Emerging pathogens: the epidemiology and evolution of species jumps

Novel pathogens continue to emerge in human, domestic animal, wildlife and plant populations, yet the population dynamics of this kind of biological invasion remain poorly understood. Here, we consider the epidemiological and evolutionary processes underlying the initial introduction and subsequent spread of a pathogen in a new host population, with special reference to pathogens that originate by jumping from one host species to another. We conclude that, although pathogen emergence is inherently unpredictable, emerging pathogens tend to share some common traits, and that directly transmitted RNA viruses might be the pathogens that are most likely to jump between host species.     

Common infection strategies of pathogenic eukaryotes

Pathogenic eukaryotes belong to several distinct phylogenetic lineages and have evolved the ability to colonize a range of hosts, including animals and plants. Pathogenic lifestyles have evolved repeatedly in eukaryotes, indicating that unique molecular processes are involved in host infection. However, evidence is now emerging that divergent eukaryotic pathogens might share common mechanisms of pathogenicity. The results from recent studies demonstrate that Plasmodium falciparum and Phytophthora infestans use equivalent host-targeting signals to deliver virulence adhesins and avirulence gene products into human and plant cells, respectively. Remodelling of host cells by different eukaryotic pathogens might therefore share some common features.     

Impact of genomics on microbial food safety

Genome sequences are now available for many of the microbes that cause food-borne diseases. The information contained in pathogen genome sequences, together with the development of themed and whole-genome DNA microarrays and improved proteomics techniques, might provide tools for the rapid detection and identification of such organisms, for assessing their biological diversity and for understanding their ability to respond to stress. The genomic information also provides insight into the metabolic capacity and versatility of microbes; for example, specific metabolic pathways might contribute to the growth and survival of pathogens in a range of niches, such as food-processing environments and the human host. New concepts are emerging about how pathogens function, both within foods and in interactions with the host. The future should bring the first practical benefits of genome sequencing to the field of microbial food safety, including strategies and tools for the identification and control of emerging pathogens.     

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.     

Extending the host range of Listeria monocytogenes by rational protein design

In causing disease, pathogens outmaneuver host defenses through a dedicated arsenal of virulence determinants that specifically bind or modify individual host molecules. This dedication limits the intruder to a defined range of hosts. Newly emerging diseases mostly involve existing pathogens whose arsenal has been altered to allow them to infect previously inaccessible hosts. We have emulated this chance occurrence by extending the host range accessible to the human pathogen Listeria monocytogenes by the intestinal route to include the mouse. Analyzing the recognition complex of the listerial invasion protein InlA and its human receptor E-cadherin, we postulated and verified amino acid substitutions in InlA to increase its affinity for E-cadherin. Two single substitutions increase binding affinity by four orders of magnitude and extend binding specificity to include formerly incompatible murine E-cadherin. By rationally adapting a single protein, we thus create a versatile murine model of human listeriosis.     

Emergence and accumulation of novel pathogens suppress an invasive species

Emerging pathogens are a growing threat to human health, agriculture and the diversity of ecological communities but may also help control problematic species. Here we investigated the diversity, distribution and consequences of emerging fungal pathogens infecting an aggressive invasive grass that is rapidly colonising habitats throughout the eastern USA. We document the recent emergence and accumulation over time of diverse pathogens that are members of a single fungal genus and represent multiple, recently described or undescribed species. We also show that experimental suppression of these pathogens increased host performance in the field, demonstrating the negative effects of emerging pathogens on invasive plants. Our results suggest that invasive species can facilitate pathogen emergence and amplification, raising concerns about movement of pathogens among agricultural, horticultural, and wild grasses. However, one possible benefit of pathogen accumulation is suppression of aggressive invaders over the long term, potentially abating their negative impacts on native communities.     

The phylogenetic range of bacterial and viral pathogens of vertebrates

Many major human pathogens are multihost pathogens, able to infect other vertebrate species. Describing the general patterns of host–pathogen associations across pathogen taxa is therefore important to understand risk factors for human disease emergence. However, there is a lack of comprehensive curated databases for this purpose, with most previous efforts focusing on viruses. Here, we report the largest manually compiled host–pathogen association database, covering 2,595 bacteria and viruses infecting 2,656 vertebrate hosts. We also build a tree for host species using nine mitochondrial genes, giving a quantitative measure of the phylogenetic similarity of hosts. We find that the majority of bacteria and viruses are specialists infecting only a single host species, with bacteria having a significantly higher proportion of specialists compared to viruses. Conversely, multihost viruses have a more restricted host range than multihost bacteria. We perform multiple analyses of factors associated with pathogen richness per host species and the pathogen traits associated with greater host range and zoonotic potential. We show that factors previously identified as important for zoonotic potential in viruses—such as phylogenetic range, research effort, and being vector‐borne—are also predictive in bacteria. We find that the fraction of pathogens shared between two hosts decreases with the phylogenetic distance between them. Our results suggest that host phylogenetic similarity is the primary factor for host‐switching in pathogens.     

Bartonella interactions with endothelial cells and erythrocytes

Bartonella species are emerging human pathogens responsible for a wide range of clinical manifestations, including Carrion's disease, trench fever, cat-scratch disease, bacillary angiomatosis-peliosis, endocarditis and bacteraemia. During infection of their human or animal reservoir host(s), these arthropod-borne pathogens typically invade and persistently colonize mature erythrocytes. However, in both reservoir and incidentally infected hosts, endothelial cells are target cells for bartonellae. Endothelial interactions involve a unique mode of cellular invasion, the activation of a proinflammatory phenotype and the formation of vasoproliferative tumours. Based on the establishment of bacterial genetics and appropriate infection models, recent work has begun to elucidate the cell and molecular biology of these unusual pathogen-host cell interactions.     

The Application of Genomics to Emerging Zoonotic Viral Diseases

Interspecies transmission of pathogens may result in the emergence of new infectious diseases in humans as well as in domestic and wild animals. Genomics tools such as high-throughput sequencing, mRNA expression profiling, and microarray-based analysis of single nucleotide polymorphisms are providing unprecedented ways to analyze the diversity of the genomes of emerging pathogens as well as the molecular basis of the host response to them. By comparing and contrasting the outcomes of an emerging infection with those of closely related pathogens in different but related host species, we can further delineate the various host pathways determining the outcome of zoonotic transmission and adaptation to the newly invaded species. The ultimate challenge is to link pathogen and host genomics data with biological outcomes of zoonotic transmission and to translate the integrated data into novel intervention strategies that eventually will allow the effective control of newly emerging infectious diseases.     

Microbial quest for food in vivo: ‘Nutritional virulence’ as an emerging paradigm

Microbial access to host nutrients is a fundamental aspect of infectious diseases. Pathogens face complex dynamic nutritional host microenvironments that change with increasing inflammation and local hypoxia. Since the host can actively limit microbial access to nutrient supply, pathogens have evolved various metabolic adaptations to successfully exploit available host nutrients for proliferation. Recent studies have unraveled an emerging paradigm that we propose to designate as ‘nutritional virulence’. This paradigm is based on specific virulence mechanisms that target major host biosynthetic and degradation pathways (proteasomes, autophagy and lysosomes) or nutrient‐rich sources, such as glutathione, to enhance host supply of limiting nutrients, such as cysteine. Although Cys is the most limiting cellular amino acid, it is a metabolically favourable source of carbon and energy for various pathogens that are auxotrophic for Cys but utilize idiosyncratic nutritional virulence strategies to generate a gratuitous supply of host Cys. Therefore, proliferation of some intracellular pathogens is restricted by a host nutritional rheostat regulated by certain limiting amino acids, and pathogens have evolved idiosyncratic strategies to short circuit the host nutritional rheostat. Deciphering mechanisms of microbial ‘nutritional virulence’ and metabolism in vivo will facilitate identification of novel microbialand host targets for treatment and prevention of infectious diseases. Host–pathogen synchronization of amino acid auxotrophy indicates that this nutritional synchronization has been a major driving force in the evolution of many intracellular bacterial pathogens.     

Hendra and Nipah viruses: pathogenesis and therapeutics

Within the past decade a number of new zoonotic paramyxoviruses emerged from flying foxes to cause serious disease outbreaks in man and livestock. Hendra virus was the cause of fatal infections of horses and man in Australia in 1994, 1999 and 2004. Nipah virus caused encephalitis in humans both in Malaysia in 1998/99, following silent spread of the virus in the pig population, and in Bangladesh from 2001 to 2004 probably as a result of direct bat to human transmission and spread within the human population. Hendra and Nipah viruses are highly pathogenic in humans with case fatality rates of 40% to 70%. Their genetic constitution, virulence and wide host range make them unique paramyxoviruses and they have been given Biosecurity Level 4 status in a new genus Henipavirus within the family Paramyxoviridae. Recent studies on the virulence, host range and cell tropisms of henipaviruses provide insights into the unique biological properties of these emerging human pathogens and suggest approaches for vaccine development and therapeutic countermeasures.     

Hendra and Nipah viruses: different and dangerous

Hendra virus and Nipah virus are highly pathogenic paramyxoviruses that have recently emerged from flying foxes to cause serious disease outbreaks in humans and livestock in Australia, Malaysia, Singapore and Bangladesh. Their unique genetic constitution, high virulence and wide host range set them apart from other paramyxoviruses. These features led to their classification into the new genus Henipavirus within the family Paramyxoviridae and to their designation as Biosafety Level 4 pathogens. This review provides an overview of henipaviruses and the types of infection they cause, and describes how studies on the structure and function of henipavirus proteins expressed from cloned genes have provided insights into the unique biological properties of these emerging human pathogens.     

Calcium Regulation of Hemorrhagic Fever Virus Budding: Mechanistic Implications for Host-Oriented Therapeutic Intervention

Hemorrhagic fever viruses, including the filoviruses (Ebola and Marburg) and arenaviruses (Lassa and Junín viruses), are serious human pathogens for which there are currently no FDA approved therapeutics or vaccines. Importantly, transmission of these viruses, and specifically late steps of budding, critically depend upon host cell machinery. Consequently, strategies which target these mechanisms represent potential targets for broad spectrum host oriented therapeutics. An important cellular signal implicated previously in EBOV budding is calcium. Indeed, host cell calcium signals are increasingly being recognized to play a role in steps of entry, replication, and transmission for a range of viruses, but if and how filoviruses and arenaviruses mobilize calcium and the precise stage of virus transmission regulated by calcium have not been defined. Here we demonstrate that expression of matrix proteins from both filoviruses and arenaviruses triggers an increase in host cytoplasmic Ca²⁺ concentration by a mechanism that requires host Orai1 channels. Furthermore, we demonstrate that Orai1 regulates both VLP and infectious filovirus and arenavirus production and spread. Notably, suppression of the protein that triggers Orai activation (Stromal Interaction Molecule 1, STIM1) and genetic inactivation or pharmacological blockade of Orai1 channels inhibits VLP and infectious virus egress. These findings are highly significant as they expand our understanding of host mechanisms that may broadly control enveloped RNA virus budding, and they establish Orai and STIM1 as novel targets for broad-spectrum host-oriented therapeutics to combat these emerging BSL-4 pathogens and potentially other enveloped RNA viruses that bud via similar mechanisms.     

Phylogenetic concordance analysis shows an emerging pathogen is novel and endemic

Distinguishing whether pathogens are novel or endemic is critical for controlling emerging infectious diseases, an increasing threat to wildlife and human health. To test the endemic vs. novel pathogen hypothesis, we present a unique analysis of intraspecific host-pathogen phylogenetic concordance of tiger salamanders and an emerging Ranavirus throughout Western North America. There is significant non-concordance of host and virus gene trees, suggesting pathogen novelty. However, non-concordance has likely resulted from virus introductions by human movement of infected salamanders. When human-associated viral introductions are excluded, host and virus gene trees are identical, strongly supporting coevolution and endemism. A laboratory experiment showed an introduced virus strain is significantly more virulent than endemic strains, likely due to artificial selection for high virulence. Thus, our analysis of intraspecific phylogenetic concordance revealed that human introduction of viruses is the mechanism underlying tree non-concordance and possibly disease emergence via artificial selection.     

How vaccinia virus has evolved to subvert the host immune response

Viruses are obligate intracellular parasites and are some of the most rapidly evolving and diverse pathogens encountered by the host immune system. Large complicated viruses, such as poxviruses, have evolved a plethora of proteins to disrupt host immune signalling in their battle against immune surveillance. Recent X-ray crystallographic analysis of these viral immunomodulators has helped form an emerging picture of the molecular details of virus-host interactions. In this review we consider some of these immune evasion strategies as they apply to poxviruses, from a structural perspective, with specific examples from the European SPINE2-Complexes initiative. Structures of poxvirus immunomodulators reveal the capacity of viruses to mimic and compete against the host immune system, using a diverse range of structural folds that are unique or acquired from their hosts with both enhanced and unexpectedly divergent functions.     

Expanding host specificity and pathogen sharing beyond viruses

Most emerging pathogens of humans can infect multiple host species (Woolhouse & Gowtage‐Sequeria, 2005). This simple fact has motivated multiple large‐scale, comparative analyses of the drivers of pathogen sharing and zoonotic pathogen richness among hosts as well as the factors determining the zoonotic potential of pathogens themselves. However, most of this work focuses on viruses, limiting a broader understanding of how host range varies within and between pathogen groups. In this issue of Molecular Ecology, Shaw et al. (2020) compile a comprehensive data set of host–pathogen associations across viruses and bacteria and test whether previous patterns observed in the former occur in the latter. They find most viruses and bacteria are specialists, and viruses are more likely to be generalists; however, generalist bacteria encompass multiple host orders, whereas viral sharing occurs more within host orders. Lastly, the authors demonstrate that many factors previously identified as predictors of zoonotic richness for viruses occur for bacteria and that host phylogenetic similarity is a primary determinant of cross‐species transmission. However, pathogen sharing with humans was more common and more weakly related to phylogenetic distance to Homo sapiens for bacteria compared to viruses, suggesting the former could pose greater spillover risks across host orders. This work represents a key advance in our understanding of host specificity and pathogen sharing beyond viruses.     

P2X7 receptors and apoptosis in tuberculosis infection.

Immune cells express P2 purinoceptors of the P2Y and P2X subtypes. Evidence accumulated has shown that many different cell types are killed by sustained exposure to high concentrations of extracellular ATP. Depending on the ATP dose, length of stimulation and receptor subtype, P2X receptor stimulation may cause necrosis or apoptosis. Triggering of apoptosis, in response to intracellular infection, has been identified for a wide range of pathogens and host organisms, and there is now emerging interest about mechanism mediating host cell death and its role in pulmonary tuberculosis. The physiological meaning of P2X receptor-dependent cell death is not completely understood, but and involvement in immune-mediated reactions is postulated.     

A Quantitative Prioritisation of Human and Domestic Animal Pathogens in Europe

Disease or pathogen risk prioritisations aid understanding of infectious agent impact within surveillance or mitigation and biosecurity work, but take significant development. Previous work has shown the H-(Hirsch-)index as an alternative proxy. We present a weighted risk analysis describing infectious pathogen impact for human health (human pathogens) and well-being (domestic animal pathogens) using an objective, evidence-based, repeatable approach; the H-index. This study established the highest H-index European pathogens. Commonalities amongst pathogens not included in previous surveillance or risk analyses were examined. Differences between host types (humans/animals/zoonotic) in pathogen H-indices were explored as a One Health impact indicator. Finally, the acceptability of the H-index proxy for animal pathogen impact was examined by comparison with other measures. 57 pathogens appeared solely in the top 100 highest H-indices (1) human or (2) animal pathogens list, and 43 occurred in both. Of human pathogens, 66 were zoonotic and 67 were emerging, compared to 67 and 57 for animals. There were statistically significant differences between H-indices for host types (humans, animal, zoonotic), and there was limited evidence that H-indices are a reasonable proxy for animal pathogen impact. This work addresses measures outlined by the European Commission to strengthen climate change resilience and biosecurity for infectious diseases. The results include a quantitative evaluation of infectious pathogen impact, and suggest greater impacts of human-only compared to zoonotic pathogens or scientific under-representation of zoonoses. The outputs separate high and low impact pathogens, and should be combined with other risk assessment methods relying on expert opinion or qualitative data for priority setting, or could be used to prioritise diseases for which formal risk assessments are not possible because of data gaps.     

Zecken als Krankheitsüberträger: Was tun bei einem Stich?

Because of its wide host‐range and capacity for transmission of multiple pathogens, Ixodes icinus poses a constant threat of human infection. Borrelia burgdorferi is the most prevalent tick‐borne pathogen affecting humans (Lyme Borreliosis), tick‐borne‐encephalitis (TBE) the most important viral tick‐borne disease in Europe. In natural foci the pathogens circulate between infected small mammals and ticks. Knowing the lifecycle of I.ricinus, their multistrategies for host finding, attachment and blood ingestion, we may understand, what makes the tick such an excellent vector. Instructions for individual behaviour in tick areas to avoid tick contact are given. Since transmission is closely related to the feeding period it is helpful to remove an attached tick as soon as possible. Protection against tick‐borne encephalitis by vaccination is possible.     

THE ORIGIN OF SPECIFICITY BY MEANS OF NATURAL SELECTION: EVOLVED AND NONHOST RESISTANCE IN HOST–PATHOGEN INTERACTIONS

Most species seem to be completely resistant to most pathogens and parasites. This resistance has been called “nonhost resistance” because it is exhibited by species that are considered not to be part of the normal host range of the pathogen. A conceptual model is presented suggesting that failure of infection on nonhosts may be an incidental by‐product of pathogen evolution leading to specialization on their source hosts. This model is contrasted with resistance that results from hosts evolving to resist challenge by their pathogens, either as a result of coevolution with a persistent pathogen or as the result of one‐sided evolution by the host against pathogens that are not self‐sustaining on those hosts. Distinguishing evolved from nonevolved resistance leads to contrasting predictions regarding the relationship between resistance and genetic distance. An analysis of cross‐inoculation experiments suggests that the resistance is often the product of pathogen specialization. Understanding the contrasting evolutionary origins of resistance is critical for studies on the genetics and evolution of host–pathogen interactions in human, agricultural, and natural populations. Research on human infectious disease using animal models may often study resistances that have quite contrasting evolutionary origins, and therefore very different underlying genetic mechanisms.