The role of nutrition in viral disease

Malnutrition has been associated with a decrease in immune function. Impairment of immune function may lead to increased susceptibility to infection with viruses. Although there are many studies documenting the effect of host nutritional status on immune functions, fewer studies have examined the effect of host nutritional status on viral pathogenesis. This review examines the relationship between viral infection and the nutritional status of the host, and documents that not only can the nutritional status of the host affect immune function, but can have profound effects on the virus itself. One mechanism by which nutritional status affects the virulence of the viral pathogen involves selection for virulent viral genotypes. Other mechanisms remain to be elucidated.     

Epistasis between mutations is host-dependent for an RNA virus

How, and to what extent, does the environment influence the way mutations interact? Do environmental changes affect both the sign and the magnitude of epistasis? Are there any correlations between environments in the variability, sign or magnitude of epistasis? Very few studies have tackled these questions. Here, we addressed them in the context of viral emergence. Most emerging viruses are RNA viruses with small genomes, overlapping reading frames and multifunctional proteins for which epistasis is abundant. Understanding the effect of host species in the sign and magnitude of epistasis will provide insights into the evolutionary ecology of infectious diseases and the predictability of viral emergence.     

Host adaptation and the emergence of infectious disease: the Salmonella paradigm

The recent emergence of food-borne pathogens, such as Salmonella enterica serotype Enteritidis (S. enteritidis) and Escherichia coli O157:H7, has generated increasing interest in how infectious diseases can invade, persist and spread within new host populations. To alter their host range pathogens require adaptations, which ensure their circulation in a new animal population. Adaptations for circulation in different populations of vertebrate hosts seem to have been acquired multiple times within the genus Salmonella because extant Salmonella serotypes differ greatly with regard to host range. In this article, mechanisms involved in host adaptation are deduced by considering the influence of the host immune response on circulation of Salmonella serotypes within populations of vertebrate animals. This approach contributes to the identification of genes involved in host adaptation and provides new insights into the emergence of food-borne pathogens.     

Host phylogeny determines viral persistence and replication in novel hosts

Pathogens switching to new hosts can result in the emergence of new infectious diseases, and determining which species are likely to be sources of such host shifts is essential to understanding disease threats to both humans and wildlife. However, the factors that determine whether a pathogen can infect a novel host are poorly understood. We have examined the ability of three host-specific RNA-viruses (Drosophila sigma viruses from the family Rhabdoviridae) to persist and replicate in 51 different species of Drosophilidae. Using a novel analytical approach we found that the host phylogeny could explain most of the variation in viral replication and persistence between different host species. This effect is partly driven by viruses reaching a higher titre in those novel hosts most closely related to the original host. However, there is also a strong effect of host phylogeny that is independent of the distance from the original host, with viral titres being similar in groups of related hosts. Most of this effect could be explained by variation in general susceptibility to all three sigma viruses, as there is a strong phylogenetic correlation in the titres of the three viruses. These results suggest that the source of new emerging diseases may often be predictable from the host phylogeny, but that the effect may be more complex than simply causing most host shifts to occur between closely related hosts.     

The future impact of societal and cultural factors on parasitic disease -- some emerging issues

A variety of societal and cultural factors will increase host exposure or susceptibility to infectious agents, particularly parasites. Such factors have already had a major impact on the emergence of infectious diseases and the situation is likely to worsen further as we enter the new millennium. The changes that are enhancing the spread and transmission of parasitic diseases, as well as those which are adversely affecting host responsiveness, are examined with reference to specific parasites.     

Chemical mutagenesis: a new strategy against the global threat of infectious diseases

The perpetual evolution of drug-resistant microbes, the overwhelming burden of acquired immune suppression due to HIV, the emergence or re-emergence of various pathogens (West Nile virus, pandemic influenza, Creutzfeld-Jacob disease), and increased fears of bioterrorism has drawn a great deal of new attention to infectious diseases. The pathogenesis of infection is characterized by complex interactions of potentially virulent microorganisms with host genetic and acquired factors. Chemical mutagenesis of the mouse genome provides a robust method to unravel this challenging problem. To deepen our understanding of the natural host response to pathogens, our team and others are interrogating the mouse genome to define genes that are crucial to the defense against infectious diseases (pathogen recognition, viral defense, bacterial defense, prion infection). In this review we highlight the current progress of these efforts and propose a toolbox for other groups that are interested in this endeavor.     

Contrasting landscape epidemiology of two sympatric rabies virus strains

Viral strain evolution and disease emergence are influenced by anthropogenic change to the environment. We investigated viral characteristics, host ecology, and landscape features in the rabies‐striped skunk disease system of the central Great Plains to determine how these factors interact to influence disease emergence. We amplified portions of the N and G genes of rabies viral RNA from 269 samples extracted from striped skunk brains throughout the distribution of two different rabies strains for which striped skunks were the reservoir. Because the distribution of these two strains overlapped on the landscape and were present in the same host population, we could evaluate how viral properties influenced epidemiological patterns in the area of sympatry. We found that South Central Skunk rabies (SCSK) exhibited intense purifying selection and high infectivity, which are both characteristics of an epizootic virus. Conversely, North Central Skunk rabies (NCSK) exhibited relaxed purifying selection and comparatively lower infectivity, suggesting the presence of an enzootic virus. The host population in the area of sympatry was highly admixed, and skunks among allopatric and sympatric areas had similar effective population sizes. Spatial analysis indicated that landscape features had minimal influence on NCSK movement across the landscape, but those same features were partial barriers to the spread of SCSK. We conclude that NCSK and SCSK have different epidemiological properties that interact differently with both host and landscape features to influence rabies spread in the central Great Plains. We suggest a holistic approach for future studies of emerging infectious diseases that includes studies of viral properties, host characteristics, and spatial features.     

Immunomodulators as an antimicrobial tool

The spectrum of infectious diseases has shifted in the past 50 years to include those caused by microbes that cause disease predominantly in immunocompromised individuals. This phenomenon has underscored the dependence of microbial virulence on the immune status of the host. The limited efficacy of the available antimicrobial armamentarium in immunocompromised individuals, combined with increasing resistance to these agents, has led to an urgent need for new therapies for infectious diseases. Immunomodulation represents a novel approach to antimicrobial therapy that depends on bolstering host immunity, rather than direct antimicrobial activity. Immunomodulators can be divided into those that are specific to pathogens (pathogen-specific) and those that are not specific to pathogens (non-specific). However, to date only a few immunomodulators have been evaluated for their efficacy as antimicrobial tools.     

常见肝炎病毒感染性疾病相关miRNA功能研究进展

病毒感染引发的疾病一直威胁着人类健康。Mi RNA是真核生物表达的一类重要的小分子RNA,可特异性的调节基因与蛋白的表达。mi RNA的研究为病毒性疾病的发生发展提供了新思路,为目前热点研究领域。随着mi RNA的研究深入,一些病毒感染中相关mi RNA的功能也被相继报道,如有些mi RNA具有抑制病毒感染宿主细胞的功能,有些mi RNA则可促进病毒在宿主细胞中的复制,有些mi RNA却参与病毒相关疾病的发生,还有些mi RNA则可作为病毒感染性疾病的特异性生物标志物。本文主要以两种常见肝炎病毒:HBV、HCV为例来系统阐述mi RNA在病毒感染中的相关功能。     

Co-infection by Semliki forest virus and malarial parasite modulates viral multipucation, pathogenesis and cytokines in mice

Environmental, technological and societal factors continue to have a dramatic effect on infectious diseases worldwide and are considered to be facilitating the emergence of several infectious diseases at a time. Co-infection with different species of viral and malaria infections are currently emerging problems of dual infection in the developing as well as developed countries. Understanding of interactions between the host, malaria and virus infection is of current concern and we have initiated studies to delineate the mechanisms involved during the progression of Semliki forest virus (SFV) and Plasmodium yoelii (P. yoelii) infection in mice. Enhanced virus multiplication and up-regulation of cytokine mRNA level in P. yoelii and SFV co-infected mice were observed on day 4 post-infection compared to respective controls. Collectively, our observations indicate that malaria infection may influence virus multiplication, pathogenesis and up-regulation of cytokine mRNA during co-infection in mice.     

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.     

How do pathogen evolution and host heterogeneity interact in disease emergence?

Heterogeneity in the parameters governing the spread of infectious diseases is a common feature of real-world epidemics. It has been suggested that for pathogens with basic reproductive number R(0)>1, increasing heterogeneity makes extinction of disease more likely during the early rounds of transmission. The basic reproductive number R(0) of the introduced pathogen may, however, be less than 1 after the introduction, and evolutionary changes are then required for R(0) to increase to above 1 and the pathogen to emerge. In this paper, we consider how host heterogeneity influences the emergence of both non-evolving pathogens and those that must undergo adaptive changes to spread in the host population. In contrast to previous results, we find that heterogeneity does not always make extinction more likely and that if adaptation is required for emergence, the effect of host heterogeneity is relatively small. We discuss the application of these ideas to vaccination strategies.     

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.     

What limits the evolutionary emergence of pathogens?

The ability of a pathogen to cause an epidemic when introduced in a new host population often relies on its ability to adapt to this new environment. Here, we give a brief overview of recent theoretical and empirical studies of such evolutionary emergence of pathogens. We discuss the effects of several ecological and genetic factors that may affect the likelihood of emergence: migration, life history of the infectious agent, host heterogeneity, and the rate and effects of mutations. We contrast different modelling approaches and indicate how details in the way we model each step of a life cycle can have important consequences on the predicted probability of evolutionary emergence. These different theoretical perspectives yield important insights into optimal surveillance and intervention strategies, which should aim for a reduction in the emergence (and re-emergence) of infectious diseases.     

Emerging viral infections in a rapidly changing world

Emerging viral infections in both humans and animals have been reported with increased frequency in recent years. Recent advances have been made in our knowledge of some of these, including severe acute respiratory syndrome-associated coronavirus, influenza A virus, human metapneumovirus, West Nile virus and Ebola virus. Research efforts to mitigate their effects have concentrated on improved surveillance and diagnostic capabilities, as well as on the development of vaccines and antiviral agents. More attention needs to be given to the identification of the underlying causes for the emergence of infectious diseases, which are often related to anthropogenic social and environmental changes. Addressing these factors might help to decrease the rate of emergence of infectious diseases and allow the transition to a more sustainable society.     

Interacting nutritional and infectious etiologies of Keshan disease

In 1979, Chinese scientists reported that selenium had been linked to Keshan disease, an endemic juvenile cardiomyopathy found in China. However, certain epidemiological features of the disease could not be explained solely on the basis of inadequate selenium nutrition. Fluctuations in the seasonal incidence of the disease suggested involvement of an infectious agent. Indeed, a coxsackievirus B4 isolated from a Keshan disease victim caused more heart muscle damage when inoculated into selenium-deficient mice than when given to selenium-adequate mice. Those results led us to study the relationship of nutritional status to viral virulence. Coxsackievirus B3/0 (CVB3/0), did not cause disease when inoculated into mice fed adequate levels of Se and vitamin E. However, mice fed diets deficient in either Se or vitamin E developed heart lesions when infected with CVB3/0. To determine if the change in viral phenotype was maintained, we passaged virus isolated from Se-deficient hosts, maintained, we passaged virus isolated from Se-deficient hosts, designated as CVB3/0 Se-, back into Se-adequate hosts. The CVB3/0 Se- virus caused disease in Se-adequate mice. To determine if the phenotype change was due to changes in the viral genome, we sequenced viruses isolated from Se-deficient mice and compared them with the input CVB3/0 virus. Six point mutations differed between the parent strain and the recovered CVB3/0 Se- isolates. When the experiment was repeated using vitamin E-deficient mice, the same 6 point mutations were found. This is the first report of a specific host nutritional deficiency altering viral genotype. Keshan disease may be the result of several interacting causes including a dominant nutritional deficiency (selenium), other nutritional factors (vitamin E, polyunsaturated fatty acids), and an infectious agent (virus).     

The Evolution and Genetics of Virus Host Shifts

Emerging viral diseases are often the product of a host shift, where a pathogen jumps from its original host into a novel species. Phylogenetic studies show that host shifts are a frequent event in the evolution of most pathogens, but why pathogens successfully jump between some host species but not others is only just becoming clear. The susceptibility of potential new hosts can vary enormously, with close relatives of the natural host typically being the most susceptible. Often, pathogens must adapt to successfully infect a novel host, for example by evolving to use different cell surface receptors, to escape the immune response, or to ensure they are transmitted by the new host. In viruses there are often limited molecular solutions to achieve this, and the same sequence changes are often seen each time a virus infects a particular host. These changes may come at a cost to other aspects of the pathogen''s fitness, and this may sometimes prevent host shifts from occurring. Here we examine how these evolutionary factors affect patterns of host shifts and disease emergence.     

Energetic stress in the honeybee Apis mellifera from Nosema ceranae infection

Parasites are dependent on their hosts for energy to reproduce and can exert a significant nutritional stress on them. Energetic demand placed on the host is especially high in cases where the parasite-host complex is less co-evolved. The higher virulence of the newly discovered honeybee pathogen, Nosema ceranae, which causes a higher mortality in its new host Apis mellifera, might be based on a similar mechanism. Using Proboscis Extension Response and feeding experiments, we show that bees infected with N. ceranae have a higher hunger level that leads to a lower survival. Significantly, we also demonstrate that the survival of infected bees fed ad libitum is not different from that of uninfected bees. These results demonstrate that energetic stress is the probable cause of the shortened life span observed in infected bees. We argue that energetic stress can lead to the precocious and risky foraging observed in Nosema infected bees and discuss its relevance to colony collapse syndrome. The significance of energetic stress as a general mechanism by which infectious diseases influence host behavior and physiology is discussed.     

Serial infection of diverse host (Mus) genotypes rapidly impedes pathogen fitness and virulence

Reduced genetic variation among hosts may favour the emergence of virulent infectious diseases by enhancing pathogen replication and its associated virulence due to adaptation to a limited set of host genotypes. Here, we test this hypothesis using experimental evolution of a mouse-specific retroviral pathogen, Friend virus (FV) complex. We demonstrate rapid fitness (i.e. viral titre) and virulence increases when FV complex serially infects a series of inbred mice representing the same genotype, but not when infecting a diverse array of inbred mouse strains modelling the diversity in natural host populations. Additionally, a single infection of a different host genotype was sufficient to constrain the emergence of a high fitness/high virulence FV complex phenotype in these experiments. The potent inhibition of viral fitness and virulence was associated with an observed loss of the defective retroviral genome (spleen focus-forming virus), whose presence exacerbates infection and drives disease in susceptible mice. Results from our experiments provide an important first step in understanding how genetic variation among vertebrate hosts influences pathogen evolution and suggests that serial exposure to different genotypes within a single host species may act as a constraint on pathogen adaptation that prohibits the emergence of more virulent infections. From a practical perspective, these results have implications for low-diversity host populations such as endangered species and domestic animals.     

Coronavirus and co-infections: A Saudi Arabian perspective

Mortality due to infectious diseases continues to rise globally, despite advances in antimicrobial therapy and supportive care. This is evident with the occurrence of coronavirus disease 2019 (COVID-19) pandemic, instigated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Saudi Arabia, an eminent country within the Arab region, has had significant impact during global pandemics, concomitant with the fact that millions of Muslims travel to Saudi Arabia for pilgrimages every year. Herein, we discuss the significance of SARS-CoV-1, SARS-CoV-2, as well as the Middle East respiratory syndrome coronavirus (MERS-CoV) in Saudi Arabia with particular reference to global transmission and/or emergence of new variants due to genetic mixing of different strains. Furthermore, we also discuss the role of Saudi Arabia with reference to novel emerging infectious diseases and re-emerging infections, such as Ebola, zika, and monkeypox, as well as in the context on coinfections. Future strategies to limit the spread of viral infections and the pivotal role of Saudi Arabia, are deliberated upon.