooted in social and economic causes or in the advice of religious leaders with substantial influence in the respective communities and represents an important contributor to the pandemic. Several interviewbased studies talk about the often-reported concern that requesting sexual partners to use condoms would bring distrust into the relationship. An established risk factor for HIV is the widespread use, in several African countries, of vaginal herbs that dry, contract, and heat the vagina to increase sexual pleasure but also create lacerations that increase susceptibility to infection. The worldwide crisis, created by an estimated 800,000 annual victims of human trafficking, 80% of whom are forced into becoming sexual workers, is compounded by the powerlessness of female sex workers in many countries and cultures. As biological, social, and economical factors made women in many countries more susceptible to infection, HIV incidence rates were reported to increase faster in females than in males in many locations worldwide. E. Esu-Williams (2000) described a “gender paradox” in relationship to HIV in Africa, pointing out that despite men often being the ones more likely to have multiple sexual partners, community stigma is directed toward women, who are blamed even when their young adult children become infected. The global mobility that made it possible to reach remote parts of the world within hours is another factor that greatly contributed to the HIV/AIDS pandemic. Due to the multitude of factors involved, it is becoming increasingly clear that medical and public health approaches are insufficient to address the pandemic, and adopting a combined perspective, including cultural, social, and political interventions, is vital in managing the pandemic.
Contacts between humans and nonhuman primates were implicated in the emergence of another retrovirus, human T-cell leukemia virus (HTLV), with four representatives identified in humans. These viruses, together with their simian counterparts, STLV-1, -2 and -3, belong to the group of primate T-cell lymphotropic viruses (PTLV). HTLV seroprevalence varies worldwide. Over 10% of some populations in southern Japan and up to 5% in sub-Saharan Africa and several Caribbean and South American countries are infected. Infection rates are from 0.01% to 0.03% in the United States and Canada and even lower in Europe, with higher prevalence among immigrants from endemic areas and their families, intravenous drug users, and multipletransfusions recipients.
HTLV-1, which was more intensively studied, is estimated to infect approximately 15 to 20 million people worldwide. While most infected people are asymptomatic, from 1% to 5% develop adult T-cell leukemia from 20 to 30 years after the initial infection, and others develop a progressive inflammatory neurological condition or rheumatoid arthritis. HTLV-2 is less pathogenic and was linked to neurological manifestations. It is unclear why certain individuals develop these severe medical conditions, while the majority of those infected remain asymptomatic. Transmission occurs by sexual activity, blood transfusion, contaminated needles, and from mother to child during breast-feeding and pregnancy.
Over 10% of the free-ranging primates in the rainforests of Cameroon harbor a variety of STLV strains, which were also identified in pet primates and in bush meat sold for human consumption. In fact, Africa is the only continent where all four viruses infecting humans, HTLV-1, -2, -3, and -4 and all three known simian counterparts, STLV-1, -2 and -3, were found.
Human HTLV infections emerged independently by the cross-species transmission, on several occasions, of their simian counterparts. N. D. Wolfe and collaborators reported that HTLV-1 strains, isolated from local villagers from Cameroon who hunted for primates, exhibited from over 97% to 98% identity at the nucleotide sequence level with STLV-1 isolates infecting free-ranging monkeys in the region. Bites and contact with the blood and body fluids of primates, during hunting and butchering, represent major risk factors that facilitate the cross-species infection of humans.
In addition to implications for human health, HTLV emerges as an important instrument in dissecting human history. In 1999, an HTLV-1 provirus was identified in a 1,500-year-old Andean mummy from northern Chile, and comparisons between several nucleotide regions of this virus and strains infecting present-day Japanese populations helped in understanding human migration from Asia to South America and reopened many questions, some of which are still controversial and insufficiently understood.
Among microorganisms that reemerged periodically through history, an important representative is the influenza virus. In addition to annual outbreaks known as seasonal flu, which usually affect mostly the very young, the elderly, and individuals with underlying medical conditions, influenza regularly emerges in the form of pandemics that spread over extensive geographical areas and cause extensive morbidity and mortality in all segments of the population. The first influenza pandemic on which all authors agree occurred in 1580 and three pandemics, the 1918 to 1919 Spanish flu, the 1957 to 1958 Asian flu, and the 1968 to 1969 Hong Kong flu, occurred in the 20th century.
Three types of influenza viruses, A, B, and C, were described in humans. The single-stranded RNA viral genome contains 8 segments for types A and B and 7 for type C viruses, all required for infectivity. Two viral genes encode hemagglutinin and neuraminidase, the proteins that decorate the viral surface as “spikes” visible by electron microscopy. Hemagglutinin is crucial for viral attachment to host cell receptors during the initial stages of the infection, and neuraminidase facilitates the subsequent cell-tocell spread of the virus. There are 16 hemagglutinin and 9 neuraminidase subtypes that represent one of the bases for classifying influenza viruses.
Two characteristics of the influenza virus are central to its ability to regularly cause disease. One of them, common for RNA viruses, is the high rate of errors during replication as compared to DNA viruses. The progressive accumulation of small errors in the influenza virus genome introduces subtle changes in the resulting proteins, a process that is known as antigenic drift, and occurs constantly in all three types of influenza viruses. As a result of these small changes, influenza viruses constantly gain the ability to reinfect individuals who already were infected during previous flu seasons.
A second type of change, called antigenic shift, that occurs more rarely, was described only in type A viruses and has by far more devastating consequences. The segmented influenza virus genome enables two viruses that coinfect the same cell to exchange one or more of their genes and create new viruses, a process known as reassortment. The 8 segments of two viruses can rearrange in 256 possible combinations, providing a great source of genetic diversity that confers new properties to the resulting strain. D. M. Morens and collaborators recently pointed out that it is more meaningful to think about influenza A viruses not as distinct entities but as “gene teams” that sometimes trade away one gene and gain new ones and acquire unique skills as a result.
The 1918 to 1919 Spanish flu infected 25% to 30% of the world’s population and caused an estimated 50 to 100 million deaths. Its origins are debated, but the virus was shown to harbor several segments originating from avianlike viruses. The virus responsible for the 1957 to 1958 Asian flu acquired three of its genes from viruses infecting wild ducks, and the strain that caused the 1968 to 1969 Hong Kong flu had two genes of avian origin.
The ability of influenza viruses from different species to undergo reassortment requires them to cross species boundaries. Despite widely held beliefs, human influenza viruses do not replicate easily in avian species, and avian viruses do not easily cause infection in humans. The biological basis of this host restriction is explained by the specificity of the interaction between hemagglutinin, which is the viral protein responsible for attachment, and sialic acid, which represents the influenza virus receptor on the surface of host respiratory epithelial cells. It was known for a long time that several types of sialic acids exist across species, but the significance of this phenomenon was not completely understood.
Human influenza viruses recognize sialic acid, which contain galactose bound by an α-2,6 linkage, and these receptors are found on human cells. Avian viruses have a predilection for sialic acid linked to galactose by α-2,3 linkages, and these receptors are mostly found on avian respiratory epithelia. This interaction is one factor that restricts influenza viruses to their respective species. However, sialic acid from pig tracheal-epithelial cells contains both types of linkages, and this explains their susceptibility to infection with both avian and human influenza viruses. Pigs are often described as “mixing vessels” that facilitate the reassortment of influenza viruses to generate new strains that infect other species.
Avian species represent the natural reservoir for type A influenza viruses. Both low- and high-pathogenicity viruses exist in birds, and mutations can convert low-pathogenicity strains into highly pathogenic ones. Ito and collaborators demonstrated that consecutive passages of an avirulent virus infecting wild birds can generate highly pathogenic strains with high lethality in chickens, accompanied by the progressive accumulation of basic amino acids at the hemagglutinin cleavage site, a widely reported feature of virulent viruses from several outbreaks.
Several influenza virus subtypes were documented in migratory waterfowl, particularly in wild ducks. In April 2005, an H5N1 influenza virus outbreak was detected among wild birds from the Qinghai Lake in western China, a major breeding site for migratory bird populations. Over 6,000 dead birds were found in this area over a 2-month period, and of several viruses that were isolated, all were lethal to chickens and most were highly lethal to mice. Moreover, between February and June 2006 over 2,400 dead birds were found in the region of Lake Constance, an important wetland habitat at the border between Germany, Austria, and Switzerland, and many tested positive for influenza A viruses. Several avian species exist at this location throughout the year, and many more migratory birds pass between October and March. Wild ducks infected with influenza viruses are often asymptomatic and were recently referred to as the “Trojan Horse” of H5N1 influenza.
In addition, Sharp and colleagues (1997) revealed that ducks can be co-infected with several subtypes of influenza A viruses, facilitating reassortment. Migratory birds should become a cardinal component of the global influenza virus surveillance. Wild birds can infect poultry and other domestic animal species, including pigs. This process is facilitated by habitat overlap, particularly in several Asian countries, where pigs and ducks are often raised in close proximity, and both are close to humans, facilitating reassortment and infection. Another practice that facilitates reassortment is the integrated pig-hen-fish farming where to reuse waste, pigs consume the feces of hens located in cages above them, and subsequently, pig manure is released into ponds situated below the pigsties. In this system, excess food from pigs and hens becomes available for the fish, and at the same time, their feces are used as pond fertilizers.
Several populations are at particular risk for influenza virus infections. These include individuals occupationally exposed to live poultry, swine farmers, and meat processing workers, who can be infected by the respective species and subsequently introduce the viruses in the community, exposing people who did not have direct animal contact. Surveillance, conducted at poultry markets in several countries, revealed that influenza viruses are present in live birds and/or meat products, and several studies that examined poultry and swine workers revealed that they have higher levels of antibodies against influenza viruses, indicating the potential to become occupationally infected.
Several reports described avian influenza virus infections in individuals who did not raise poultry and were not exposed in their neighborhood, and the only epidemiologyrelevant events were visits to live bird markets within the days or weeks preceding the disease. Therefore, it appears that visits to poultry or animal markets are sometimes sufficient to become infected. In this respect, it is important to remember the role of feathers as a potential route of infection. Yamamoto and collaborators reported that viruses were able to replicate in the feather-epithelial cells of domestic poultry infected with H5N1 viruses, even in asymptomatic birds, opening the possibility that feathers can represent a source of infection. In fact, Marek’s disease virus, a herpes virus that infects chickens, was previously shown to exist in high concentrations in many feather-follicle-epithelial cells, from sites where they can be shed into the environment. Certain human behaviors, such as increasing numbers of poultry kept in the vicinity of wild waterfowl, and extensive contacts between animal and bird species, and humans in and around the household and in wet markets, represent important risk factors facilitating influenza virus infections in animals and humans. Wet markets are live animal markets that sell poultry, mammals, and fish and animals reside in close proximity to each other and to humans, for days and sometimes weeks.
The first outbreak to attract global attention during the 21st century was the 2002 to 2003 severe acute respiratory syndrome (SARS) pandemic that infected over 8,000 people and claimed over 700 lives worldwide. The outbreak was caused by SARS coronavirus (SARS-CoV), a member of the coronaviruses, which includes representatives previously implicated only in mild respiratory infections.
The outbreak started in the Guangdong province in China, and the observation that many of the first patients in China were chefs or animal handlers raised the possibility that the outbreak involved zoonotic exposure. The initial investigation of animals from a market in Guangdong detected SARS-CoV-like viruses in several species, including palm civets, a raccoon dog, and a Chinese ferret badger. In addition, animal traders and workers involved in slaughtering animals at the same market had significantly more antibodies to the virus than did vegetable traders. The genomic sequence of two viruses isolated from palm civets had over 99% homology with viruses isolated from humans, revealing the possibility that market animals represent the source of human infections. Importantly, during the winter of 2003 to 2004, after the SARS outbreak ended, 4 new human cases were reported from the same province. Epidemiologic investigations linked two of the patients to a restaurant that served palm civets. One patient was a waitress who worked close to the animal cages located within the restaurant, and the other was a guest whose dining table was close to the civet cages. All six palm civets from the same restaurant tested positive for SARS; sequencing of the S gene, which encodes the “spike” protein that helps the virus attach to the surface of target cells on human or animal hosts, revealed that these civets were the source of the outbreak, as opposed to the continued circulation of SARS in the population. Civet cats thus emerged as a potential source that contributed to the SARS outbreak. Civets represent a culinary delicacy in southern China and this explains why food handlers, caterers, and chefs were overrepresented several-fold among the first victims during the outbreak.
However, while several subsequent studies confirmed that civets from animal markets harbor the virus, others failed to reach the same conclusion and reported that civets, particularly the ones growing on farms, were not infected. This pointed to the possibility that even though palm civets can harbor the virus, additional species could be involved. Taking into account that approximately 66 virus species were isolated from or detected in bats, the bat population was examined as a potential source of SARS. Two independent virological surveillance studies revealed that several species of horseshoe bats from China have high seroprevalence for a coronavirus that was called batSARS-CoV. Bats were able to support viral replication without becoming sick, indicating that they may represent the natural reservoir for the virus; sequence analysis of several bat viruses revealed that they are closely related to viruses isolated from humans and civets. Subsequently, SARS-like coronaviruses were documented in bats from Europe, North America, and Africa. From bats, the virus can be directly transmitted to humans or first infect other species that subsequently infect humans.
The slaughtering of bats and the consumption of bat meat represent possible pathways for infection. Bat meat is considered a delicacy in Southern China and is believed to cure various ailments such as asthma, kidney conditions, and general malaise. Bat feces are sometimes used in traditional medicine in Asia. In many locations from southern China, such as the Guangdong province, considered to be the epicenter of the SARS outbreak, eating a wide range of wild animals, including civets and bats, is considered beneficial for general health and sexual performance. In many countries that have a centralized slaughtering system, contacts between the general population and animals are limited, and zoonoses usually emerge either occupationally among individuals who handle animals or recreationally among people who come in contact with animals in the wild. However, in other countries where people live close to the animal supply or regularly visit wet markets where several live species are sold and sacrificed in close proximity to humans, much larger segments of the population are exposed to the risk of zoonotic infections.
Retroviruses, the same family that includes HIV, have a unique replication strategy as their distinguishing feature. These viruses harbor reverse transcriptase, an enzyme that uses the viral RNA genome to generate a double-stranded DNA molecule that becomes integrated into the host genome and subsequently replicates together with the host. Two retrovirus subfamilies exist: the Orthoretroviridae, comprising six genera and the Spumaretrovirinae, comprising one genus, the Spumavirus, or foamy viruses. Foamy viruses infect a broad range of mammals, including nonhuman primates, horses, cows, and cats. The highly vacuolated appearance of infected cells provided the name for these viruses.
Despite being discovered over 40 years ago, foamy viruses are still among the least characterized retroviruses. Of the seven known retrovirus genera, foamy viruses appear to represent the only exception to pathogenicity, and it is unclear whether this might change as new findings become available. The most studied representatives are simian foamy viruses, which infect nonhuman primate hosts and are thought to have coevolved with them for over 30 million years.
The first report of a foamy virus infection in humans was in 1971 when it was isolated from a Kenyan patient with nasopharyngeal carcinoma. The high amino acid similarity between this virus and a strain infecting chimpanzees pointed toward its animal origin. High prevalence of foamy virus infection was reported among nonhuman primates, including rhesus macaques, African green monkeys, baboons, and chimpanzees. In all species, infection rates are higher among captive than free-ranging animals and in adults as compared to juveniles. Bovine foamy virus infections were reported in cows, and feline foamy viruses infect wild and domestic cats.
Animal-to-human transmission of foamy viruses can occur in two broad settings, occupational and recreational. Populations at risk for occupational transmission include zoo workers, veterinarians and laboratory workers in contact with primates, individuals involved in hunting primates, and employees in monkey temples. Owning primate pets, close contact with performance monkeys, ecotourism, and visiting monkey temples represent some of the routes facilitating recreational exposure. Calattini and colleagues reported that 1.8% of adults living in primate habitats from southern Cameroon had serological evidence of exposure, and N. D. Wolfe and collaborators found that 1% of individuals residing around primate habitats from southern Cameroon had antibodies against simian foamy viruses. W. M. Switzer and collaborators tested 187 lab and zoo workers recruited from five different institutions and revealed that 10 were infected.
Visiting monkey temples provides, worldwide, more human-primate contact opportunities than any other setting and increasingly emerges as a significant risk factor for infection. Taking into account that 700,000 tourists visit the four main monkey forests in Bali annually,
- Schillaci et al. estimated that approximately 2,100 visitors would become seropositive, and assuming that only 10% of them originate from North America and only 1% to 2% donate blood, they predicted 2 to 4 infected individuals would contribute to the North American blood supply at least once a year. These predictions were modeled based on only the four main monkey temples in Bali and did not take into account other sites on the island or in several other Asian and African countries.
Blood transfusion and organ transplantation represent potential transmission routes, but the risks are still unclear. A recent study reported that blood products transfused from an individual, confirmed retrospectively to be infected, did not infect any of the four recipients. Transplantation becomes relevant under two circumstances: Tissue and organ donors infected with foamy viruses could transmit the virus to recipients, and baboons used for liver transplantation could infect humans. In two human recipients of baboon liver transplants, simian viruses were identified in several tissues in the recipients. It is unclear whether human-to-human transmission can occur. Foamy viruses were not identified in blood samples collected from infected individuals’ spouses, but very few individuals were examined so far.
The involvement of foamy viruses in human disease is controversial and unclear, and this, too, is partly due to the small number of reports. There is a contrast between the in vitro ability of foamy viruses to induce rapid cytopathic effects in several cell types, and their apparent lack of pathogenic effects in infected individuals. While some studies implicated foamy viruses in Graves’ disease, de Quervain thyroiditis, multiple sclerosis, amyotrophic lateral sclerosis, and myasthenia gravis, other reports did not replicate these associations, and many authors reported nonspecific or age-related symptoms among foamy virusinfected individuals. However, mice infected with various combinations of foamy virus genes were reported to develop neurodegenerative conditions.
It will be important to understand whether foamy viruses are linked to medical conditions in humans or whether they persist in the genome without causing disease. A third scenario, which deserves serious consideration, is also possible and becomes relevant, particularly when considering the recent report of the first two human co-infections with HIV-1 and simian foamy viruses in a blood donor from Cameroon and a commercial sex worker from the Democratic Republic of the Congo. Foamy viruses could shape other viral infections. Reports showing that foamy viruses make human T-cells become more permissive for HIV-1 binding and cell-to-cell transmission, together with mouse models indicating that foamy virus transcription factors can activate HIV in certain tissues, strongly support this possibility. Under this third scenario, even if foamy viruses turn out not to cause disease on their own, they could well become the pandemic that shapes another pandemic.
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