3
Factors in Emergence

Six factors in the emergence of infectious diseases were elucidated in a 1992 Institute of Medicine (IOM) report, Emerging Infections: Microbial Threats to Health in the United States. A decade later, our understanding of the factors in emergence has been substantially influenced by a broader acceptance of the global nature of microbial threats. As a result, this report expands the original list, identifying thirteen factors in emergence (see Box 3-1). These thirteen factors are reviewed in turn in this chapter. The chapter ends with a case example—influenza—illustrating the interaction among the factors in the emergence of an infectious disease.

Future scientific discoveries and an increased understanding of the complexity of the emergence of infectious diseases will no doubt add to the list of factors identified in this report. In this light, the committee developed a model for conceptualizing how the factors in emergence converge to impact on the human–microbe interaction and result in infectious disease (see Figure 3-1). This model organizes the various factors into four broad domains: (1) genetic and biological factors; (2) physical environmental factors; (3) ecological factors; and (4) social, political, and economic factors. As we examine the individual factors, envisioning each as belonging to one or more of these four domains may simplify the understanding of the complex dynamics of emergence.

MICROBIAL ADAPTATION AND CHANGE

Microbes live on us and within us and inhabit virtually every available ecological niche of the external environment, and they will expand into new



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3 Factors in Emergence Six factors in the emergence of infectious diseases were elucidated in a 1992 Institute of Medicine (IOM) report, Emerging Infections: Microbial Threats to Health in the United States. A decade later, our understanding of the factors in emergence has been substantially influenced by a broader acceptance of the global nature of microbial threats. As a result, this report expands the original list, identifying thirteen factors in emergence (see Box 3-1). These thirteen factors are reviewed in turn in this chapter. The chapter ends with a case example—influenza—illustrating the interaction among the factors in the emergence of an infectious disease. Future scientific discoveries and an increased understanding of the complexity of the emergence of infectious diseases will no doubt add to the list of factors identified in this report. In this light, the committee developed a model for conceptualizing how the factors in emergence converge to impact on the human–microbe interaction and result in infectious disease (see Figure 3-1). This model organizes the various factors into four broad domains: (1) genetic and biological factors; (2) physical environmental factors; (3) ecological factors; and (4) social, political, and economic factors. As we examine the individual factors, envisioning each as belonging to one or more of these four domains may simplify the understanding of the complex dynamics of emergence. MICROBIAL ADAPTATION AND CHANGE Microbes live on us and within us and inhabit virtually every available ecological niche of the external environment, and they will expand into new

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BOX 3-1 Factors in Emergence 1992 Microbial adaptation and change Economic development and land use Human demographics and behavior International travel and commerce Technology and industry Breakdown of public health measures 2003 Microbial adaptation and change Human susceptibility to infection Climate and weather Changing ecosystems Human demographics and behavior Economic development and land use International travel and commerce Technology and industry Breakdown of public health measures Poverty and social inequality War and famine Lack of political will Intent to harm niches that occur as we continue to alter the environment and extend our contact with the microbial world. Most of the microbes that live on or inside humans or exist in the environment do not cause disease in humans (see Box 3-2). These microbes may appear to be unimportant. However, they are often crucial to the human ecosystem. Moreover, microbes that have heretofore not affected humans directly may still represent a potent threat. Microbes that are pathogenic to the animals and plants on which we depend for survival, for example, are an indirect threat to human health. Other microbes live in apparent harmony with animals but can be pathogenic for humans, as evidenced by the number of emerging zoonotic diseases that are transmitted to humans from animals. Microbes are also adept at adaptation and change under selective pressures for survival and replication, including the use of antimicrobials by humans. Microbial adaptation and change continually challenge our responses to disease control and prevention. For example, the influenza virus is renowned for its ability to continually evolve so that new strains emerge each year, giving rise to

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FIGURE 3-1 The Convergence Model. At the center of the model is a box representing the convergence of factors leading to the emergence of an infectious disease. The interior of the box is a gradient flowing from white to black; the white outer edges represent what is known about the factors in emergence, and the black center represents the unknown (similar to the theoretical construct of the “black box” with its unknown constituents and means of operation). Interlocking with the center box are the two focal players in a microbial threat to health—the human and the microbe. The microbe–host interaction is influenced by the interlocking domains of the determinants of the emergence of infection: genetic and biological factors; physical environmental factors; ecological factors; and social, political, and economic factors.

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annual epidemics and necessitating the ongoing development of new influenza vaccine strains. When the “germ theory” of disease was born in the late nineteenth century, Robert Koch and his contemporaries were convinced that diseases were caused by invariant, monomorphic microbial species. Early microbiologists dismissed the variants seen in petri dishes as mere contaminants— foreign entities that had floated into the culture medium from the atmosphere. Now, of course, the inherently variable nature of these early microbial species is well known. Microbes have enormous evolutionary potential and are continually undergoing genetic changes that allow them to bypass the human immune system, infect human cells, and spread disease. They may also traverse an alternative pathway that is a symbiotic accommodation to their hosts (see Box 3-2). Numerous microbes have developed mechanisms to exchange or incorporate new genetic material into their genomes; even unrelated species can exchange virtually any stretch of DNA or RNA. Genomic sequencing of pathogens made possible by technological advances shows that horizontal movement, or lateral transfer, of DNA is common and may be responsible for the emergence of many new microbial species. Lateral transfer can involve the exchange of virulence genes (genes that confer pathogenicity) and/or other genes required for adapting to a particular host or environment. Indeed, the exchange of virulence genes is so pervasive among bacterial pathogens that species-specific chromosome regions containing virulence genes have inspired their own name—“pathogenicity islands” (Ochman and Moran, 2001; Groisman and Ochman, 1996; Hacker et al., 1997; Hacker and Kaper, 2000). Some pathogenicity islands encompass very large genetic regions, as many as 100 kilobases long. The transfer of just a single pathogenicity island in E. coli is sufficient to convert a benign strain into a pathogenic one (McDaniel and Kaper, 1997). Pathogens have devised other means of adapting rapidly to new circumstances in their environment. RNA viruses, and retroviruses in particular, can mutate at very high rates, allowing them to adapt rapidly to changes in their external environment, including the presence of therapeutic drugs. Because microbes reproduce so quickly—as often as every 10 minutes— even very rare mutations build up rapidly in viral and bacterial populations. Many pathogenic bacteria have short runs of identical bases (“repeats”) in their DNA; very minor changes in these repeats occur commonly and result in changes in gene expression. Moreover, many bacteria and viruses can sense changes in the external environment, and depending on what they sense, their genes can enable virtually instant changes in the regulation of certain sets of other genes, thus allowing the microbe to adapt to the new environment.

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The more we learn about microbial genetics, structure, and function, the more we marvel at the sophistication of the survival strategies of microbes. Their mechanisms of survival are many and varied, and specific pathogens are generally tailored to flourish in particular niches. Many viruses and bacteria use our own cellular receptors to attach to and enter human cells; others utilize various human proteins for their own essential needs. Microbes use several means to defend themselves from being disabled or destroyed by the human immune system, including the rapid evolution of new antigenic variants, the masking of crucial surface antigens, inhibition of the immune system, and escape from the immune system by “hiding” inside human cells. Some microbes coat their surfaces with mimics of human tissue to prevent recognition by their human host as “nonself.” As a result, the human immune response is not activated, and the microbe is ignored and left to survive and reproduce at will. Some microbes have evolved mechanisms to downregulate the human innate immune system, which would otherwise serve as the human body’s first line of defense. Others stimulate an immune response that is injurious to the human host; for example, a sustained anti-self response may be triggered by viral or bacterial antigens that are molecular mimics of human antigens leading to chronic inflammation. Other strategies for survival include the ability to cause latent infections that can reactivate years later at a time when the host’s immune responses are blunted. Clearly, pathogens are extraordinarily adept (and successful) in carrying out their game of survival of the fittest. The development of preventive vaccines and antimicrobial therapies is among the greatest achievements of modern medicine. Unfortunately, the tremendous evolutionary potential of microbes empowers them with adeptness at developing resistance to even the most potent therapies and complicating attempts to create effective vaccines. In some cases, the antimicrobial drug target on the microbe mutates in such a way that binding of the antiviral or antibiotic no longer inhibits the virus or bacteria. For example, one of the major obstacles to the development of an effective vaccine against HIV is the very rapid antigenic change that the viral surface proteins undergo regularly. In fact, their mutation rate is so high that almost every retroviral particle is genetically different from every other particle by at least one nucleotide substitution. In other cases, bacteria have evolved enzymes that modify or destroy the antibiotic before it can reach its target inside the bacterium, or they “pump it back out” before it can do any damage to the microbe. Many genes for resistance can be transferred readily among different bacterial species; resistance can easily spread through multiple populations of species that occupy the same host environment. Acquisition of genes for resistance is advantageous for the microbe only when it is under attack by therapeutics. The adapted microbe may be slightly less fit in the absence of antimicrobial therapy, and thus the organ-

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BOX 3-2 The Microbiome Medical science is imbued with the Manichaean view of the microbe–human host relationship: “we good; they evil.” Indeed, the ascription of microbes to pathology has pervaded the teaching of biomedical science for over a century and consequently has left us with certain blind spots in our biological perspective of the pathogen–human host relationship. Obviously, microbes do have a knack for making us ill, killing us, and even recycling our remains to the geosphere. Nevertheless, in the long run, microbes have a shared interest in our survival. After all, if a pathogen does too much damage to its host, it will kill off not only the host but itself as well. “Domesticating” the host is a much better long-term strategy, and thus natural selection tends to favor less virulent pathogens that do not cause quite so much harm. Most successful parasites likely travel a middle path with regards to the amount of damage they do to their host; they need to be aggressive enough to enter the body surfaces and toxic enough to counter their host’s defenses, but once established they also do themselves (and their hosts) well by moderating their virulence. A better understanding of the host–pathogen relationship might be achieved by thinking of the host as a superorganism—or “microbiome”—with the host’s genome and those of all of the host’s indigenous microbes yoked into a chimera of sorts (Lederberg, 2000; Hooper and Gordon, 2001). The microbiome refers to the small biotic community that defines each of us as individuals, as well as the collective set of genomes that inhabit our skin, gut lumen, mucosal surfaces, and other body spaces. For the most part, the microbiome is a poorly catalogued ensemble, of which the majority of entries have yet to be cultivated and characterized, let alone understood with regard to their pathogenicity. Indeed, from a microbiome perspective, the mitochondria—which provide the oxidative metabolism machinery for every eukaryotic cell, from yeast to protozoa to multicellular organisms—can be regarded as the most successful of all human microbes. Mitochondria derive from an ancient lineage within the proteobacteria (Gray et al., 1999) and illustrate just how far the genomic collaboration between a host and a member of its indigenous microbial community can evolve. Until recently, infectious disease research has given sparse attention to how microbes have evolved adaptations for sustaining themselves as chronic inhabitants or “domesticators” of their human hosts. The evolutionary rate of large, complex multicellulars such as ourselves is, for the most part, simply too slow to evolve their own resistance and keep pace with the rapid evolution of microbes. A year in microbial history matches all of primate, perhaps mammalian, evolution. Not only do microbes evolve much more quickly than humans, but their enormous evolutionary potential is further enhanced by their sheer numbers as well as their many ingenious mechanisms of gene exchange (e.g., conjugation and plasmid interchange). Microbes can go beyond inhabiting our body space to completely set up genetic shop. Retroviruses, for example, are unable to replicate until they have become integrated into the host DNA; thereafter, their replication involves simply the fairly standard transcription of host chromosomal DNA into RNA copies. Indeed, it appears that some of the so-called HERVs (human endogenous retroviruses), with which the human genome is so heavily populated, have evolved so far as to participate in the physiology of our placenta and in our gustatory behavior. We have no idea what pathways HERVs have used to reach their target, nor can we predict the long-term consequences of their further evolution. But experience has shown we have every reason to expect that our

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most notorious retrovirus, HIV, will find a way to lodge itself in the germ line as well. The human genome encodes some 223 proteins with significant homology to bacterial proteins, suggesting that they were acquired from bacterial sources via horizontal transfer (Lander et al., 2001). These apparent insertions from microbial sources serve as further evidence of a historic host–microbe collaboration among the various components of the microbiome. Our focus on “conquering” infectious disease may deflect from more ambitious, yet perhaps more pragmatic, aims; little consideration has been given to the notion that perhaps we could learn to live with a pathogen instead of being so insistent on getting rid of it. Natural history abounds with infections that have, over the course of evolutionary history, achieved a mutually tolerable state of equilibrium with their host. Genetic variation of the influenza A virus, for example, has remained stable in its wild aquatic bird reservoir, and infected avians often show no sign of disease. Although the recognition of AIDS in 1981 has inspired the most intense biomedical research program in history, the incidence of disease is only increasing. Would this trend reverse if, instead of focusing exclusively on ways to conquer HIV, we were to give equal weight to developing therapeutic measures that nurtured the immune system that HIV erodes? Indeed, consider that many of the microbes that reside in our gut—such as Lactobacillus spp.—actually serve a protective, not a pathogenic, role. In fact, their protective advantage is currently being exploited in so-called “probiotic” therapy—the administration of live, benign microbes that benefit the host and aid in the treatment of disease (Hooper and Gordon, 2001; IOM, 2002b). Although scientists have known about the health benefits of lactic acid bacteria in particular for more than a century, the broader concept of probiotic therapy is a recent one (IOM, 2002b; Fuller, 1989). In addition to Lactobacillum, other probiotic preparations have contained Bifidobacterium, Streptococcus spp., and E. coli. Thus far, probiotic therapy has proven most beneficial in treating active ulcerative colitis, as well as complications following surgical intervention for that condition (Gionchetti et al., 2000; Rembacken et al., 1999). Probiotic lactobacillus may even prove useful in strengthening immune responses in persons infected with HIV. Normal bacterial flora are altered in HIV infection, as evidenced by the frequency of bacteremia associated with altered gastrointestinal function, diarrhea, and malabsorption; and failure-to-thrive, which is linked to altered gastrointestinal function, is relatively common in congenital HIV infection. Recent studies have shown that the effect of L. plantarum 299v, a specially developed probiotic lactobacillus, has a generally beneficial effect on the immune response in HIV-infected children (Cunningham-Rundles and Nesin, 2000). The concept of probiotic therapeutics extends even beyond simply introducing a living microbe. Recent studies have demonstrated that genetically engineered gut commensal bacteria can be used as drug delivery platforms to treat infectious disease (Steidler et al., 2000; Beninati et al., 2000; Shaw et al., 2000). Other possible uses of probiotic therapy include using microbial products that target specific disease processes, such as weakened epithelial barriers or reduced activity of the mucosal immune system (Hooper and Gordon, 2001); using microbes that bear relevant cross-reacting epitopes instead of vaccines; and using them as optional food additives (Lederberg, 2000). The rewards of a microbiomal perspective on infectious disease could be great. Not only would we achieve new insights with regard to how we and the microbes around and within us adapt to each other, and thus how pathogens emerge, but we would likely develop new approaches to preventing and treating infectious diseases.

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ism may slowly revert to a sensitive state when therapy is withdrawn. Thus, the frequency of antimicrobial use is key; less use results in less resistance, while more use leads to more resistance. Unfortunately, antibiotics are frequently used when they are not truly needed (see the discussion of inappropriate use of antimicrobials in Chapter 4). HUMAN SUSCEPTIBILITY TO INFECTION Many properties of the human body—from its genetic makeup to its innate biological defenses—affect whether a microbe will cause disease. The body has evolved an abundance of physical, cellular, and molecular barriers that protect it from microbial infection, beginning with the skin. Even minor breaks in the skin increase susceptibility to infection. The normal bacterial flora of the gut and inner mucosal surfaces serve a protective role; not only do they occupy receptors to which pathogenic bacteria would otherwise attach themselves, but they produce antimicrobial substances that inhibit the growth of their pathogenic competitors. When these normal bacterial flora are reduced, as happens when a broad-spectrum antibiotic is used to treat an infection or when acidity in the stomach is reduced through various medications, the body is more susceptible to pathogens. Another protective defense mechanism is seen with the enzyme lactoferrin, which is plentiful in breast milk and on mucosal surfaces. Lactoferrin serves a protective role by sequestering iron, thereby making the mineral unavailable to invading pathogens that need it to reproduce. Susceptibility to infection can result when these normal defense mechanisms are altered or when host immunity is otherwise compromised as a result of impaired immune function; genetic polymorphisms; and other factors, such as aging and poor nutrition. Impaired Host Immunity The innate or nonspecific immune response is the body’s initial inflammatory reaction to any kind of injury or microbial invasion. Innate immune defenses are believed to have first evolved in insects and other lower organisms that lack the ability to produce antibodies and thus depend entirely on this primitive but effective system for their protection against infection. In humans, more than a dozen different so-called TLRs (TOLL-like receptors)1 have been found on cells that make up the mucosa and skin (including macrophages and dendritic cells), which is where pathogens first encounter their human host. When foreign molecules, such as bacterial DNA 1   TOLL is a gene first discovered in Drosophila.

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or flagella, bind to TLRs, they trigger a complex set of responses that leads to the production of inflammatory cytokines and local antimicrobial peptides. When the inflammation is inadequate to deal with an injury or microbial invader, the so-called adaptive or acquired specific immune response kicks in. This mechanism encompasses both cell-mediated and humoral responses. The former involves the production of antigen-specific T cells, which, depending on their surface protein makeup, serve a variety of functions, such as influencing the activities of other immune cells; the latter involves the production of antigen-specific B cells, which produce humoral antibodies. New knowledge about the innate and specific immune responses is being used to develop potential therapies for infectious disease control. For example, the key to a good innate immune system defense is a balanced, regulated production of inflammatory cytokines. Otherwise, microbial infection can provoke such a massive release of inflammatory cytokines as to seriously damage and even kill their host. Researchers are exploring ways to interrupt the TLR pathways in order to either downregulate overly active inflammatory responses or upregulate weak responses. These could be useful strategies in the treatment of infectious diseases for which no otherwise effective specific therapies exist. Genetic Polymorphisms J.B.S. Haldane (1949) was among the first to suggest that pathogens serve as potent natural selective forces that have helped shape the evolution of human defenses against infection (Hill, 1998; Weatherall, 1996a; Lederberg, 1999). In particular, Haldane predicted that people who live in historically malaria-laden areas may have evolved genetic polymorphisms—in particular, heterozygous hemoglobinopathies—that increase their ability to survive infection with malaria. Hemoglobinopathies are a group of diseases caused by or associated with the presence of abnormal hemoglobin in the blood; they are one of the most common single-gene disorders in humans. The hemoglobin gene has several allelic variants, including hemoglobin S, which, if homozygous, causes sickle cell disease. Hemoglobin S heterozygotes have the sickle cell trait and are virtually asymptomatic; however, they exhibit 80 to 95 percent protection against P. falciparum infection (Weatherall, 1996b). Hemoglobin S homozygosity exacts a cost in adverse health effects (as many persons of African descent have sickle cell disease), but clearly the protective power of this particular allelic variant is still under major selective pressure. Indeed, in areas free of malaria, sickle cell trait and sickle cell disease are very rare, or generally found only in lineages who have migrated from malaria-laden areas. Another structural hemoglobin variant, hemo-

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globin E, occurs at high frequencies throughout the Indian subcontinent, Burma, and Southeast Asia; in some areas, carriers make up as much as 50 percent of the population. Like hemoglobin S, hemoglobin E protects against P. falciparum (Flint et al., 1993; Weatherall, 1996b). More common than the structural variants hemoglobin S and E are a group of anemias known as thalassemias, which result from a defective production rate of either the alpha or the beta chain of the hemoglobin polypeptide. Again, heterozygotes are usually asymptomatic, and protection against malaria appears to have been the major selective force responsible for the more than 120 different beta thalassemia mutations, as well as the many different alpha thalassemia mutations (Weatherall, 1996b). The biological mechanism underlying the protective power of the heterozygous hemoglobinopathies is still unclear. The presence of malaria in a population does more than modify hemoglobin. Several other malaria-related balanced polymorphisms, many of which involve the red blood cell structure and metabolism, have likewise evolved in response to the tremendous selective force exerted by the disease. Glucose-6-phosphate dehydrogenase deficiency (an X-linked chromosomal disorder), for example, serves a protective role in heterozygous female carriers and hemizygous males (Ruwende et al., 1995). Heterozygous carriers of a mutation in band 3 of the red blood cell membrane, which in its homozygous state causes the potentially lethal melanesian ovalocytosis, may also have a protective advantage. Finally, different blood group antigens may have evolved in response to past exposure to malaria (Miller, 1994). Racial differences in the distribution of certain red blood cell receptors for malaria parasites have been observed, possibly as a result of evolutionary genetic selection (IOM, 1991; Barragan et al., 2000; Hamblin et al., 2002). The Duffy antigen (a name taken from the hemophilia patient in whom it was first identified) is a parasite receptor on red blood cells that is recognized by certain forms of malaria, including P. vivax and P. knowlesi. Many persons of African descent lack the Duffy gene and therefore cannot be infected by either of these malaria parasites. Other balanced polymorphisms have apparently evolved in response to malaria. For example, the tumor necrosis factor alpha gene and the HLA-DR class II genes both have polymorphic systems that have been linked to malaria (Hill et al., 1991). The remarkable human genetic diversity that has evolved in response to malaria, and that scientists have only just begun to uncover, suggests that other less common or less studied infections have probably generated extraordinary diversity as well. Fortunately, knowledge gleaned from the human genome project and its technological offshoots is leading to a dramatic explosion in new understandings of polymorphisms in a variety of genes that alter the response to infection. One of the most recently reported links between infection and natural selection is a deletion

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in the host-cell chemokine receptor CCR5, which reduces the risk of acquiring HIV infection after exposure (Sullivan et al., 2001). As another example, certain major histocompatibility complex class I molecules have been shown to reduce the risk of dying from HIV infection (Kaslow et al., 1996; Gao et al., 2001). Likewise, several different mutations or polymorphic systems influence the susceptibility to or likelihood of death from meningococcal infection (Read et al., 2000; Nadel et al., 1996; Westendorp et al., 1997). Numerous other examples exist of genetic associations with diseases, including cancers and chronic diseases, and the list is growing rapidly (Hill, 2001; Topcu et al., 2002; Chen et al., 2002a; Calhoun et al., 2002; Helminen et al., 2001; Pain et al., 2001). Malnutrition Host susceptibility to infection is aggravated by malnutrition. A strong and consistent relationship has been found between childhood malnutrition and increased risk of death from diarrhea, acute respiratory infection, and possibly malaria (Rice et al., 2000). Conversely, infectious processes, especially those associated with diarrhea, drive malnutrition in young children (Mata, 1992; Mata et al., 1977), so that diarrheal illness is both a cause and an effect of malnutrition (Guerrant et al., 1992; Wierzba et al., 2001; Lima et al., 1992). Clinically, malnutrition is characterized by inadequate intake of protein, energy, and micronutrients and by frequent infections or disease (WHO, 2002d). Malnutrition has been associated with 50 percent of all deaths among children worldwide (Rice et al., 2000). In 2000, an estimated 150 million of the world’s children under age 5 were malnourished on the basis of low weight for age (WHO, 2002d). More than two-thirds (70 percent) of these children were in Asia, especially southern Asia. The number of malnourished children living in Africa—26 percent of the world’s malnourished children—has risen as a result of population growth in the region, as well as natural disasters, wars, civil disturbances, and population displacement (WHO, 2000b). Malnutrition diminishes host resistance to infection through a number of mechanisms. Virtually all bodily processes and physical barriers that keep infectious agents from invading the host are affected. These include the skin, mucous membranes, gastric acidity, absorptive capacity, intestinal flora, cell-mediated immunity, phagocyte function, and cytokine production (Chandra, 1997; Levander, 1997). Although multiple-nutrient deficiencies are much more common than single-nutrient deficiencies, lack of even one vitamin or mineral (e.g., zinc; selenium; iron; copper; vitamins A, C, E, B-6, and folic acid) can impair the immune response. For example, vitamin A deficiency significantly increases the risk of severe illness and death from common childhood infections, such as diarrheal disease and

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20 million deaths worldwide and affected more than 200 million people. In only a few months, it killed more people than had been killed in battle during the 4 years of World War I (1914 to 1918). Viruses descended from the pandemic strain continued to cause annual epidemics from 1920 to 1956. The “Asian flu” pandemic (caused by an H2N2 virus) killed approximately 70,000 persons in the United States. The most recent pandemic, the 1968 “Hong Kong flu,” killed approximately 34,000 persons in the United States. Thus, a pattern is evident: each pandemic is followed by relatively mild yearly epidemics caused by related viruses for which the populace enjoys widespread immunity. After a time, however, the evolving influenza virus gene pool inevitably produces a strain to which humans have no immunity. If we are unlucky, it is a highly transmissible and lethal strain. Disturbingly, in 1977 an H1N1 virus similar in all respects to a virus from 1957 reappeared in humans in Northern China. This virus was not highly lethal—in fact, it caused only moderate respiratory illness in persons under 20 years of age. The cause of great concern was the possibility that this virus could have come from a frozen source, released accidentally from a laboratory. This event raises the specter of the reappearance of H2N2 influenza viruses that have been stored since the pandemic of 1957. No one born after 1957 has high-level immunity to these viruses, and the biosecurity of such agents is a matter of increasing concern. It has now been more than 30 years since a new pandemic influenza virus has emerged. The world’s influenza advisory groups have warned that a new pandemic is not only inevitable, but overdue. Impact of Influenza on Society and the Economy The social and economic impacts of influenza are most apparent during a pandemic. During the lethal wave of the 1918 Spanish flu pandemic (October–November 1918), cities throughout the world were unable to bury their dead; in undeveloped areas, entire villages perished. The social and economic burden of influenza during interpandemic periods is less well studied, especially in tropical areas where malaria and diarrheal diseases remain major problems. However, studies in Canada, the United States, and Holland have shown that annual epidemics of influenza have a major impact on hospital costs among children and the elderly and reduce productivity. Indeed, after evaluating the economic impact of interpandemic influenza, several countries have recommended the annual use of influenza vaccine. In the United States, this recommendation has been extended to all persons aged 50 years or older and those at high risk because of underlying diseases or immunosuppression. The province of Ontario, Canada, has made the most progress in this respect; in 2002, vaccination was offered free of charge to everyone over 6 months of age. In other provinces of

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Canada, vaccination is still recommended for those aged 65 and older and for all high-risk groups. Broader vaccination has not been pressed in the United States, purportedly because of limited supplies of vaccine. The result is a vicious cycle, however, as manufacturers will not produce quantities in excess of the certain demand. Genetic and Biological Factors Microbial Adaptation and Change Influenza virus is ideally designed for continuous evolution. Its highly variable antigenic domains, which are situated at the outer end of the spike glycoproteins, permit maximal variability without compromising the function or assembly of the virion (see Figure 3-10) (Lamb and Krug, 2001). The virus’s genome comprises eight RNA segments that can be shuffled or reassorted in cells that are coinfected with multiple viruses. Because of the lack of proofreading mechanisms, influenza virus undergoes an extremely high rate of mutation as it replicates (approximately 1.5 × 10–5 mutations per nucleotide per replication cycle). To cope with the continual genetic variation of human influenza viruses, WHO has established a worldwide network of more than 100 laboratories that isolate viruses for antigenic and molecular analysis (Cox and Subbarao, 2000). These analyses form the basis of WHO’s annual recommendations for influenza vaccines for the Northern and Southern Hemispheres. Unlike influenza viruses in humans, influenza viruses in their natural aquatic bird reservoirs appear to be in evolutionary stasis (Webster et al., 1992). Some avian influenza viruses have shown no changes in their surface glycoproteins for more than 50 years. The RNA continues to undergo mutation, but the mutations provide no selective advantage; these influenza viruses have become perfectly adapted to their natural hosts over the course of time. After transfer to a new host, however, the viruses evolve rapidly, undergoing a high rate of nonsynonymous mutation that alters their amino acid structure. The existence of five host-specific lineages of influenza (in humans, horses, pigs, domestic poultry, and sea mammals) indicates that aquatic avian influenza viruses have adapted to these species, overcoming differences between avian and mammalian hosts in body temperature, cell surface receptors, and mode of transmission (see Figure 3-11). In aquatic birds, influenza virus is an enteric parasite that is transmitted by ingestion of fecally contaminated water. In humans, the virus replicates in the respiratory tract and is transmitted via aerosol. The available evidence suggests that the avian–human transition is accomplished via infection of pigs. Pigs possess receptors for both avian (α 2–3 terminal sialic acid) and human

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FIGURE 3-10 Diagram of influenza virus. The surface of the influenza virus particle is comprised of three kinds of spike glycoproteins—the hemagglutinin (HA) that attaches the viruses to sialic acid residue on the respiratory tract; neuraminidase (NA), an enzyme that releases the influenza virus from infected cells and is the target of the anti-neuraminidase drugs; and matrix (M2) protein, which is an ion channel and is the target for the antiviral agents amandatine and rimantadine. The spike glycoproteins are embedded in a lipid bilayer obtained from the host cell. The inside of the lipid bilayer is lined by the matrix protein (M1). A core of the virus contains eight single-stranded RNA segments of negative sense that permits genetic mixing (reassortment) when two different viruses infect a single cell. The polymerase complex (PB2, PB1, PA, NP) is involved in viral replication. The two smallest segments (M and NS) each encode two proteins in different reading frames. The NS gene is important in regulating the host cell response to influenza virus infection.

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FIGURE 3-11 The reservoir of influenza A viruses. The working hypothesis is that wild aquatic birds are the primordial reservoir of all influenza viruses for avian and mammalian species. Transmission of influenza has been demonstrated between pigs and humans and between chickens and humans but not between wild birds and humans (dotted lines). There is extensive evidence for transmission of influenza viruses between wild ducks and other species (solid lines). The five different host groups are based on phylogenetic analysis of the nucleoprotein genes of a large number of different influenza viruses. (α 2–6 terminal sialic acid) influenza viruses and thus can act as intermediate hosts. In this respect, it is noteworthy that both the 1918 Spanish and the 1968 Hong Kong pandemic viruses were isolated from pigs and from humans at approximately the same time. The interspecies transmission of influenza usually results only in transitory, localized disease that may be mild to severe. The H5N1 “bird flu” incident in Hong Kong in 1997 was such an incident. Six of eighteen infected persons died, but a stable lineage was not established (see Figure 3-12). The possibility that the virus might

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FIGURE 3-12 Direct transmission of avian influenza viruses to humans. In 1997, avian influenza viruses transmitted directly to humans in Hong Kong killed 6 of 18 persons(Left). In 1999, a quail influenza virus transmitted to humans in Hong Kong and caused mild respiratory infection in two children (Right). Five additional cases of H9N2 influenza have been reported from humans in Mainland China. It is noteworthy that the two influenza viruses from avian species that infected humans contain identical internal genes (PB2, PB1, PA, NP, M, NS—black gene segments) suggesting that these gene segments contain unique regions that facilitated transmission to humans. adapt to humans, however, was sufficiently disquieting to prompt the wholesale slaughter of poultry in Hong Kong on two occasions. During and after adaptation of influenza viruses to a new host, a continuing battle for supremacy occurs between microbe and host. The innate and adaptive human immune responses battle to clear the virus, while the virus evolves strategies to circumvent the immune responses. The virus stays a few steps ahead of natural or vaccine-induced human immunity by means of antigenic drift, or the accumulation of amino acid substitutions in the antigenic epitopes on the spike glycoproteins (hemagglutinin [HA] and neuraminidase [NA]) to which neutralizing antibodies bind. Genetic shift, or the acquisition of new gene segments from the aquatic bird reservoir, can completely change the epitopes that evoke humoral and cell-mediated immunity. This phenomenon may explain in part the devastation wreaked by

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the 1918 Spanish flu pandemic. The microbe has also developed ways to downregulate the innate immune response. One of the nonstructural proteins of influenza A viruses (NS1) is an interferon agonist that downregulates interferon—a natural inhibitor of influenza viruses (Garcia-Sastre, 2002). The yearly epidemics of influenza attest to the ongoing battle between host and virus. Human interventions—vaccines and antivirals—are efficacious on an individual basis, but have had little effect on the global spread of the disease. Two classes of antivirals are used against influenza viruses: the adamantines, which block the ion channel formed by the influenza matrix (M2) protein, and the neuraminidase inhibitors, which prevent virus release by blocking NA enzyme activity (Hayden, 2001). The virus is able to circumvent these antivirals through the natural selection of resistant mutants. Resistance to the adamantines emerged in the first patients who were treated. However, the microbe has had less success in developing resistance to the NA inhibitors. Resistance to these agents requires mutations in both HA and NA, and the NA mutation compromises transmission of the virus. Thus, resistance can be achieved only at a price to the virus. In summary, the challenges presented by influenza virus reflect its ability to alter itself with remarkable rapidity. This characteristic allows it to survive, to adapt to new hosts, and to evade control strategies. Human Susceptibility to Infection The most severe influenza virus infection experienced by most humans is the first infection acquired after the decline of maternal antibodies; the outcome depends on the competency of the individual’s immune function and on the pathogenic potential of the specific variant of influenza virus. Patients who are immunosuppressed because of disease or therapy may shed influenza virus for long periods, and a greater likelihood exists in these individuals that the virus will acquire resistance to natural immune mechanisms and to antiviral therapy. The pathogenicity of influenza virus strains may also differ among host groups. Young adults were most susceptible in the 1918 pandemic, despite peak immune competence at that age. The future may reveal that the virus was able to downregulate the host immune response through as-yet unrecognized mechanisms. Pacific Island communities also appeared to differ in their susceptibility to the 1918 Spanish flu. The death rate among the Maori population in New Zealand was 43.3 per 1,000 people—almost six times the death rate among New Zealanders of European extraction. Socioeconomic factors account for some but not all of this difference. Other possible factors include the absence of previous exposure of the Maori population to any influenza virus.

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The main preventive human defense mechanism against influenza virus infection is humoral immunity (i.e., antibodies) to the highly variable HA and NA spike glycoproteins of the virus. To recover from influenza infection and remove infected cells, on the other hand, the body depends on cell-mediated immunity. Thymus-derived lymphocytes (T cells) recognize specific antigenic epitopes on the viral nucleoprotein and polymerase proteins, and they cross-react with these epitopes on other influenza virus strains. Both types of specific immune response require prior exposure to the virus. Therefore, an immune-naïve child, who has developed neither humoral nor cell-mediated immunity to the virus, may have a severe respiratory infection. On exposure to a second influenza virus that is antigenically similar to the first but has undergone antigenic drift, the child will be infected but will recover more rapidly because of the cross-reactive cell-mediated immune response. However, there is a conundrum associated with the immune response to highly variable microbes. The child’s second exposure to influenza virus will induce a response directed mainly against the first influenza virus encountered. In this phenomenon, known as original antigenic sin, the immune system retains a lifelong memory of the first virus exposure in childhood. Thus, the antibody response is misdirected, and the efficacy of humoral immunity is reduced. This mechanism affects immunity to all infectious agents that undergo antigenic drift, including HIV. Ecological Factors Fifteen HA and nine NA subtypes of influenza A viruses circulate in the aquatic birds of the world. The viruses cause no apparent disease in these natural hosts, with which they appear to be in near-perfect equilibrium (Webster et al., 1992). Phylogenetically, these viruses can be divided into two clades, one in the Americas and the other in Eurasia. To date, only three of the fifteen HA subtypes have established lineages in humans. It is possible that only those subtypes have the capacity to infect humans. However, the direct transmission of avian H5N1 and H9N2 influenza viruses to humans in Hong Kong in 1997 and 1999 suggests the possibility that all subtypes can infect humans. The adaptation of influenza viruses to wild aquatic birds that migrate over vast distances (e.g., from southern South America to the North Slopes of Alaska) is an evolutionary strategy that allows the widespread fecal dissemination of the viruses at no apparent cost to the host. It is only after transmission and adaptation to mammals or domestic poultry that the virus evolves into a disease-causing microbe.

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Social, Political, and Economic Factors Animal Husbandry, Human Behavior, and Travel The human population of the world continues to increase, as does the number of animals required to feed it. China has seen the most dramatic rise in the number of animals over the past decade. The demand for meat protein has increased strikingly as the result of socioeconomic progress, and populations of pigs and chickens have grown exponentially. Zoonotic disease potential inevitably increases in proportion to the animal population. Poultry, pigs, and people are the known hosts of influenza viruses, and most of the influenza pandemics of the twentieth century have originated in China. Substantial influenza activity has been noted in Hong Kong, which is hypothesized to be a documentable epicenter for the emergence of influenza pandemics. In 1997, avian H5N1 influenza virus was transmitted directly from poultry to humans, killing six of eighteen infected persons. In 1999, avian H9N2 influenza viruses were transmitted to two children and caused mild respiratory disease (see Figure 3-12). In 2001 and 2002, H5N1 viruses that are highly pathogenic to poultry and to mammals (as shown by testing in mice) reappeared in Hong Kong. To prevent spread to humans of the 2001/H5N1 viruses, all of the poultry in Hong Kong was killed and buried. Since 2001, all poultry markets in Hong Kong have been emptied on the same day each month to reduce the buildup of virus. Despite these precautions, however, all of the elements are in place to generate a new pandemic: vast numbers of the primary and secondary susceptible hosts on the mainland and in Hong Kong, and a constantly evolving pathogen. It is inevitable that an influenza pandemic strain will emerge from this mix. However, the purchase of live poultry is a long-standing tradition, and thousands of people are employed in that industry. A change to the Western-style sale of chilled or frozen slaughtered poultry will meet with resistance until health authorities and the public recognize the ultimate cost of a new pandemic in Asia. Technical and political factors are also at work. The wide availability of refrigeration has now rendered the live poultry markets obsolete, but cultural preferences remain a strong political impediment to regulatory change. As a long-term solution, live poultry markets should be closed not only in Asia, but also in New York City. The markets in New York City are a factor in the emergence of the H7N2 influenza viruses that are causing great losses in the poultry industry in the northeastern United States. More than 4 million birds have had to be slaughtered, and the disease outbreak has prompted a ban on U.S. poultry in Japan. Besides the live markets, close monitoring of other crowded flocks of poultry will be needed.

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Modern air travel (discussed earlier) will inevitably hasten the spread of a new pandemic of influenza. Once the virus appears in a major urban area, modern travel will allow its global distribution within a matter of days. The economic impact of an outbreak of highly pathogenic influenza was clearly seen in Hong Kong in 1997. The tourist and poultry industries collapsed because of the H5N1 “bird flu” incident, and Hong Kong suffered a severe economic downturn. Intent to Harm Recent advances in reverse genetics of influenza viruses now make it possible to generate influenza viruses to order (Neumann and Kawaoka, 2001). This new technology can reduce the time needed for vaccine preparation by 1 to 2 months if all other necessary resources are available. Perhaps more important, it will allow us to discover the molecular basis of the lethality of some viruses, such as the 1918 Spanish flu pathogen, and identify new targets for intervention in both the microbe and the host. Unfortunately, this new knowledge will also make it possible to generate extremely deadly agents—to recreate the 1918 Spanish flu virus, for example, or to add the H5N1 bird flu genes to a human influenza strain. Although influenza is not high on the list of bioterrorism agents, it has the potential to wreak widespread havoc on human life or to devastate important agricultural resources. Influenza is an exemplar of nature’s natural biowarfare; it now has the added potential to be used by humans for intentional harm. Pandemic Preparedness Influenza is not an eradicable disease. It has now been more than 34 years since the Hong Kong/68 (H3N2) pandemic, and, as noted, all influenza virologists agree that a new pandemic is imminent. All of the developed countries of the world and WHO have created influenza pandemic plans to deal with such an event, and WHO is in the process of developing a Global Agenda for Influenza. Key issues in the global agenda are improvement of global surveillance, assessment of the global burden of influenza, and acceleration of vaccine development and usage. The disturbing reality is that despite the certainty of a pandemic, even the developed countries of the world are quite unprepared for such an event. The public health infrastructure is inadequate. Hospitals lack the capacity to accommodate a surge of patients. Vaccine manufacturers had severe problems in meeting the demand in 2001 and 2002, the mildest influenza years in two decades, and the repertoire of antiviral drugs is completely inadequate. And increasing bacterial resistance to antibiotics

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raises questions about our ability to deal effectively with secondary pneumonia, a common cause of influenza deaths. If a country cannot cope with interpandemic influenza, it is likely that the pandemic, when it does occur, will cause massive societal disruption. Such disruption cannot be prevented, but it can be lessened if we take action now. A minimum of 6 months is needed to prepare a new influenza vaccine. Only 11 companies worldwide manufacture influenza vaccine, and all of these companies together could not prepare a sufficient quantity even for national, let alone global needs. Therefore, the only immediately available strategy in the face of an influenza pandemic is the use of antivirals. Supplies of these agents are currently tailored to meet very low demand, and it takes an estimated 18 months to manufacture significant quantities of the drugs from the starting materials. Therefore, anti-influenza drugs will be available only if they are stockpiled in advance of a pandemic. Modeling studies are needed to plan the most effective use of such a stockpile of drugs. The steps needed to deal effectively with interpandemic influenza can also help in preparing for an influenza pandemic. The new initiative promoting universal influenza vaccination in Ontario, Canada, can serve as a model for the world. If demonstrated to be effective, it should be expanded to other areas. Unless vaccine usage is substantially increased during interpandemic years, vaccine manufacturing capacity will be inadequate to meet the demand generated by a pandemic.

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