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5 Infectious Disease Emergence: Past, Present, and Future
Pages 193-272

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From page 193...
... In the chapter's first paper, Morse describes two distinct stages in the emergence of infectious diseases: the introduction of a new infection to a host population, and the establishment within and dissemination from this population. He considers the vast and largely uncharacterized "zoonotic pool" of possible human pathogens and the increasing opportunities for infection presented by ecological upheaval and globalization.
From page 194...
... In contrast to other contributors to this chapter, who focus on what, why, and where infectious diseases emerge, Jonathan Eisen, of the University of California, Davis, considers how new functions and processes evolve to generate novel pathogens. Eisen investigates the origin of microbial novelty by integrating evolutionary analyses with studies of genome sequences, a field he terms "phylogenomics." In his essay, he illustrates the results of such analyses in a series of "phylogenomic tales" that describe the use of phylogenomics to predict the function of uncharacterized genes in a variety of organisms, and in elucidating the genetic basis of a complex symbiotic relationship involving three species.
From page 195...
... Daszak's group constructed a database of emerging infectious disease "events" first reported in human populations between 1940 and 2004, which they have used to examine correspondences between events and ecological variables, such as human population density and wildlife diversity, in a geographical context. These analyses have revealed "hotspots" for infectious disease emergence.
From page 196...
... Of course, there are also forgotten infections that reappear. We sometimes call those "reemerging infections." I tend to think of most of the "reemerging" infections as reminding us that many infectious diseases in our highly mechanized modern societies, with the standard of living we enjoy, have been pushed to the margins, but have never been entirely eliminated.
From page 197...
... But a disease that actually kills by undermining the immune system directly was a novel mechanism of pathogenesis. How often does one find a new mechanism of pathogenesis in an infectious disease, considering the thousands of years of experience that we have had?
From page 198...
... You can pick your favorite: Ebola in 1976; hantavirus pulmonary syndrome, which I will discuss briefly in a moment; Nipah, which Peter Daszak addressed at the workshop (and his group has done some excellent work on this) ; SARS; and, of course, influenza, which still continues to surprise us.
From page 199...
... bitmap image SOURCE: Reprinted from Morens et al.
From page 200...
... Table 5-1 lists just some of these cases. The basic point is that there are a number of ecological changes, many of them anthropogenic, which provide new opportunities for pathogens to emerge and gain access to human populations.
From page 201...
... Jim Hughes, who is a Forum member and was the director of the National Center for Infectious Diseases (NCID) at the Centers for Disease Control and Prevention (CDC)
From page 202...
... , natural host for the Sin Nombre (hantavirus pulmonary syndrome) Figure 5-3.eps virus, with her young.
From page 203...
... and another hantavirus of rats, Seoul virus, and related variants that could be found in port cities; neither was associated with serious acute disease in the United States. After 1993, we had to add another: the virus that causes hantavirus pulmonary syndrome.
From page 204...
... In pandemic influenza viruses, the novel or new genes tend to come from avian influenza viruses that then reassort, often with mammalian influenza genes (or at times the virus may possibly go directly from avian to human, although that seems to be a relatively rare event)
From page 205...
... there is certainly open territory for influenza virus dissemination along any of the Old World flyways for bird migration. As a result of all of those movements of birds, both migratory fowl and domestic poultry, we have seen a number of outbreaks of H5N1 avian influenza, starting in Asia, but extending into Europe and Africa as well.
From page 206...
... Clinicians usually assume community-acquired pneumonia is not very transmissible -- a major mistake here, as this turned out to be, unfortunately, an exception. He then went to Hong Kong, where he stayed at the Hotel Metropole, a popular business hotel, and became sick.
From page 207...
... report. These factors have since been augmented and embellished in the new version of the IOM Emerging Infections report, titled Microbial Threats to Health, published in 2003 (Box WO-3; IOM, 2003)
From page 208...
... . 4 Centre for Infectious Diseases, University of Edinburgh, Edinburgh, United Kingdom.
From page 209...
... This focus on novel pathogens differs somewhat from the more general topic of "emerging infectious diseases," which is often taken to include previously rare disease which are now on the increase, and sometimes diseases once considered to be in decline but which are now resurgent -- the socalled "re-emerging" diseases. However, our focus does fairly reflect one of the major public health concerns of the early 21st century, the possible emergence of new pathogens species and novel variants (OSI 2006)
From page 210...
... , making direct comparisons of different "species" potentially problematic. With these caveats noted however, a survey of recognized species represents a natural starting point for investigations of the diversity of human pathogens.
From page 211...
... Strictly speaking, only the first of these possibilities constitutes an "emerging" infectious disease as defined earlier. In practice, however, most post-1980 pathogens probably fall into categories (2)
From page 212...
... . Moreover, some new human pathogens were already endemic or ubiquitous in the human population when they were first discovered; examples include human metapneumovirus and human bocavirus.
From page 213...
...  INFECTIOUS DISEASE EMERGENCE TABLE 5-3 Dates of First Reports of Human Infection with Novel Pathogen Species Human bocavirus 2005 Dobrava-Belgrade virus 1992 Human coronavirus HKU1 2005 1991 Ehrlichia chaffeensis Human T-lymphotropic Virus 3 2005 1991 Encephalitozoon hellem Human T-lymphotropic Virus 4 2005 Guanarito virus 1991 Human coronavirus NL63 2004 1991 Nosema ocularum SARS coronavirus 2003 Banna virus 1990 2002 Gan gan virus 1990 Cryptosporidium hominis Baboon cytomegalovirus 2001 Reston Ebola virus 1990 Human metapneumovirus 2001 Semliki Forest virus 1990 2001 Trubanaman virus 1990 Cryptosporidium felis Whitewater Arroyo virus 2000 1990 Vittaforma corneae 1999 1989 Brachiola algerae Corynebacterium amycolatum 1999 European bat lyssavirus 1 1989 Ehrlichia ewingii Nipah virus 1999 Hepatitis C virus 1989 TT virus 1999 Barmah Forest virus 1988 1998 Picobirnavirus 1988 Brachiola vesicularum Menangle virus 1998 Dhori virus 1987 1998 Sealpox virus 1987 Trachipleistophora Suid herpesvirus 1 1987 anthropophthera 1997 1986 Bartonella clarridgeiae Cyclospora cayetanensis Laguna Negra virus 1997 European bat lyssavirus 2 1986 Andes virus 1996 Human herpesvirus 6 1986 Australian bat lyssavirus 1996 Human immuno-deficiency virus 2 1986 BSE/CJD agent 1996 Kasokero virus 1986 1996 Kokobera virus 1986 Ehrlichia canis Juquitiba virus 1996 Rotavirus C 1986 1996 Borna disease virus 1985 Metorchis conjunctus 1996 1985 Trachipleistophora hominis Enterocytozoon bieneusi Usutu virus 1996 1985 Pleistophora ronneafiei Bayou virus 1995 Human torovirus 1984 Black Creek Canal virus 1995 Rotavirus B 1984 Cote d'Ivoire Ebola virus 1995 1984 Scedosporium prolificans Hepatitis G virus 1995 Candiru virus 1983 New York virus 1995 1983 Capnocytophaga canimorsus 1994 1983 Anaplasma phagocytophila Helicobacter pylori Hendra virus 1994 Hepatitis E virus 1983 Human herpesvirus 7 1994 Human adenovirus F 1983 Human herpesvirus 8 1994 Human immuno-deficiency virus 1 1983 Sabia virus 1994 1982 Borrelia burgdorferi 1993 Human T-lymphotropic Virus 2 1982 Bartonella elizabethae 1993 Seoul virus 1982 Encephalitozoon intestinalis 1993 1981 Gymnophalloides seoi Microsporidian africanum Sin Nombre virus 1993 Human T-lymphotropic Virus 1 1980 1992 Puumala virus 1980 Bartonella henselae
From page 214...
... , jiggled as necessary to avoid overlap. bitmap image landscape
From page 215...
... Process of Pathogen Emergence Reservoirs of Infection Relatively few human pathogens are known solely as human pathogens. The remainder also occur in other contexts: as commensals; or free-living in the wider environment; or as infections of hosts other than humans.
From page 216...
... , noting that this framework was devised with reference to all emerging and re-emerging infectious diseases, not just newly discovered pathogen species. The most commonly cited drivers fall within the following IOM categories: economic development and land use; human demographics and behavior; inter
From page 217...
... national travel and commerce; changing ecosystems; human susceptibility; and hospitals. Economic development and land use, and especially changes in eco nomic development and land use, are associated with the emergence of pathogens such as Nipah virus and Borrelia burgdorferi through activities such as intensi fication of farming and forest encroachment respectively.
From page 218...
... . Other categories listed by the IOM -- such as "intent to harm" -- have not been or are not commonly cited as associated with the emergence of novel human pathogen species.
From page 219...
... subdivided epidemic spread into (in their terminology) : Stages 4a, b, and c, infectious diseases that exist in animals but with different balances of animal-to-human and human-to-human spread (where Stage 4c corresponds to reverse zoonoses as defined above)
From page 220...
... We do not know how many potential human pathogen species there are which we have not yet been exposed to, but we do know that human pathogens make up only a fraction of the known biodiversity of viruses, bacteria, fungi, protozoa and helminths, which in turn probably makes up only a fraction of the biodiversity which exists (Dykhuizen 1998)
From page 221...
... Level 4: Epidemic Spread The fourth and, in our version, final level of the pathogen pyramid is reached if a pathogen is sufficiently transmissible within the human population to cause major epidemics or pandemics and/or to become endemic, without the involvement of the original reservoir. This represents a quantitative rather than qualitative distinction and it can be made more formally precise by reference to the concept of the basic reproduction number, R0.
From page 222...
... a plausible estimate is that 100 to 150 pathogen species are capable of causing major outbreaks within human populations, with half to two-thirds of these being specialist human pathogens and the remainder also occurring in animal reservoirs or the wider environment. This implies considerable attrition between levels 3 and 4 of the pathogen pyramid.
From page 223...
... . This pattern -- many small outbreaks and a few larger ones -- is typical of a wide range of infectious diseases (Woolhouse, Taylor, and Haydon 2001)
From page 224...
... . Similarly, several human pathogens with much deeper evolutionary origins, perhaps even pre-dating Homo sapiens as a distinct species, are also most closely related to modern primate pathogens.
From page 225...
... and, especially, to the rate of genetic change and the genetic distance to be traveled. As discussed earlier, the initial R0 value is a function not only of pathogen biology but also of features of human demography and behavior which promote transmission and thus the kinds of changes in these mentioned above have the potential to increase the likelihood of the evolution of new human pathogens.
From page 226...
... With a handful of exceptions, such as the simian immunodeficiency viruses, we typically have very little information on the genetic and functional diversity of human pathogens or their immediate ancestors in nonhuman reservoirs. This is a potentially important topic for future research but a reasonable working hypothesis, supported by our knowledge of the origins of HIV, is that genetic variation in nonhuman pathogen populations does occasionally and incidentally produce human infective variants, and this explains why so many novel human pathogens are RNA viruses (Woolhouse, Taylor, and Haydon 2001)
From page 227...
... ; 2. Nonhuman animal reservoir (most new human pathogens are associ ated with or originate from other kinds of host, usually other species of mammal)
From page 228...
... Multi-Disciplinarity Another key lesson from surveying novel pathogens is the importance of animal reservoirs in the emergence of new infectious diseases. One implication of this is that surveillance in reservoir populations likely to be an effective tool for monitoring risks to humans (Cleaveland, Meslin, and Breiman 2007)
From page 229...
... On the other hand, for many of the rarer human pathogens we do not currently know whether or not they are transmissible between humans (Woolhouse 2002)
From page 230...
... Since Lederberg was also keen on evolutionary studies (Lederberg, 1997, 1998) , it is appropriate for a workshop in his honor to focus on Microbial Evolution and Co-Adaptation.
From page 231...
... Phylogenomics and Novelty I: Predicting Gene Functions Using Evolutionary Trees Throughout this workshop, we have seen many examples of genome sequencing leading to wonderful insights about the microbial world. Indeed, it can be said that genome sequence data have sparked a renaissance in microbiology.
From page 232...
... student at Stanford, I was relentlessly badgering everyone I knew, attempting to convince them that evolutionary analysis could help in the prediction of gene function. I had become convinced of this myself through analysis of the trickle of genome sequence data for humans, yeast, and other organisms that had already begun to flow before the first complete genome was published.
From page 233...
... I note that this "determining the absence" of something from a genome is one of the key benefits of determining complete genome sequences (Fraser et al., 2002)
From page 234...
...  TABLE 5-5 BLAST Search Results as They Were Seen in 1997 Using the MutS-like Protein from Helicobacter pylori as a Query Score E Sequences producing significant alignments (bits) Value sp|P73625|MUTS_SYNY3 DNA MISMATCH REPAIR PROTEIN 117 3e-25 sp|P74926|MUTS_THEMA DNA MISMATCH REPAIR PROTEIN 69 1e-10 sp|P44834|MUTS_HAEIN DNA MISMATCH REPAIR PROTEIN 64 3e-09 sp|P10339|MUTS_SALTY DNA MISMATCH REPAIR PROTEIN 62 2e-08 sp|O66652|MUTS_AQUAE DNA MISMATCH REPAIR PROTEIN 57 4e-07 sp|P23909|MUTS_ECOLI DNA MISMATCH REPAIR PROTEIN 57 4e-07
From page 235...
... Thus, the question arises: Do all of these organisms have high mutation rates? Or have they evolved some compensatory process that reduces mutation rate even without mismatch repair?
From page 236...
... . It is worth noting that this adaptation of character state reconstruction methods for predicting the functions of uncharacterized genes is analogous to predicting the biology of a species based on the position of that organism in the tree of life.
From page 237...
... PHYLOGENETIC PREDICTION OF GENE FUNCTION  INFECTIOUS DISEASE EMERGENCE EXAMPLE A METHOD EXAMPLE B CHOOSE GENE(S) 2A 5 OF INTEREST 1 34 3A 2 2B 5 IDENTIFY HOMOLOGS 1A 2A 1B 3B 6 ALIGN SEQUENCES 1 2 3 4 5 6 1A 2A 3A 1B 2B 3B CALCULATE GENE TREE Duplication?
From page 238...
... We did this by scanning complete genomes, looking for gene families that are expanded in one lineage compared to related lineages. As far as I know, we were the first
From page 239...
... . One thing I did was to scan the genome for gene families that had undergone lineage-specific duplications (i.e., duplications that occurred since the organism last shared a common ancestor with any other organism for which we also had the complete genome sequence available)
From page 240...
... Homologs of MCPs were identified by FASTA3 searches of all available complete genomes. Amino acid sequences of the proteins were aligned using CLUSTALW, and a neighbor-joining phylogenetic tree was generated from the alignment using the PAUP*
From page 241...
... Here's how one actually carries out phylogenetic profiling. You start with a set of genes in which you are interested, perhaps all the genes in the complete genome sequence of "your" organism.
From page 243...
... hydrogenoformans genome, a profile was created of the presence or absence of orthologs of that protein in the predicted proteomes of all other complete genome sequences. Proteins were then clustered by the similarity of their profiles, thus allowing the grouping of proteins by their distribution patterns across species.
From page 244...
... The insect provides the bacteria with sugars from sap, and the bacteria, in turn, make amino acids for their hosts. Xylem sap, which moves from the roots to the rest of the plant, tends to be even more nutrient-poor than phloem sap, and obligate xylem feeders also have bacterial symbionts living inside specialized cells in the gut (see Moran et al., 2008, for a review on heritable symbionts)
From page 245...
... Based on our prior knowledge of these types of symbioses, we expected to find pathways for the synthesis of the essential amino acids required by the sharpshooter -- but we could not find any. In thinking about the mechanisms for the evolution of novelty, it seemed unlikely to us that this host, the MutS MutL Baumannia cicadellinicola + + Buchnera aphidicola Bp + + 95 99 Buchnera aphidicola str APS + + 100 Buchnera aphidicola str Sg + + 95 Blochmannia floridanus – – 98 Wigglesworthia glossinidia – – FIGURE 5-13 There is significant variation in the rate of evolution among endosymbi Figure 5-13.eps onts, with the highest rates tending to be found in those that lack homologs of mismatch redrawn repair genes.
From page 246...
... A second possibility was that the glassywinged sharpshooter was getting the essential amino acids from the xylem sap. Though we could not rule this out, it seemed unlikely because there should be strong selection on the plants to keep essential amino acids out of the xylem sap and because xylem generally was not known to have such amino acids.
From page 247...
... of DNA we mapped to this organism, we found that it encoded in essence all the essential amino acid synthesis pathways (Wu et al., 2006) ; this was later confirmed by the complete genome (McCutcheon and Moran, 2007)
From page 248...
... One aspect of what we do not know that influences our ability to make useful functional predictions is that genome-sequencing projects are highly biased in terms of what types of organisms have been sequenced. For example, I and many others noticed a few years ago (Eisen, 2000; Hugenholtz, 2002)
From page 249...
... (C) Phylogenetic tree of read GEBA412TN_001.
From page 250...
... Sampling from across the tree will take some effort because there are many, many, major groups of Bacteria, Archaea, and microbial Eukaryotes, and many of these do not have any cultured representatives. However, the benefits will likely be enormous.9 It is important to point out however that just having genome sequences from across the tree is not sufficient.
From page 251...
... The method we were using to look for DNA repair genes would not have found this since we were looking primarily for homologs of genes that were shown in other species to be involved in DNA repair processes. Even using novel methods such as phylogenetic profiling would not necessarily help if the new genes in this species were not connected in any way to known DNA repair pathways.
From page 252...
... Epidemiological studies of host-parasite dynamics demonstrate that infectious diseases cannot become endemic until host populations reach a certain threshold density. In the case of measles, repeated introductions of the virus to 10 Executive director.
From page 253...
... . This early phase of human infectious disease emergence may have been preceded by another such period during the Pleistocene Era, 12 when the human population contracted during glaciation, then expanded and migrated afterward.
From page 254...
... In the second stage, wildlife pathogens "spill over" to human populations causing single cases, small clusters of cases, or localized outbreaks, as has occurred with Nipah virus or Ebola virus. In the final stage, "pandemic spread," pathogens either adapt to, or are already adapted to, human-to-human transmission, and move rapidly across nations.
From page 255...
...  Figure 5-17.eps bitmap image w/ some type masked Landscape
From page 256...
... This is because the drivers responsible for this are simple and well-defined: human travel and trade patterns. Our group has used this approach to predict future patterns of West Nile virus and avian influenza spread.
From page 257...
... Our analyses suggest that the virus spread initially within Southeast Asia due to the poultry trade, but once it moved out of the region, it was rapidly spread via migratory pathways to and within Europe. For countries where H5N1 had not yet been reported, we then proceeded to calculate the risk of introduction associated with trade in poultry and wild birds, and with bird migration (expressed as infectious bird days, as shown in Figure 5-19; Kilpatrick et al., 2006a)
From page 258...
... (b) Estimated number of ducks, geese, and swans migrating between mainland continents, number of infectious bird bitmap image w/ vector type in key landscape
From page 259...
... Wild Birds only Wild Birds, then Poultry FIGURE 5-19 Continued Figure 5-19d COLOR.eps bitmap image w/ vector type in key days, and number of species (in parentheses)
From page 260...
... It emerged in people in Malaysia after spilling over from bats to pigs, which actFigure 5-20.eps as amplifier hosts. SOURCE: Wildlifebitmap images w/ vector elements Trust Inc.
From page 261...
... Emerging Disease Database With the above challenges in mind, we constructed a database (based on an earlier published list of emerging infectious diseases [EIDs] ; Taylor et al., 2001)
From page 262...
... Circles represent one degree grid cells, and the area of the circle is proportional to the number of events in the cell. bitmap image SOURCE: Jones et al.
From page 263...
... is dependent on human population density (i.e., those regions with dense human populations and presumably lots of human-driven changes are most likely to lead to a new EID)
From page 264...
... However, perhaps one of the key findings of our analysis is that if we plot out the geographic distribution of all 17,000 JID authors, we find that the global effort for infectious disease research has largely focused on regions from where the next EID is least likely to emerge. Indeed, few EID hotspots -- located primarily in developing countries -- are under thorough surveillance for infectious pathogens (Jones et al., 2008)
From page 265...
... Green corresponds to bitmap image lower values; red to higher values. landscape SOURCE: Jones et al.
From page 266...
... Fogarty International Center R01-TW00824, by core funding to the Consortium for Conservation Medicine from the V Kann Rasmussen Foundation and is published in collaboration with the Australian Biosecurity Cooperative Research Center for Emerging Infectious Diseases (AB-CRC)
From page 267...
... 2003. The role of evolution in the emer gence of infectious diseases.
From page 268...
... 2003. Emerging human infectious diseases: anthroponoses, zoonoses, and sapronoses.
From page 269...
... 2007. Origins of major human infectious diseases.
From page 270...
... Emerging Infectious Diseases 3(4)
From page 271...
... 2005. Life in hot carbon monoxide: the complete genome sequence of Carboxydothermus hydrogenoformans Z-2901.
From page 272...
... 1996. Infectious diseases and human population history.


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