季节性流感病毒与其他病原混合或继发感染的研究进展与思考

流感病毒包括甲(A)、乙(B)、丙(C)和丁(D)四种型。人流行性感冒是由甲型和乙型季节性流感病毒引起的一种急性呼吸道传染病。流感病毒感染患者主要表现出呼吸道症状,严重时可以导致肺炎。此外,与其他病毒、细菌和支原体等病原体混合或继发感染时,会增加流感患者的重症率和死亡率。近几年,流感病毒与其他病原协同感染的病例有增加趋势。本文归纳总结了流感病毒与其他病原混合及继发感染的研究现状,希望为流感病毒复杂感染情况的临床诊断和治疗方案的制定提供线索。     

Innovations in modeling influenza virus infections in the laboratory

Respiratory viruses represent one of the most substantial infectious disease burdens to the human population today, and in particular, seasonal and pandemic influenza viruses pose a persistent threat to public health worldwide. In recent years, advances in techniques used in experimental research have provided the means to better understand the mechanisms of pathogenesis and transmission of respiratory viruses, and thus more accurately model these infections in the laboratory. Here, we briefly review the model systems used to study influenza virus infections, and focus particularly on recent advances that have increased our knowledge of these formidable respiratory pathogens.     

Host sex,size, and hemoparasite infection influence the effects of ectoparasitic burdens on free‐ranging iguanas

Investigations focusing on host–ectoparasite interactions in animals have revealed asymptomatic to severe health and fitness consequences suggesting that species mobilize different interspecific response mechanisms. Fewer studies, however, have examined intraspecific responses to ectoparasitic burdens. In this study, we analyzed host health and fitness responses to increasing ectoparasite burdens along with the presence/absence of hemoparasites of free‐ranging insular rock iguanas (Cyclura cychlura) in The Bahamas. Using hematology, plasma biochemistry, as well as body condition and growth rate comparisons, we failed to find significant associations of tick burdens with annual growth rate, corticosterone, packed cell volume, total white blood cell, and heterophil, monocyte, eosinophil or hemoglobin measures. We did, however, find mixed and significant associations of tick burdens with lymphocyte and basophil counts, heterophil‐to‐lymphocyte ratios, and body condition indices. These associations varied by sex, size, and hemoparasite infection status suggesting that different life stages of iguanas may invest differently in immune responses, and impacts may be modulated based on size and sex of hosts, and coinfection status.     

From host immunity to pathogen invasion: the effects of helminth coinfection on the dynamics of microparasites

Concurrent infections with multiple parasites are ubiquitous in nature. Coinfecting parasites can interact with one another in a variety of ways, including through the host's immune system via mechanisms such as immune trade-offs and immunosuppression. These within-host immune processes mediating interactions among parasites have been described in detail, but how they scale up to determine disease dynamic patterns at the population level is only beginning to be explored. In this review, we use helminth-microparasite coinfection as a model for examining how within-host immunological effects may influence the ecological outcome of microparasitic diseases, with a specific focus on disease invasion. The current literature on coinfection between helminths and major microparasitic diseases includes many studies documenting the effects of helminths on individual host responses to microparasites. In many cases, the observed host responses map directly onto parameters relevant for quantifying disease dynamics; however, there have been few attempts at integrating data on individual-level effects into theoretical models to extrapolate from the individual to the population level. Moreover, there is considerable variability in the particular combination of disease parameters affected by helminths across different microparasite systems. We develop a conceptual framework identifying some potential sources of such variability: Pathogen persistence and severity, and resource availability to hosts. We also generate testable hypotheses regarding diseases and the environmental contexts when the effects of helminths on microparasite dynamics should be most pronounced. Finally, we use a case study of helminth and mycobacterial coinfection in the African buffalo to illustrate both progress and challenges in understanding the population-level consequences of within-host immunological interactions, and conclude with suggestions for future research that will help improve our understanding of the effects of coinfection on dynamics of infectious diseases.     

Short Term Minimum Water Temperatures Determine Levels of Infection by the Amphibian Chytrid Fungus in Alytes obstetricans Tadpoles

Amphibians are one of the groups of wildlife most seriously threatened by emerging infectious disease. In particular, chytridiomycosis, caused by the aquatic fungus Batrachochytrium dendrobatidis, is responsible for amphibian species declines on a worldwide scale. Population-level outcomes following the introduction of the pathogen are context dependent and mediated by a large suite of abiotic and biotic variables. In particular, studies have shown that temperature has a key role in determining infection dynamics owing to the ectothermic nature of the amphibian host and temperature-dependency of pathogen growth rates. To assess the temperature-dependent seasonality of infectious burdens in a susceptible host species, we monitored lowland populations of larval midwife toads, Alytes obstetricians, in Central Spain throughout the year. We found that infections were highly seasonal, and inversely correlated against water temperature, with the highest burdens of infection seen during the colder months. Short-term impacts of water-temperature were found, with the minimum temperatures occurring before sampling being more highly predictive of infectious burdens than were longer-term spans of temperature. Our results will be useful for selecting the optimal time for disease surveys and, more broadly, for determining the key periods to undertake disease mitigation.     

Population dynamics of the parasitic stages of Oesophagostomum dentatum in pigs in single and trickle infections

A mathematical model was developed to describe the dynamics of the parasitic stages of Oesophagostomum dentatam in pigs. An immigration-death model with constant establishment, development and death rates was fitted to L3, L4 and adult worm burdens observed in a single-infection experiment. Female worm length was modelled by a function of worm age and total worm burden, while worm egg production (eggs per gram faeces per female worm) was modelled by a function of worm age and worm length. The model was then used to predict worm burdens observed in a trickle-infection experiment. The predicted worm burdens were much higher than those observed, suggesting that worm death rates were higher during the trickle infection. After increusing worm death rates to fit the observed worm burdens, female worm lengths and egg production in the trickle infection were predicted. At the medium- and high-dose rates, predicted worm lengths and, thus, egg preduction were lower than observed, while at the low-dose rate predicted egg production was too high. It appeared that in the trickle infections, total worm burden had less influence on observed female worm length and egg production than in the single infections. The results suggest that the demography of O. dentatum in pigs differs between single and trickle infections.     

Circadian orchestration of host and gut microbiota in infection

Circadian rhythms are present in almost every organism and regulate multiple aspects of biological and physiological processes (e.g. metabolism, immune responses, and microbial exposure). There exists a bidirectional circadian interaction between the host and its gut microbiota, and potential circadian orchestration of both host and gut microbiota in response to invading pathogens. In this review, we summarize what is known about these intestinal microbial oscillations and the relationships between host circadian clocks and various infectious agents (bacteria, fungi, parasites, and viruses), and discuss how host circadian clocks prime the immune system to fight pathogen infections as well as the direct effects of circadian clocks on viral activity (e.g. SARS-CoV-2 entry and replication). Finally, we consider strategies employed to realign normal circadian rhythmicity for host health, such as chronotherapy, dietary intervention, good sleep hygiene, and gut microbiota-targeted therapy. We propose that targeting circadian rhythmicity may provide therapeutic opportunities for the treatment of infectious diseases.     

Alternatively activated macrophages in intestinal helminth infection: effects on concurrent bacterial colitis

The distribution of several pathogenic helminth infections coincides geographically with many devastating microbial diseases, including enteric bacterial infections. To dissect the mechanisms by which helminths modulate the host's response to enteric bacteria and bacteria-mediated intestinal inflammation, we have recently established a coinfection model and shown that coinfection with the helminth Heligmosomoides polygyrus exacerbates colitis induced by infection with the gram-negative bacterial pathogen Citrobacter rodentium. The disease severity of the coinfected mice was correlated with high Citrobacter loads in the gut, translocation of the bacteria into mucosal and systemic immune compartments, delayed bacterial clearance, and a significantly enhanced colonic TNF-alpha response. In the present study, using our in vivo coinfection model as well as in vitro approaches, we test the hypothesis that the phenotypic and functional alterations in macrophages induced by the helminth-driven T cell response may contribute to the observed alterations in the response to C. rodentium. We show that via a STAT6-dependent mechanism H. polygyrus coinfection results in a marked infiltration into the colonic lamina propria of F4/80+ cells that have the phenotype of alternatively activated macrophages. Functional analysis of these macrophages further shows that they are impaired in their killing of internalized bacteria. Yet, these cells produce an enhanced amount of TNF-alpha in response to C. rodentium infection. These results demonstrate that helminth infection can impair host protection against concurrent enteric bacterial infection and promote bacteria-induced intestinal injury through a mechanism that involves the induction of alternatively activated macrophages.     

Drivers of Inequality in Millennium Development Goal Progress: A Statistical Analysis

Background

Many low- and middle-income countries are not on track to reach the public health targets set out in the Millennium Development Goals (MDGs). We evaluated whether differential progress towards health MDGs was associated with economic development, public health funding (both overall and as percentage of available domestic funds), or health system infrastructure. We also examined the impact of joint epidemics of HIV/AIDS and noncommunicable diseases (NCDs), which may limit the ability of households to address child mortality and increase risks of infectious diseases.

Methods and Findings

We calculated each country''s distance from its MDG goals for HIV/AIDS, tuberculosis, and infant and child mortality targets for the year 2005 using the United Nations MDG database for 227 countries from 1990 to the present. We studied the association of economic development (gross domestic product [GDP] per capita in purchasing-power-parity), the relative priority placed on health (health spending as a percentage of GDP), real health spending (health system expenditures in purchasing-power-parity), HIV/AIDS burden (prevalence rates among ages 15–49 y), and NCD burden (age-standardised chronic disease mortality rates), with measures of distance from attainment of health MDGs. To avoid spurious correlations that may exist simply because countries with high disease burdens would be expected to have low MDG progress, and to adjust for potential confounding arising from differences in countries'' initial disease burdens, we analysed the variations in rates of change in MDG progress versus expected rates for each country. While economic development, health priority, health spending, and health infrastructure did not explain more than one-fifth of the differences in progress to health MDGs among countries, burdens of HIV and NCDs explained more than half of between-country inequalities in child mortality progress (R ²-infant mortality  = 0.57, R ²-under 5 mortality  = 0.54). HIV/AIDS and NCD burdens were also the strongest correlates of unequal progress towards tuberculosis goals (R ² = 0.57), with NCDs having an effect independent of HIV/AIDS, consistent with micro-level studies of the influence of tobacco and diabetes on tuberculosis risks. Even after correcting for health system variables, initial child mortality, and tuberculosis diseases, we found that lower burdens of HIV/AIDS and NCDs were associated with much greater progress towards attainment of child mortality and tuberculosis MDGs than were gains in GDP. An estimated 1% lower HIV prevalence or 10% lower mortality rate from NCDs would have a similar impact on progress towards the tuberculosis MDG as an 80% or greater rise in GDP, corresponding to at least a decade of economic growth in low-income countries.

Conclusions

Unequal progress in health MDGs in low-income countries appears significantly related to burdens of HIV and NCDs in a population, after correcting for potentially confounding socioeconomic, disease burden, political, and health system variables. The common separation between NCDs, child mortality, and infectious syndromes among development programs may obscure interrelationships of illness affecting those living in poor households—whether economic (e.g., as money spent on tobacco is lost from child health expenditures) or biological (e.g., as diabetes or HIV enhance the risk of tuberculosis). Please see later in the article for the Editors'' Summary     

Multiple infection dynamics has pronounced effects on the fitness of RNA viruses

Several factors play a role during the replication and transmission of RNA viruses. First, as a consequence of their enormous mutation rate, complex mixtures of genomes are generated immediately after infection of a new host. Secondly, differences in growth and competition rates drive the selection of certain genetic variants within an infected host. Thirdly, but not less important, a random sampling occurs at the moment of viral infectious passage from an infected to a healthy host. In addition, the availability of hosts also influences the fate of a given viral genotype. When new hosts are scarce, different viral genotypes might infect the same host, adding an extra complexity to the competition among genetic variants. We have employed a two‐fold approach to analyse the role played by each of these factors in the evolution of RNA viruses. First, we have derived a model that takes into account all the preceding factors. This model employs the classic Lotka‐Volterra competition equations but it also incorporates the effect of mutation during RNA replication, the effect of the stochastic sampling at the moment of infectious passage among hosts and, the effect of the type of infection (single, coinfection or superinfection). Secondly, the predictions of the model have been tested in an in vitro evolution experiment. Both theoretical and experimental results show that in infection passages with coinfection viral fitness increased more than in single infections. In contrast, infection passages with superinfection did not differ from the single infection. The coinfection frequency also affected the outcome: the larger the proportion of viruses coinfecting a host, the larger increase in fitness observed.     

Latent Coinfection and the Maintenance of Strain Diversity

Technologies for strain differentiation and typing have made it possible to detect genetic diversity of pathogens, both within individual hosts and within communities. Coinfection of a host by more than one pathogen strain may affect the relative frequency of these strains at the population level through complex within- and between-host interactions; in infectious diseases that have a long latent period, interstrain competition during latency is likely to play an important role in disease dynamics. We show that SEIR models that include a class of latently coinfected individuals can have markedly different long-term dynamics than models without coinfection, and that coinfection can greatly facilitate the stable coexistence of strains. We demonstrate these dynamics using a model relevant to tuberculosis in which people may experience latent coinfection with both drug sensitive and drug resistant strains. Using this model, we show that the existence of a latent coinfected state allows the possibility that disease control interventions that target latency may facilitate the emergence of drug resistance.     

Towards the endgame and beyond: complexities and challenges for the elimination of infectious diseases

Successful control measures have interrupted the local transmission of human infectious diseases such as measles, malaria and polio, and saved and improved billions of lives. Similarly, control efforts have massively reduced the incidence of many infectious diseases of animals, such as rabies and rinderpest, with positive benefits for human health and livelihoods across the globe. However, disease elimination has proven an elusive goal, with only one human and one animal pathogen globally eradicated. As elimination targets expand to regional and even global levels, hurdles may emerge within the endgame when infections are circulating at very low levels, turning the last mile of these public health marathons into the longest mile. In this theme issue, we bring together recurring challenges that emerge as we move towards elimination, highlighting the unanticipated consequences of particular ecologies and pathologies of infection, and approaches to their management.     

COVID-19 Pandemic: Insights into Interactions between SARS-CoV-2 Infection and MAFLD

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become an ongoing global health pandemic. Since 2019, the pandemic continues to cast a long shadow on all aspects of our lives, bringing huge health and economic burdens to all societies. With our in-depth understanding of COVID-19, from the initial respiratory tract to the later gastrointestinal tract and cardiovascular systems, the multiorgan involvement of this infectious disease has been discovered. Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly named nonalcoholic fatty liver disease (NAFLD), is a major health issue closely related to metabolic dysfunctions, affecting a quarter of the world''s adult population. The association of COVID-19 with MAFLD has received increasing attention, as MAFLD is a potential risk factor for SARS-CoV-2 infection and severe COVID-19 symptoms. In this review, we provide an update on the interactions between COVID-19 and MAFLD and its underlying mechanisms.     

Age‐specific infectious period shapes dynamics of pneumonia in bighorn sheep

Superspreading, the phenomenon where a small proportion of individuals contribute disproportionately to new infections, has profound effects on disease dynamics. Superspreading can arise through variation in contacts, infectiousness or infectious periods. The latter has received little attention, yet it drives the dynamics of many diseases of critical public health, livestock health and conservation concern. Here, we present rare evidence of variation in infectious periods underlying a superspreading phenomenon in a free‐ranging wildlife system. We detected persistent infections of Mycoplasma ovipneumoniae, the primary causative agent of pneumonia in bighorn sheep (Ovis canadensis), in a small number of older individuals that were homozygous at an immunologically relevant genetic locus. Interactions among age‐structure, genetic composition and infectious periods may drive feedbacks in disease dynamics that determine the magnitude of population response to infection. Accordingly, variation in initial conditions may explain divergent population responses to infection that range from recovery to catastrophic decline and extirpation.     

Get the News Out Loudly and Quickly: The Influence of the Media on Limiting Emerging Infectious Disease Outbreaks

During outbreaks of infectious diseases with high morbidity and mortality, individuals closely follow media reports of the outbreak. Many will attempt to minimize contacts with other individuals in order to protect themselves from infection and possibly death. This process is called social distancing. Social distancing strategies include restricting socializing and travel, and using barrier protections. We use modeling to show that for short-term outbreaks, social distancing can have a large influence on reducing outbreak morbidity and mortality. In particular, public health agencies working together with the media can significantly reduce the severity of an outbreak by providing timely accounts of new infections and deaths. Our models show that the most effective strategy to reduce infections is to provide this information as early as possible, though providing it well into the course of the outbreak can still have a significant effect. However, our models for long-term outbreaks indicate that reporting historic infection data can result in more infections than with no reporting at all. We examine three types of media influence and we illustrate the media influence with a simulated outbreak of a generic emerging infectious disease in a small city. Social distancing can never be complete; however, for a spectrum of outbreaks, we show that leaving isolation (stopping applying social distancing measures) for up to 4 hours each day has modest effect on the overall morbidity and mortality.     

Diseases and causes of death in European bats: dynamics in disease susceptibility and infection rates

Background

Bats receive increasing attention in infectious disease studies, because of their well recognized status as reservoir species for various infectious agents. This is even more important, as bats with their capability of long distance dispersal and complex social structures are unique in the way microbes could be spread by these mammalian species. Nevertheless, infection studies in bats are predominantly limited to the identification of specific pathogens presenting a potential health threat to humans. But the impact of infectious agents on the individual host and their importance on bat mortality is largely unknown and has been neglected in most studies published to date.

Methodology/Principal Findings

Between 2002 and 2009, 486 deceased bats of 19 European species (family Vespertilionidae) were collected in different geographic regions in Germany. Most animals represented individual cases that have been incidentally found close to roosting sites or near human habitation in urban and urban-like environments. The bat carcasses were subjected to a post-mortem examination and investigated histo-pathologically, bacteriologically and virologically. Trauma and disease represented the most important causes of death in these bats. Comparative analysis of pathological findings and microbiological results show that microbial agents indeed have an impact on bats succumbing to infectious diseases, with fatal bacterial, viral and parasitic infections found in at least 12% of the bats investigated.

Conclusions/Significance

Our data demonstrate the importance of diseases and infectious agents as cause of death in European bat species. The clear seasonal and individual variations in disease prevalence and infection rates indicate that maternity colonies are more susceptible to infectious agents, underlining the possible important role of host physiology, immunity and roosting behavior as risk factors for infection of bats.     

Tick-borne infections of animals and humans: a common ground

A wide variety of pathogens is transmitted from ticks to vertebrates including viruses, bacteria, protozoa and helminths, of which most have a life cycle that requires passage through the vertebrate host. Tick-borne infections of humans, farm and companion animals are essentially associated with wildlife animal reservoirs. While some flying insect-borne diseases of humans such as malaria, filariasis and Kala Azar caused by Leishmania donovani target people as their main host, major tick-borne infections of humans, although potentially causing disease in large numbers of individuals, are typically an infringement of a circulation between wildlife animal reservoirs and tick vectors. While new tick-borne infectious agents are frequently recognised, emerging agents of human tick-borne infections were probably circulating among wildlife animal and tick populations long before being recognised as clinical causes of human disease as has been shown for Borrelia burgdorferi sensu lato. Co-infection with more than one tick-borne infection is common and can enhance pathogenic processes and augment disease severity as found in B. burgdorferi and Anaplasma phagocytophilum co-infection. The role of wild animal reservoirs in co-infection of human hosts appears to be central, further linking human and animal tick-borne infections. Although transmission of most tick-borne infections is through the tick saliva, additional routes of transmission, shown mostly in animals, include infection by oral uptake of infected ticks, by carnivorism, animal bites and transplacentally. Additionally, artificial infection via blood transfusion is a growing threat in both human and veterinary medicine. Due to the close association between human and animal tick-borne infections, control programs for these diseases require integration of data from veterinary and human reporting systems, surveillance in wildlife and tick populations, and combined teams of experts from several scientific disciplines such as entomology, epidemiology, medicine, public health and veterinary medicine.     

A branching model for the spread of infectious animal diseases in varying environments

This paper is concerned with a stochastic model, describing outbreaks of infectious diseases that have potentially great animal or human health consequences, and which can result in such severe economic losses that immediate sets of measures need to be taken to curb the spread. During an outbreak of such a disease, the environment that the infectious agent experiences is therefore changing due to the subsequent control measures taken. In our model, we introduce a general branching process in a changing (but not random) environment. With this branching process, we estimate the probability of extinction and the expected number of infected individuals for different control measures. We also use this branching process to calculate the generating function of the number of infected individuals at any given moment. The model and methods are designed using important infections of farmed animals, such as classical swine fever, foot-and-mouth disease and avian influenza as motivating examples, but have a wider application, for example to emerging human infections that lead to strict quarantine of cases and suspected cases (e.g. SARS) and contact and movement restrictions.     

Half the story: Thermal effects on within‐host infectious disease progression in a warming climate

Immune defense is temperature dependent in cold‐blooded vertebrates (CBVs) and thus directly impacted by global warming. We examined whether immunity and within‐host infectious disease progression are altered in CBVs under realistic climate warming in a seasonal mid‐latitude setting. Going further, we also examined how large thermal effects are in relation to the effects of other environmental variation in such a setting (critical to our ability to project infectious disease dynamics from thermal relationships alone). We employed the three‐spined stickleback and three ecologically relevant parasite infections as a “wild” model. To generate a realistic climatic warming scenario we used naturalistic outdoors mesocosms with precise temperature control. We also conducted laboratory experiments to estimate thermal effects on immunity and within‐host infectious disease progression under controlled conditions. As experimental readouts we measured disease progression for the parasites and expression in 14 immune‐associated genes (providing insight into immunophenotypic responses). Our mesocosm experiment demonstrated significant perturbation due to modest warming (+2°C), altering the magnitude and phenology of disease. Our laboratory experiments demonstrated substantial thermal effects. Prevailing thermal effects were more important than lagged thermal effects and disease progression increased or decreased in severity with increasing temperature in an infection‐specific way. Combining laboratory‐determined thermal effects with our mesocosm data, we used inverse modeling to partition seasonal variation in Saprolegnia disease progression into a thermal effect and a latent immunocompetence effect (driven by nonthermal environmental variation and correlating with immune gene expression). The immunocompetence effect was large, accounting for at least as much variation in Saprolegnia disease as the thermal effect. This suggests that managers of CBV populations in variable environments may not be able to reliably project infectious disease risk from thermal data alone. Nevertheless, such projections would be improved by primarily considering prevailing thermal effects in the case of within‐host disease and by incorporating validated measures of immunocompetence.