From Pasteur to genomics: progress and challenges in infectious diseases

Over the past decade, microbiology and infectious disease research have undergone the most profound revolution since the times of Pasteur. Genomic sequencing has revealed the much-awaited blueprint of most pathogens. Screening blood for the nucleic acids of infectious agents has blunted the spread of pathogens by transfusion, the field of antiviral therapeutics has exploded and technologies for the development of novel and safer vaccines have become available. The quantum jump in our ability to detect, prevent and treat infectious diseases resulting from improved technologies and genomics was moderated during this period by the greatest emergence of new infectious agents ever recorded and a worrisome increase in resistance to existing therapies. Dozens of new infectious diseases are expected to emerge in the coming decades. Controlling these diseases will require a better understanding of the worldwide threat and economic burden of infectious diseases and a global agenda.     

Infectious disease and amphibian population declines

Abstract. A series of recent papers have implicated pathogens and parasites in amphibian population declines. Here, we review evidence on the link between infectious disease and amphibian population declines. We conclude that available data provide the clearest link for the fungal disease amphibian chytridiomycosis, although other pathogens are also implicated. We suggest additional experimental and observational data that need to be collected to provide further support that these other pathogens are associated with declines. We suggest that, in common with many emerging infectious diseases (EIDs) of humans, domestic animals and other wildlife species, emergence of chytridiomycosis may be driven by anthropogenic introduction (pathogen pollution). Finally, we review a number of recent advances in the host–parasite ecology of chytridiomycosis that help explain its emergence and impact.     

Perspectives and hopes in infectious pathology]

Over the last few decades, changes in socio-economic conditions and social practices as well as aggressive therapy of many diseases have led to the emergence of new infectious pathologies. These new pathologies are either associated with newly identified microbial species or the emergence of known microbes which have encountered new environments in which they are able to cause disease. Recent progress has allowed us to understand the mechanisms by which these pathogens express their virulence and will certainly allow us to diagnose and treat these infections more efficiently in the future.     

Evolution of highly pathogenic H5N1 avian influenza viruses in Vietnam between 2001 and 2007

Highly pathogenic avian influenza (HPAI) H5N1 viruses have caused dramatic economic losses to the poultry industry of Vietnam and continue to pose a serious threat to public health. As of June 2008, Vietnam had reported nearly one third of worldwide laboratory confirmed human H5N1 infections. To better understand the emergence, spread and evolution of H5N1 in Vietnam we studied over 300 H5N1 avian influenza viruses isolated from Vietnam since their first detection in 2001. Our phylogenetic analyses indicated that six genetically distinct H5N1 viruses were introduced into Vietnam during the past seven years. The H5N1 lineage that evolved following the introduction in 2003 of the A/duck/Hong Kong/821/2002-like viruses, with clade 1 hemagglutinin (HA), continued to predominate in southern Vietnam as of May 2007. A virus with a clade 2.3.4 HA newly introduced into northern Vietnam in 2007, reassorted with pre-existing clade 1 viruses, resulting in the emergence of novel genotypes with neuraminidase (NA) and/or internal gene segments from clade 1 viruses. A total of nine distinct genotypes have been present in Vietnam since 2001, including five that were circulating in 2007. At least four of these genotypes appear to have originated in Vietnam and represent novel H5N1 viruses not reported elsewhere. Geographic and temporal analyses of H5N1 infection dynamics in poultry suggest that the majority of viruses containing new genes were first detected in northern Vietnam and subsequently spread to southern Vietnam after reassorting with pre-existing local viruses in northern Vietnam. Although the routes of entry and spread of H5N1 in Vietnam remain speculative, enhanced poultry import controls and virologic surveillance efforts may help curb the entry and spread of new HPAI viral genes.     

The Shanidar cave Proto-Neolithic human population: Aspects of demography and paleopathology

This paper presents bio-anthropological data concerning the Shanidar cave, Proto-Neolithic, Homo sapiens population at the dawn of sedentary life in SW Asia. It was proposed that changes in human organizational systems and perceived environmental contexts, as reflected by ecofacts and tool assemblages, indicating the intensification of harvesting of resources during this Proto-Neolithic cultural component, could have altered existing interrelationships between pathogens, vectors, and human hosts. The individuals comprising the skeletal collection represent both sex subcategories and most age subgroups. Further, no evidence of bio-distance has been documented between them judging from morphometrics and mensurational analyses. Paleopathological investigations of the skeletal record revealed the presence of infectious diseases, lesions of the joints, lesions of the jaws and teeth, benign tumors, hemopoietic and metabolic disorders, as well as severe traumatic conditions. Bone isotopic testing for investigations of dietary patterns indicated a diet heavily based on C3 plants, while the animal protein component was calculated to an intake of less than 10%. The paleopathological profile in conjunction with the archeometric studies, and the rest of the archaeological record present significant reflections of the lives of these Proto-Neolithic people in SW Asia, during this transitional time period.     

Issues related to the use of animals in biocontainment research facilities

The expansion and improvement of high-containment animal facilities has been driven by terrorism, economics, the emergence of new pathogens, and the re-emergence of other pathogens in new areas. Working with highly infectious viral agents requires a team of trained scientists, laboratory technicians, veterinarians, animal care staff, biological safety officers, engineers, and physical plant staff to ensure safety, biocontainment, and the animals' well being, while providing essential scientific data. The challenges of working with infectious disease agents in high levels of containment, and some solutions to these challenges, are described from an animal care point of view.     

Infectious disease in the Pleistocene: Old friends or old foes?

The impact of endemic and epidemic disease on humans has traditionally been seen as a comparatively recent historical phenomenon associated with the Neolithisation of human groups, an increase in population size led by sedentarism, and increasing contact with domesticated animals as well as species occupying opportunistic symbiotic and ectosymbiotic relationships with humans. The orthodox approach is that Neolithisation created the conditions for increasing population size able to support a reservoir of infectious disease sufficient to act as selective pressure. This orthodoxy is the result of an overly simplistic reliance on skeletal data assuming that no skeletal lesions equated to a healthy individual, underpinned by the assumption that hunter-gatherer groups were inherently healthy while agricultural groups acted as infectious disease reservoirs. The work of van Blerkom, Am. J. Phys. Anthropol., vol. suppl 37 (2003), Wolfe et al., Nature, vol. 447 (2007) and Houldcroft and Underdown, Am. J. Phys. Anthropol., vol. 160, (2016) has changed this landscape by arguing that humans and pathogens have long been fellow travelers. The package of infectious diseases experienced by our ancient ancestors may not be as dissimilar to modern infectious diseases as was once believed. The importance of DNA, from ancient and modern sources, to the study of the antiquity of infectious disease, and its role as a selective pressure cannot be overstated. Here we consider evidence of ancient epidemic and endemic infectious diseases with inferences from modern and ancient human and hominin DNA, and from circulating and extinct pathogen genomes. We argue that the pandemics of the past are a vital tool to unlock the weapons needed to fight pandemics of the future.     

Changing patterns of health and disease among the Aleuts

Compared to other regions of North America, there have been relatively few paleopathological studies of arctic populations to date, particularly those aimed at elucidating patterns of health and disease prior to contact, and assessing temporal changes in disease patterns. In the present study, four Aleut skeletal samples representing one pre-contact population from Umnak Island in the eastern Aleutian Islands (N=65), and three late pre-contact/early contact period populations from Umnak, Kagamil, and Shiprock Islands (N=227), were examined macroscopically for indicators of health status. The analysis revealed some evidence of declining health in the late pre-contact/early contact period. Statistical comparisons of the earlier and later samples indicated a significantly higher frequency of cribra orbitalia and cranial infection in the later sample compared to the earlier one. Archaeological, epidemiological, and historical data point to several possible explanations for these findings, including the introduction of new pathogens by Europeans.     

Homo medicus: The transition to meat eating increased pathogen pressure and the use of pharmacological plants in Homo

The human lineage transitioned to a more carnivorous niche 2.6 mya and evolved a large body size and slower life history, which likely increased zoonotic pathogen pressure. Evidence for this increase includes increased zoonotic infections in modern hunter-gatherers and bushmeat hunters, exceptionally low stomach pH compared to other primates, and divergence in immune-related genes. These all point to change, and probably intensification, in the infectious disease environment of Homo compared to earlier hominins and other apes. At the same time, the brain, an organ in which immune responses are constrained, began to triple in size. We propose that the combination of increased zoonotic pathogen pressure and the challenges of defending a large brain and body from pathogens in a long-lived mammal, selected for intensification of the plant-based self-medication strategies already in place in apes and other primates. In support, there is evidence of medicinal plant use by hominins in the middle Paleolithic, and all cultures today have sophisticated, plant-based medical systems, add spices to food, and regularly consume psychoactive plant substances that are harmful to helminths and other pathogens. We propose that the computational challenges of discovering effective plant-based treatments, the consequent ability to consume more energy-rich animal foods, and the reduced reliance on energetically-costly immune responses helped select for increased cognitive abilities and unique exchange relationships in Homo. In the story of human evolution, which has long emphasized hunting skills, medical skills had an equal role to play.     

Evolution of virulence in heterogeneous host communities under multiple trade-offs

Many pathogens and parasites are transmitted through hosts that differ in species, sex, genotype, or immune status. In addition, virulence (here defined as disease-induced mortality) and transmission can vary during the infectious period within hosts of different state. Most models of virulence evolution assume that transmission and virulence are constant over the infectious period and that the host population is homogenous. Here, we examine a multispecies susceptible-infected-recovered (SIR) model where transmission occurs within and between species, and transmission and virulence varied during the infectious period. This allows us to understand virulence evolution in a broader range of situations that characterize many emerging diseases. Because emerging pathogens are by definition new to their host populations, they should be expected to rapidly adapt after emergence. We illustrate these evolutionary effects using the framework of adaptive dynamics to examine how virulence evolves after emergence in response to the relative strength of selection on pathogen fitness and mutational variance for virulence. We illustrate the role of evolution by simulating adaptive walks to an evolutionarily stable virulence. We found that the magnitude of between-species transmission and the relative timing of transmission and mortality across species were of primary importance for determining the evolutionarily stable virulence.     

Dental indicators of health and stress in early Egyptian and Nubian agriculturalists: a difficult transition and gradual recovery

Although agriculture is now the globally predominant mode of food production, studies of the skeletal remains of early agriculturalists have indicated high levels of physiological stress and poor health relative to hunter-gatherers in similar environments. Previous studies identifying this trend in different regions prompt further research of the causes and effects of subsistence transitions in human societies. Here, 242 dentitions from five ancient Egyptian and Nubian populations are examined: 38 individuals from Jebel Sahaba (Upper Paleolithic), 56 from Badari (Predynastic), 54 from Naqada (Predynastic), 47 from Tarkhan (Dynastic), and 47 from Kerma (Dynastic). These populations span the early period of agricultural intensification along the Nile valley. Skeletal remains were scored for the presence of linear enamel hypoplasia (LEH) of the dentition, an established indicator of physiological stress and growth interruption. The prevalence of LEH was highest in the "proto-agricultural" (pastoralist) Badari population, with a gradual decline throughout the late Predynastic and early Dynastic periods of state formation. This suggests that the period surrounding the emergence of early agriculture in the Nile valley was associated with high stress and poor health, but that the health of agriculturalists improved substantially with the increasing urbanization and trade that accompanied the formation of the Egyptian state. This evidence for poor health among proto- and early agriculturalists in the Nile valley supports theories that agricultural intensification occurred as a response to ecological or demographic pressure rather than simply as an innovation over an existing stable subsistence strategy.     

The Role of Immunotoxic Environmental Contaminants in Facilitating the Emergence of Infectious Diseases in Marine Mammals

A series of high profile outbreaks of newly described diseases in humans, domestic animals and wildlife has attracted widespread interest in the topic of Emerging Infectious Diseases (EIDs). Marine mammals are no exception: since 1987 several mass mortalities have been observed following infection with viruses previously undescribed in the populations or species in question. As with terrestrial examples, some of these outbreaks have followed either migrations associated with large-scale ecological changes or the introduction of virus from domestic animals. However, marine mammals warrant special concern in the context of emerging infectious diseases: they typically occupy high trophic levels and can therefore be highly contaminated with immunotoxic chemicals. Persistent Organic Pollutants (POPs), including polychlorinated -biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), -dibenzofurans (PCDFs) and related compounds, are demonstrated immunotoxicants in laboratory animals, as well as marine mammals. Immunotoxic contaminants may represent a factor that facilitates disease emergence, and may lead to the creation of susceptible “reservoirs” for new pathogens in contaminated marine mammal populations. The factors underlying the emergence and exchange of pathogens among marine mammals, domestic animals, and humans demand multidisciplinary study and invite regulatory and conservation scrutiny. The complexity of this issue may be best addressed through an integrated human and ecological risk assessment framework.     

Relative tibia long bone growth in the Libben and Bt-5 prehistoric skeletal populations

Patterns of tibia long bone growth were examined for the Libben Late Woodland and Bt-5 Late Archaic hunter-gatherer skeletal groups. Subadults included in the analyses ranged in age from birth to 10 years. The primary goals were to identify potential differences in relative tibia growth and evaluate the extent to which such differences were concordant with demographic and epidemiological characteristics of the two groups. Methods used were designed to minimize the shortcomings of unknown age and sex of the skeleton, small sample sizes, and population differences in adult size attained. Results showed that Bt-5 preadolescent growth performance and health status in general were superior to those of the Libben group. Modifications in the rate and timing of Libben tibia growth occurred early and were primarily restricted to the weaning period. It is suggested that high levels of infectious disease experienced in the first years of life at Libben played a substantial role in the etiology of early long bone growth retardation, a greater prevalence of iron deficiency anemia in the childhood years, and elevated levels of subadult morbidity and mortality compared to Bt-5. Paleodemographic, paleoepidemiological, and modern comparative population data that support these inferences are discussed. No evidence of chronic malnutrition owing to dietary inadequacy was observed for either group. Alternatively, higher population density and greater degree of sedentism alone may have been responsible for elevated disease loads at Libben compared to low levels that were observed for the seasonally mobile semisedentary Bt-5 hunter-gatherers.     

Emerging infectious disease: what are the relative roles of ecology and evolution?

The increasing threat of infectious diseases in humans has renewed interest in factors leading to the emergence of new diseases and the re-emergence of familiar diseases. Examples of seemingly novel diseases currently spreading in human populations include HIV, dengue hemorrhagic fever and Lyme disease; drug-resistant forms of well-known diseases such as tuberculosis are also increasing. The problem of disease emergence also extends to other animal and plant populations. In most current epidemics, ecological factors (e.g. migration, climate, agricultural practices) play a more significant role in disease emergence than evolutionary changes in pathogens or hosts. Evolutionary biologists and ecologists have much to offer to the development of strategies for the control of emerging diseases.     

Infectious disease among enslaved African Americans at Eaton's Estate, Warren County, North Carolina, ca. 1830-1850

The skeletal remains of 17 people buried in the Eaton Ferry Cemetery in northern North Carolina provide a means of examining health and infectious disease experience in the XIX century South. The cemetery appears to contain the remains of African Americans enslaved on the Eaton family estate from approximately 1830-1850, and thus offers a window into the biological impacts of North American slavery in the years preceding the Civil War. The sample includes the remains of six infants, one child, and one young and nine mature adults (five men, four women, and one unknown). Skeletal indices used to characterize health and disease in the Eaton Ferry sample include dental caries, antemortem tooth loss, enamel hypoplasia, porotic hyperostosis, periosteal lesions, lytic lesions, and stature. These indicators reveal a cumulative picture of compromised health, including high rates of dental disease, childhood growth disruption, and infectious disease. Specific diseases identified in the sample include tuberculosis and congenital syphilis. Findings support previous research on the health impacts of slavery, which has shown that infants and children were the most negatively impacted segment of the enslaved African American population.     

Diseases of humans and their domestic mammals: pathogen characteristics, host range and the risk of emergence

Pathogens that can be transmitted between different host species are of fundamental interest and importance from public health, conservation and economic perspectives, yet systematic quantification of these pathogens is lacking. Here, pathogen characteristics, host range and risk factors determining disease emergence were analysed by constructing a database of disease-causing pathogens of humans and domestic mammals. The database consisted of 1415 pathogens causing disease in humans, 616 in livestock and 374 in domestic carnivores. Multihost pathogens were very prevalent among human pathogens (61.6%) and even more so among domestic mammal pathogens (livestock 77.3%, carnivores 90.0%). Pathogens able to infect human, domestic and wildlife hosts contained a similar proportion of disease-causing pathogens for all three host groups. One hundred and ninety-six pathogens were associated with emerging diseases, 175 in humans, 29 in livestock and 12 in domestic carnivores. Across all these groups, helminths and fungi were relatively unlikely to emerge whereas viruses, particularly RNA viruses, were highly likely to emerge. The ability of a pathogen to infect multiple hosts, particularly hosts in other taxonomic orders or wildlife, were also risk factors for emergence in human and livestock pathogens. There is clearly a need to understand the dynamics of infectious diseases in complex multihost communities in order to mitigate disease threats to public health, livestock economies and wildlife.     

Skeletal pathology in a prehistoric Pacific Island sample: issues in lesion recording, quantification, and interpretation

This paper presents a profile of evidence of disease in a skeletal sample from Taumako Island, Southeast Solomon Islands, Melanesia, and aims to increase awareness of the prehistoric Pacific Island disease environment. It also addresses issues of lesion recording, quantification, and interpretation. Two methodologies for the determination of lesion prevalence were applied, one based on prevalence in observable individuals and one in skeletal elements. The aim of these methodologies was to provide objective data on skeletal lesions in this sample, with transparency in methods for application in comparative studies. The types of lesions observed were predominantly osteoblastic and affecting multiple bones, particularly in the lower limbs. The individual analysis yielded a prevalence of lesions affecting 56.4% of the postcranial sample from birth to old age. As expected, the skeletal element analysis yielded a lower prevalence, with 15.0% of skeletal elements affected. The skeletal element analysis also revealed a pattern of greater lower limb involvement, with a predilection for the tibia. The pattern of skeletal involvement was similar in both analyses, suggesting the validity of employing either method in paleopathological studies. A differential diagnosis of the lesions included osteomyelitis, treponemal disease, and leprosy. Metabolic disease was also considered for subadult lesions. Based on lesion type, skeletal distribution, and epidemiology of lesions in the sample, an etiology of yaws (Treponema pertenue) was suggested as responsible for nearly half the adult lesions, while multiple causes, including yaws, were suggested for the lesions in subadults.     

The neolithic demographic transition and oral health: The Southeast Asian experience

The purpose of this article is to present new oral health data from Neolithic An Son, southern Vietnam, in the context of (1) a reassessment of published data on other Neolithic, Bronze, and Iron Age Southeast Asian dental series, and (2) predictions of the Neolithic Demographic Transition (NDT). To this end, frequencies for three oral conditions (caries, antemortem tooth loss, and alveolar lesions) were investigated for seven Southeast Asian adult dental series from Thailand and Vietnam with respect to time period, age‐at‐death and sex. A clear pattern of elevated rates for oral disease in the Neolithic followed by a marked improvement in oral health during the Bronze and Iron Ages was observed. Moreover, rates of caries and antemortem tooth loss for females were almost without exception higher than that for males in all samples. The consensus view among Southeast Asian bioarchaeologists that oral health did not decline with the adoption/intensification of agriculture in Southeast Asia, can no longer be supported. In light of evidence for (1) the low cariogenicity of rice; (2) the physiological predisposition of females (particularly when pregnant) to poorer oral health; and (3) health predictions of the NDT model with respect to elevated levels of fertility, the most plausible chief explanation for the observed patterns in oral health in Southeast Asia is increased levels of fertility during the Neolithic, followed by a decline in fertility during the subsequent Bronze and Iron Ages. Am J Phys Anthropol 152:197–208, 2013. © 2013 Wiley Periodicals, Inc.     

Vitamin D,Calcium, and Cardiovascular Mortality: A Perspective from A Plenary Lecture Given at the Annual Meeting of the American Association of Clinical Endocrinologists

ObjectiveTo examine data showing associations between serum 25-hydroxyvitamin D levels and calcium intake and cardiovascular mortality.MethodsThe articles reviewed include those published from 1992-2011 derived from search engines (PubMed, Scopus, Medscape) using the following search terms: vitamin D, calcium, cardiovascular events, cardiovascular mortality, all-cause mortality, vascular calcification, chronic kidney disease, renal stones, and hypercalci- uria. Because these articles were not weighted (graded) on the level of evidence, this review reflects my own perspective on the data and how they should be applied to clinical management.ResultsFor skeletal health, vitamin D and calcium are both needed to ensure proper skeletal growth (modeling) and repair (remodeling). Nutritional deficiencies of either vitamin D or calcium may lead to a spectrum of metabolic bone disorders. Excessive consumption of either nutrient has been linked to a variety of medical disorders, such as hypercalcemia or renal stones. There have also been associations between vitamin D or calcium intake and cardiovascular disease. However, neither of these associations have established evidence nor known causality for increasing cardiovascular risk or all-cause mortality in patients with creatinine clearances greater than 60 mL/ min. In patients with more severe chronic kidney disease, stronger data link excess calcium (or phosphorus) intake and increase in vascular calcification, but not mortality. The safe upper limit for vitamin D intake is at least 4000 IU daily and probably 10 000 IU daily; for calcium, the safe upper limit is between 2000 and 3000 mg daily.ConclusionsWhile no solid scientific evidence validates that serum vitamin D levels between 15 and 70 ng/ mL are associated with increased cardiovascular disease risk, stronger but inconsistent evidence shows an association between calcium supplementation greater than 500 mg daily and an increase in cardiovascular disease risk. Most professional societies suggest that replacement levels of these nutrients be personalized with the goal of reaching a 25-hydroxyvitamin D concentration between 30 and 50 ng/ mL and a calcium intake of 1200 mg daily. (Endocr Pract. 2011;17:798-806)