Cluster formation for multi-strain infections with cross-immunity

Many infectious diseases exist in several pathogenic variants, or strains, which interact via cross-immunity. It is observed that strains tend to self-organise into groups, or clusters. The aim of this paper is to investigate cluster formation. Computations demonstrate that clustering is independent of the model used, and is an intrinsic feature of the strain system itself. We observe that an ordered strain system, if it is sufficiently complex, admits several cluster structures of different types. Appearance of a particular cluster structure depends on levels of cross-immunity and, in some cases, on initial conditions. Clusters, once formed, are stable, and behave remarkably regularly (in contrast to the generally chaotic behaviour of the strains themselves). In general, clustering is a type of self-organisation having many features in common with pattern formation.     

Bifurcation, stability, and cluster formation of multi-strain infection models

Clustering behaviours have been found in numerous multi-strain transmission models. Numerical solutions of these models have shown that steady-states, periodic, or even chaotic motions can be self-organized into clusters. Such clustering behaviours are not a priori expected. It has been proposed that the cross-protection from multiple strains of pathogens is responsible for the clustering phenomenon. In this paper, we show that the steady-state clusterings in existing models can be analytically predicted. The clusterings occur via semi-simple double zero bifurcation from the quotient networks of the models and the patterns which follow can be predicted through the stability analysis of the bifurcation. We calculate the stability criteria for the clustering patterns and show that some patterns are inherently unstable. Finally, the biological implications of these results are discussed.     

Generative models versus underlying symmetries to explain biological pattern

Mathematical models play an increasingly important role in the interpretation of biological experiments. Studies often present a model that generates the observations, connecting hypothesized process to an observed pattern. Such generative models confirm the plausibility of an explanation and make testable hypotheses for further experiments. However, studies rarely consider the broad family of alternative models that match the same observed pattern. The symmetries that define the broad class of matching models are in fact the only aspects of information truly revealed by observed pattern. Commonly observed patterns derive from simple underlying symmetries. This article illustrates the problem by showing the symmetry associated with the observed rate of increase in fitness in a constant environment. That underlying symmetry reveals how each particular generative model defines a single example within the broad class of matching models. Further progress on the relation between pattern and process requires deeper consideration of the underlying symmetries.     

On state-space reduction in multi-strain pathogen models, with an application to antigenic drift in influenza A

Many pathogens exist in phenotypically distinct strains that interact with each other through competition for hosts. General models that describe such multi-strain systems are extremely difficult to analyze because their state spaces are enormously large. Reduced models have been proposed, but so far all of them necessarily allow for coinfections and require that immunity be mediated solely by reduced infectivity, a potentially problematic assumption. Here, we suggest a new state-space reduction approach that allows immunity to be mediated by either reduced infectivity or reduced susceptibility and that can naturally be used for models with or without coinfections. Our approach utilizes the general framework of status-based models. The cornerstone of our method is the introduction of immunity variables, which describe multi-strain systems more naturally than the traditional tracking of susceptible and infected hosts. Models expressed in this way can be approximated in a natural way by a truncation method that is akin to moment closure, allowing us to sharply reduce the size of the state space, and thus to consider models with many strains in a tractable manner. Applying our method to the phenomenon of antigenic drift in influenza A, we propose a potentially general mechanism that could constrain viral evolution to a one-dimensional manifold in a two-dimensional trait space. Our framework broadens the class of multi-strain systems that can be adequately described by reduced models. It permits computational, and even analytical, investigation and thus serves as a useful tool for understanding the evolution and ecology of multi-strain pathogens.     

Animal models for filovirus infections

The family Filoviridae, which includes the genera Marburgvirus and Ebolavirus, contains some of the most pathogenic viruses in humans and non-human primates(NHPs), causing severe hemorrhagic fevers with high fatality rates. Small animal models against filoviruses using mice, guinea pigs, hamsters, and ferrets have been developed with the goal of screening candidate vaccines and antivirals, before testing in the gold standard NHP models. In this review, we summarize the different animal models used to understand filovirus pathogenesis, and discuss the advantages and disadvantages of each model with respect to filovirus disease research.     

Animal models simulating anaerobic infections

Animal models simulating human disease have played an important role in our understanding of the pathogenesis and treatment of infections caused by obligately anaerobic bacteria. These models helped document the primary source of such infections as the host's own normal microflora. In addition, the polymicrobial nature of anaerobic infections was documented by using animal models for intraabdominal sepsis. Subsequent studies using animal models have led to an understanding of the nature of the host immune response to abscess causing agents and have been instrumental in defining the molecular basis for the virulence and protection provided by the polysaccharide capsule of Bacteroides fragilis. Animal models have also been important components for studies of toxigenic clostridial diseases, such as antibiotic associated colitis and ulcerative colitis. A discussion of some of these models is provided in this review.     

Animal models of human microsporidial infections

Two new models have been described for Enterocytozoon bieneusi, non-human primates and immuno-suppressed gnotobiotic pigs, but there still is no successful cell culture system. The intestinal xenograft system holds promise as an animal model for Encephalitozoon intestinalis. Encephalitozoon hellem is easily propagated in mice, and also may be an important cause of spontaneous disease of psittacine birds. Encephalitozoon cuniculi occurs spontaneously in a wide variety of animals and can be induced experimentally in athymic mice. This is a useful experimental system and animal model, but the infection is relatively rare in man. Mammalian microsporidioses first were recognized as spontaneous diseases of animals that later confounded studies intended to elucidate the nature of diseases of humans. Much was learned about both experimental and spontaneous animal microsporidial infections that subsequently has been applied to the human diseases. In addition, new diseases have appeared, in both animals and humans, for which models are being developed. Since there are now animal models for almost all the known human microsporidioses, information on pathogenesis, host defenses, and effective treatments may become available soon. The microsporidioses provide a good example of the value of comparative pathology. Dr. Payne: Joe Payne. How much accidental infection has occurred with adjacent laboratory animals? Dr. Shadduck: A hard question. The organisms are thought to spread horizontally, and there is some pretty good evidence for that in rabbits. One assumes that this also is the explanation for the occurrence in infected kennels. Horizontal transmission probably occurs via contaminated urine, at least in the case of rabbits and dogs. Experimentally, horizontal transmission has been difficult to demonstrate in mice. Relative to the danger in people, I don't know how to answer that. I have always treated this as one of those things where you should be careful, but you shouldn't get paranoid. So, we have handled infected cell cultures and animals as if they were potentially infectious for man, but not as if they were something as hot as the human AIDS virus, for example. With the increasing number of reports in humans, I think it is clear that one would never want anybody who was at risk of being immunocompromised to work with these organisms. Dr. Fenkel: Are there other questions? Dr. Mysore: How do the parasites spread within the infected hosts? Dr. Shadduck: The usual answer is hematogenously via infected macrophages, but data that actually support that statement are rare. One does see infected macrophages in tissues, so it is not unreasonable to think that some of them escape and lodge in other tissues. But that has never actually been formally demonstrated. Dr. Nakeeb: Is E. bieneusi a human pathogen? Dr. Shadduck: The answer depends on which paper you read and what approach the authors took. There are papers in which the authors argue that the organism is not a cause of clinical disease in AIDS patients, but the general belief today is that the parasite does cause diarrhea and enteritis. I think the evidence for pathogenicity is quite strong for the various species of the Encephalitozoon, based on the severity and distribution of the lesions.     

Stochastic models of some endemic infections

Stochastic models are established and studied for several endemic infections with demography. Approximations of quasi-stationary distributions and of times to extinction are derived for stochastic versions of SI, SIS, SIR, and SIRS models. The approximations are valid for sufficiently large population sizes. Conditions for validity of the approximations are given for each of the models. These are also conditions for validity of the corresponding deterministic model. It is noted that some deterministic models are unacceptable approximations of the stochastic models for a large range of realistic parameter values.     

幽门螺杆菌动物模型研究进展

幽门螺杆菌动物模型用于HP相关疾病和HP疫苗作用的研究。常规实验动物包括悉生猪、悉生狗、非人类灵长动物、猫、雪貂、小鼠、大鼠、沙鼠等。猫螺杆菌和雪貂螺杆菌感染也被用于模型研究。最近,转基因小鼠和基因敲除小鼠也被用作幽门螺杆菌动物模型研究。     

Epidemiological models of Mycobacterium tuberculosis complex infections

The resurgence of tuberculosis in the 1990s and the emergence of drug-resistant tuberculosis in the first decade of the 21st century increased the importance of epidemiological models for the disease. Due to slow progression of tuberculosis, the transmission dynamics and its long-term effects can often be better observed and predicted using simulations of epidemiological models. This study provides a review of earlier study on modeling different aspects of tuberculosis dynamics. The models simulate tuberculosis transmission dynamics, treatment, drug resistance, control strategies for increasing compliance to treatment, HIV/TB co-infection, and patient groups. The models are based on various mathematical systems, such as systems of ordinary differential equations, simulation models, and Markov Chain Monte Carlo methods. The inferences from the models are justified by case studies and statistical analysis of TB patient datasets.     

Epidemic cycling in a multi-strain SIRS epidemic network model

Background

One common observation in infectious diseases caused by multi-strain pathogens is that both the incidence of all infections and the relative fraction of infection with each strain oscillate with time (i.e., so-called Epidemic cycling). Many different mechanisms have been proposed for the pervasive nature of epidemic cycling. Nevertheless, the two facts that people contact each other through a network rather than following a simple mass-action law and most infectious diseases involve multiple strains have not been considered together for their influence on the epidemic cycling.

Methods

To demonstrate how the structural contacts among people influences the dynamical patterns of multi-strain pathogens, we investigate a two strain epidemic model in a network where every individual randomly contacts with a fixed number of other individuals. The standard pair approximation is applied to describe the changing numbers of individuals in different infection states and contact pairs.

Results

We show that spatial correlation due to contact network and interactions between strains through both ecological interference and immune response interact to generate epidemic cycling. Compared to one strain epidemic model, the two strain model presented here can generate epidemic cycling within a much wider parameter range that covers many infectious diseases.

Conclusion

Our results suggest that co-circulation of multiple strains within a contact network provides an explanation for epidemic cycling.

     

Genetic control of susceptibility to bacterial infections in mouse models

Historically, the laboratory mouse (Mus musculus) has been the experimental model of choice to study pathophysiology of infection with bacterial pathogens, including natural and acquired host defence mechanisms. Inbred mouse strains differ significantly in their degree of susceptibility to infection with various human pathogens such as Mycobacterium, Salmonella, Legionella and many others. Segregation analyses and linkage studies have indicated that some of these differences are under simple genetic control whereas others behave as complex traits. Major advances in genome technologies have greatly facilitated positional cloning of single gene effects. Thus, a number of genes playing a key role in initial susceptibility, progression and outcome of infection have been uncovered and the functional characterization of the encoded proteins has provided new insight into the molecular basis of antimicrobial defences of polymorphonuclear leukocytes, macrophages, as well as T and B lymphocytes. The multigenic control of susceptibility to infection with certain human pathogens is beginning to be characterized by quantitative trait locus mapping in genome wide scans. This review summarizes recent progress on the mapping, cloning and characterization of genes and proteins that affect susceptibility to infection with major intracellular bacterial pathogens.     

Anidulafungin: experimental therapy of fungal infections in animal models

We have reviewed the existing data on the efficacy of anidulafungin, which is the most recent echinocandin in the experimental treatment of fungal infections. The scarce published data practically only refers to disseminated and pulmonary aspergillosis and to disseminated candidiasis. Anidulafungin shows fungistatic activity against Aspergillus fumigatus, and fungicidal activity against Candida albicans and Candida glabrata.     

Protective activity of thymosin against opportunistic infections in animal models

Animal models for opportunistic infections were developed by using mice immunosuppressed by 5-FU. These mice were susceptible to various microorganisms, while normal mice had greater tolerance to such microbial infections. In these models, thymosin alpha 1 was found to protect mice against lethal infections with Candida albicans, Listeria monocytogenes, Pseudomonas aeruginosa, and Serratia marcescens when it was administered during 5-FU treatment prior to the infections. Thymosin alpha 1 was effective in some infections at 0.4-400 micrograms/kg/day IP, about 1/100 of the dose required for thymosin fraction 5. Activity was also demonstrated against L-monocytogenes and Ps. aeruginosa by counting the viable bacteria in the liver after infection. The protective activity against Candida, elimination of which macrophages were essential, was abrogated by anti-thymocyte serum and/or carrageenan, indicating that thymosin alpha 1 serves to maintain the functions of macrophages by reducing the damage to T cells by 5-FU. On the other hand, the activity against Pseudomonas infection was not affected by anti-thymocyte serum or carrageenan. It is probable that thymosin alpha 1 also exerts its effect on neutrophils without participation of T cells and macrophages.     

SCID mice as models for parasitic infections

Mice with severe combined immunodeficiency (SCID mice) have become a favored model system for the study of many parasitic diseases. In this review, Samuel Stanley Jr and Herbert Virgin IV provide a brief overview of the biology of the SCID mouse, and review some examples of how the SCID mouse model has been applied to the study of the immunology of a number of different parasitic diseases.     

Rapid identification of multi-strain HBV infection in patient by high-throughput DNA sequencing

Hepatitis B is a well-known risk factor for the development of liver cancer and is closely associated with patient morbidity and mortality. Viral mutants and variants have the potential to evade immune response and prolong infection, and thus it is crucial to develop a methodology for the rapid identification of multi-strain hepatitis infections in patients. Here we describe a method based on selective region amplification of viral genome and deep sequencing, which may be used for rapid identification of multi-strain hepatitis B virus (HBV) infection in patients. The method works even with significantly low amounts of patients’ serum samples, where the wet-lab procedures take about 1.5 days, followed by a quick bioinformatic analysis to reveal the final results. Our method can potentially be applied to the rapid and reliable identification of multi-strain HBV infection and help improve treatment regiments.     

Immune changes of Schistosoma japonicum infections in various rodent disease models

Rodent models for Schistosoma japonicum infections have demonstrated that these animals possess a degree of resistance to schistosome infections that may be both T and B lymphocyte-mediated. However, their exact role is not well-defined and other immune mechanisms are likely to also play a role in protecting against infection. Immunosuppressed and immunocompetent reed voles (Microtus fortis, Mf), rats and mice (n=24/group) were infected with S. japonicum, and animals were sacrificed 42 days later under anesthesia. Neither worms nor eggs were observed in infected immunosuppressed Mf or rats, with the exception of one rat that presented with few eggs. In immunosuppressed mice, changes in the number and size of the worms were not significantly different compared to immunocompetent mice, but worm fecundity was affected. The size and number of granulomas in immunosuppressed animals was also reduced. Analysis of serum antibodies specific to schistosome adult worm antigen at 3 weeks post-infection demonstrated that the levels of antibodies in the sera of rats were significantly higher than in Mf and mice. In addition, Mf serum levels of IL-4 and IL-12 were significantly higher than levels observed in rats and mice. Antibodies and cytokines in the sera of Mf peaked 3 weeks post-infection and then began to decrease, while antibody responses in rats and mice increased gradually between weeks 3-7 post-infection. It is possible that T and B cells have a dual role in both mediating protection and exacerbating disease outcomes.