Estimation of Cross-Immunity Between Drifted Strains of Influenza A/H3N2

To determine the cross-immunity between influenza strains, we design a novel statistical method, which uses a theoretical model and clinical data on attack rates and vaccine efficacy among school children for two seasons after the 1968 A/H3N2 influenza pandemic. This model incorporates the distribution of susceptibility and the dependence of cross-immunity on the antigenic distance of drifted strains. We find that the cross-immunity between an influenza strain and the mutant that causes the next epidemic is 88%. Our method also gives estimates of the vaccine protection against the vaccinating strain, and the basic reproduction number of the 1968 pandemic influenza.     

Theoretical considerations of cross-immunity, recombination and the evolution of new parasitic strains.

We explore the dynamics of multiple strains of a parasite in order to assess the conditions under which a novel strain, perhaps a mutant or migrant, may invade a population that already carries an endemic strain. Multiple strain dynamics can be modeled through coinfection or complete cross-immunity. We examine these three modes to discuss the relationships among cross-immunity, the basic reproductive rates of each strain, and the invasion of the new strain. Superinfection is more restrictive than coinfection in the proportion of parameters that allows invasion. The coinfection model is extended to allow haploid strains to undergo recombination within the host. We investigate the effects of recombination and cross-immunity on the invasion of new strains. Interestingly, although recombination is understood to generate diversity, it is not always advantageous.     

Epidemiological models with age structure,proportionate mixing,and cross-immunity

Infection by one strain of influenza type A provides some protection (cross-immunity) against infection by a related strain. It is important to determine how this influences the observed co-circulation of comparatively minor variants of the H1N1 and H3N2 subtypes. To this end, we formulate discrete and continuous time models with two viral strains, cross-immunity, age structure, and infectious disease dynamics. Simulation and analysis of models with cross-immunity indicate that sustained oscillations cannot be maintained by age-specific infection activity level rates when the mortality rate is constant; but are possible if mortalities are age-specific, even if activity levels are independent of age. Sustained oscillations do not seem possible for a single-strain model, even in the presence of age-specific mortalities; and thus it is suggested that the interplay between cross-immunity and age-specific mortalities may underlie observed oscillations.     

The Possible Impact of Vaccination for Seasonal Influenza on Emergence of Pandemic Influenza via Reassortment

Background

One pathway through which pandemic influenza strains might emerge is reassortment from coinfection of different influenza A viruses. Seasonal influenza vaccines are designed to target the circulating strains, which intuitively decreases the prevalence of coinfection and the chance of pandemic emergence due to reassortment. However, individual-based analyses on 2009 pandemic influenza show that the previous seasonal vaccination may increase the risk of pandemic A(H1N1) pdm09 infection. In view of pandemic influenza preparedness, it is essential to understand the overall effect of seasonal vaccination on pandemic emergence via reassortment.

Methods and Findings

In a previous study we applied a population dynamics approach to investigate the effect of infection-induced cross-immunity on reducing such a pandemic risk. Here the model was extended by incorporating vaccination for seasonal influenza to assess its potential role on the pandemic emergence via reassortment and its effect in protecting humans if a pandemic does emerge. The vaccination is assumed to protect against the target strains but only partially against other strains. We find that a universal seasonal vaccine that provides full-spectrum cross-immunity substantially reduces the opportunity of pandemic emergence. However, our results show that such effectiveness depends on the strength of infection-induced cross-immunity against any novel reassortant strain. If it is weak, the vaccine that induces cross-immunity strongly against non-target resident strains but weakly against novel reassortant strains, can further depress the pandemic emergence; if it is very strong, the same kind of vaccine increases the probability of pandemic emergence.

Conclusions

Two types of vaccines are available: inactivated and live attenuated, only live attenuated vaccines can induce heterosubtypic immunity. Current vaccines are effective in controlling circulating strains; they cannot always help restrain pandemic emergence because of the uncertainty of the oncoming reassortant strains, however. This urges the development of universal vaccines for prevention of pandemic influenza.     

A unifying theory for genetic epidemiological analysis of binary disease data

Background

Genetic selection for host resistance offers a desirable complement to chemical treatment to control infectious disease in livestock. Quantitative genetics disease data frequently originate from field studies and are often binary. However, current methods to analyse binary disease data fail to take infection dynamics into account. Moreover, genetic analyses tend to focus on host susceptibility, ignoring potential variation in infectiousness, i.e. the ability of a host to transmit the infection. This stands in contrast to epidemiological studies, which reveal that variation in infectiousness plays an important role in the progression and severity of epidemics. In this study, we aim at filling this gap by deriving an expression for the probability of becoming infected that incorporates infection dynamics and is an explicit function of both host susceptibility and infectiousness. We then validate this expression according to epidemiological theory and by simulating epidemiological scenarios, and explore implications of integrating this expression into genetic analyses.

Results

Our simulations show that the derived expression is valid for a range of stochastic genetic-epidemiological scenarios. In the particular case of variation in susceptibility only, the expression can be incorporated into conventional quantitative genetic analyses using a complementary log-log link function (rather than probit or logit). Similarly, if there is moderate variation in both susceptibility and infectiousness, it is possible to use a logarithmic link function, combined with an indirect genetic effects model. However, in the presence of highly infectious individuals, i.e. super-spreaders, the use of any model that is linear in susceptibility and infectiousness causes biased estimates. Thus, in order to identify super-spreaders, novel analytical methods using our derived expression are required.

Conclusions

We have derived a genetic-epidemiological function for quantitative genetic analyses of binary infectious disease data, which, unlike current approaches, takes infection dynamics into account and allows for variation in host susceptibility and infectiousness.     

Identification of mutations at the antigenic and glycosylation sites in hemagglutinin protein of H5N1 strain

Hemagglutinin (HA) is the principal antigen, present on the viral surface. It is the primary target for neutralizing antibodies. In this paper, we have carried out studies on human hemagglutinin protein from H5N1 strain with homologous hemagglutinin from non-human sources of H5N1 strains. In all strains, part of the antigenic site (128-141) predicted by computer program “Antigenic”, corresponds to immunodominant site Sa of H1 subtype. In {"type":"entrez-protein","attrs":{"text":"AAF02304","term_id":"6048753","term_text":"AAF02304"}}AAF02304 strain, A156→S156 mutation lies at the antigenic subsite of site 2 that corresponds to site B in the H3 subtype. In some strains of non-human origins, there are mutations at the antigenic sites. Interestingly, in {"type":"entrez-protein","attrs":{"text":"AAY56367","term_id":"66775625","term_text":"AAY56367"}}AAY56367 strain mutation L138→H138 lies at the receptor binding site, which also overlaps the antigenic site. Therefore, this amino acid substitution may influence both the specificity of receptor recognition and antibody binding. Seven potential glycosylation sites in human HA and in some strains of non-human sources have been predicted by computer program, Scan Prosite. In some strains of HA from non-human sources because of mutation, an additional glycosylation site appeared at the antigenic site. Therefore in these strains the oligosaccharides will mask the surface of HA as well as antigenic site. Hence these strains will not be recognized by host immune system.     

Molecular analysis of the first avian influenza H5N1 isolates from fowl in Romania

Since the events of avian influenza (AI) caused by H5N1 subtype from Hong Kong (1997), the people worldwide have been confronted with new waves of epizootic influenza. In 2005 in Romania an unprecedent H5N1 epizootic occurred in domestic and wild birds. Therefore an immediate investigation by molecular approach of this highly pathogenic H5N1 strain was necessary. The virus isolation and the RNA extraction were performed in the Institute of Diagnosis and Animal Health while PCR and sequencing were carried out in Cantacuzino Institute. Herein we report the first evidence of H5N1 presence in Romanian fowls. The phylogenetic analysis of haemagglutinin and neuraminidase gene indicated a close relationship of Romanian strains to those from Siberia and China. The virological and molecular analysis of the first strains of avian virus from Romania confirmed the presence of H5N1 subtype, belonging to the genetic line Z. These results indicate that the avian virus from this genetic line is directly derived from the highly pathogenic viruses isolated in China and Russia in 2005.     

Localized contacts between hosts reduce pathogen diversity

We investigate the dynamics of a simple epidemiological model for the invasion by a pathogen strain of a population where another strain circulates. We assume that reinfection by the same strain is possible but occurs at a reduced rate due to acquired immunity. The rate of reinfection by a distinct strain is also reduced due to cross-immunity. Individual based simulations of this model on a 'small-world' network show that the proportion of local contacts in the host contact network structure significantly affects the outcome of such an invasion, and as a consequence will affect the patterns of pathogen evolution. In particular, hosts interacting through a 'small-world' network of contacts support lower prevalence of infection than well-mixed populations, and the region in parameter space for which an invading strain can become endemic and coexist with the circulating strain is smaller, reducing the potential to accommodate pathogen diversity. We discuss the underlying mechanisms for the reported effects, and we propose an effective mean-field model to account for the contact structure of the host population in 'small-world' networks.     

Strain variation in the susceptibility and immune response to Clonorchis sinensis infection in mice

Mice have shown various susceptibility to infection by Clonorchis sinensis. To compare the intra-specific variation in the host-parasite relationship of C. sinensis, 6 strains of mice (ICR, BALB/c, C57BL/6, DDY, CBA/N, and C3H/HeN) with 3 different haplotypes were evaluated on their susceptibility. The worm recovery rate and immunological responses were observed after 4 and 8 weeks of infection with 30 metacercariae. The highest worm recovery rate was observed as 20.7% in the C3H/HeN strain after 4 weeks of infection along with histopathological changes. The rate was 10.0% in C57BL/6 mice after 8 weeks. ICR, BALB/c, and CBA/N showed elevated levels of IgE at both time points when compared to the rest of the strains. The serum IgG1 and IgG2a levels were elevated in most of the strains; however, the C57BL/6 strain showed a lower level of IgG2a that indicated the IgG1 predominance over IgG2a. The production of IL-4 after concanavalin-A stimulation of splenocytes slightly increased among the mouse strains except C3H/HeN after 4 or 8 weeks of infection, but each strain produced high levels of IFN-γ after 8 weeks, which implied mixed Th1/Th2 responses. ICR, DDY, CBA/N, and C3H/HeN strains showed a significantly increased level of IL-10 after 8 weeks as compared to C57BL/6. All of the strains showed an increased level of IL-13 and suggested fibrotic changes in the mice. In conclusion, mice are insusceptible to infection with C. sinensis; however, the C57BL/6, BALB/c and ICR strains are relatively susceptible after 8 weeks of infection among the six strains. Worm expulsion may be one of the causes of low susceptibility of C3H/HeN mice strain at the 8th week. Elevated IgE, IFN-γ, and IL-13 of infected mice suggest both Th1 and Th2 responses that may be related to the low host susceptibility.     

Primary structure of the avian influenza virus A/FVP/Weybridge hemagglutinin gene

The complete primary structure of cDNA for hemagglutinin gene of influenza virus A/FPV/weybridge/27 subtype H7 has been determined. Its comparison with the structures of analogous genes from other strains of the same subtype has shown 75% of base changes resulting in silent mutations. This suggests the weak immunological pressing in course of evolution of this subtype strains. The reason for apathogenicity of this avian strain is supposed to be elimination of a glycosylation site present in the strain A/FPV/Rostock/34. The possibility of using the obtained data for construction of the new generation of vaccines is discussed.     

Absence of catalase reduces long-term survival of Helicobacter pylori in macrophage phagosomes

BACKGROUND: Some Helicobacter pylori strains can survive within macrophage phagosomes for up to 24 hours. The factors that play a role in this survival remain ill-defined. Therefore, the contribution of catalase in mediating the survival of H. pylori following phagocytosis was investigated in vitro. METHODS: An isogenic, catalase-deficient strain of H. pylori was generated and tested for sensitivity to hydrogen peroxide and susceptibility to macrophage-mediated killing. RESULTS: The isogenic, catalase-deficient strain of H. pylori was effectively killed by hydrogen peroxide within 3 minutes compared to wild-type H. pylori which maintained 100% survival up to 21 minutes. The catalase-deficient mutant was also significantly more susceptible to macrophage-mediated killing than the parent strain, even when the ratio of bacteria to macrophage was increased. CONCLUSION: These results indicate that although some strains of H. pylori are capable of survival within the macrophage phagosome, survival is dependent on virulence factors such as catalase for evasion of innate host defense.     

Mapping of clinical and expression quantitative trait loci in a sex-dependent effect of host susceptibility to mouse-adapted influenza H3N2/HK/1/68

Seasonal influenza outbreaks and recurrent influenza pandemics present major challenges to public health. By studying immunological responses to influenza in different host species, it may be possible to discover common mechanisms of susceptibility in response to various influenza strains. This could lead to novel therapeutic targets with wide clinical application. Using a mouse-adapted strain of influenza (A/HK/1/68-MA20 [H3N2]), we produced a mouse model of severe influenza that reproduces the hallmark high viral load and overexpression of cytokines associated with susceptibility to severe influenza in humans. We mapped genetic determinants of the host response using a panel of 29 closely related mouse strains (AcB/BcA panel of recombinant congenic strains) created from influenza-susceptible A/J and influenza-resistant C57BL/6J (B6) mice. Combined clinical quantitative trait loci (QTL) and lung expression QTL mapping identified candidate genes for two sex-specific QTL on chromosomes 2 and 17. The former includes the previously described Hc gene, a deficit of which is associated with the susceptibility phenotype in females. The latter includes the phospholipase gene Pla2g7 and Tnfrsf21, a member of the TNFR superfamily. Confirmation of the gene underlying the chromosome 17 QTL may reveal new strategies for influenza treatment.     

Cross-immunity, invasion and coexistence of pathogen strains in epidemiological models with one-dimensional antigenic space

Several epidemic models with many co-circulating strains have shown that partial cross-immunity between otherwise identical strains of a pathogen can lead to exclusion of a subset of the strains. Here we examine the mechanisms behind these solutions by considering a host population in which two strains are endemic and ask when it can be invaded by a third strain. If the function relating antigenic distance to cross-immunity is strictly concave or linear invasion is always possible. If the function is strictly convex and has an initial gradient of zero invasion depends on the degree of antigenic similarity between strains and the basic reproductive number. Examining specific concave and convex functions shows that the shape of the cross-immunity function affects the role of secondary infections in invasion. The basic reproductive number affects the importance of tertiary infections. Thus the form of the relationship between antigenic distance and cross-immunity determines whether the pathogen population will consist of an unstructured cloud of strains or a limited number of strains with strong antigenic structuring. In the latter case the basic reproductive number determines the maximum number of strains that can coexist. Analysis of the evolutionary trajectory shows that attaining the maximum diversity requires large spontaneous changes in antigenic structure and cannot result from a sequence of small point mutations alone.     

H9N2型禽流感病毒传播途径分子机制的研究

选择禽流感病毒(avian influenza virus,AIV)A/chicken/Zhuhai/154/2003(H9N2)(AZHl54)株作为骨架病毒,与来自A/chicken/Guangdong/SS/94(H9N2)(SS94)AIV的NA基因和HA基因进行H9N2亚型重排.动物传播性实验发现:AZH154、SS94和3株重排的H9N2亚型AIV都可以经直接接触途径传播;5株H9N2 AIV都不经过粪便接触传播;且AZH154株和重组的H9N2亚型AZH154/SSHA能经过气溶胶传播.实验结果表明:AIV(H9N2)的NA基因与该病毒气溶胶传播途径有重要关系,即2003年珠海地区AIV(H9N2)的大流行可能是因为病毒获得气溶胶传播途径的特性,且病毒的NA基因发挥了重要的作用.     

The size of cagA based on repeat sequence has the responsibility of the location of Helicobacter pylori in the gastric mucus and the degree of gastric mucosal inflammation

The aim of this study was to examine whether there is a relationship between cagA size of Japanese Helicobacter pylori strains and the location of these strains in the mucous layer, the degree of gastric inflammation and acid survival. Upper gastrointestinal endoscopies were done to 144 patients with dyspeptic symptom with informed consent, sera, biopsy specimens and H. pylori strains were obtained, and gastric histology and susceptibility to pH 3 of the strains were evaluated. To determine cagA size of Japanese strains using PCR, cagA of strain CPY3401 was sequenced. 74 H. pylori samples (72 cagA+) were obtained from the body and 56 samples (56 cagA +) obtained from the antrum. cagA size of 72 H. pylori strains from the body was mainly classified into 3 groups (short (48), middle (8), long (9), and others (7)) by PCR and all of that of 56 strains from the antrum except 2 was short. The size of cagA of isolated strains from the body is associated with enhanced gastritis, acid survival, and the location in the mucus. The long size cagA of which strain is acid sensitive, may be a strong selective pressure on strain that colonizes close to the host, which enhanced gastritis.     

Effect of the hybridization of Schistosoma mansoni strains on the degree of compatibility of the parthenitae with their mollusk intermediate hosts

After-effects of hybridization of S. mansoni strains, having Biomphalaria pfeifferi as an intermediate host, have been revealed for the first time. The crossing of two african strains (malarial-M and guinea-G), which have different compatibility rates with their specific intermediate hosts, has shown that hybrids display a higher virulence in respect to molluscs-hosts than maternal strains. The compatibility rate of the first generation hybrids with B. pfeifferi decreased, the breachs in the compatibility being the more significant the higher the degree of adaptation between the maternal strain and specific intermediate host. The infectiousness of the second generation hybrids in respect to molluscs of two populations of B. pfeifferi (M and G) virtually did not differ and varied in the ranges of mean values between the initial infectiousness of two maternal strains.     

Evolutionary Invasion and Escape in the Presence of Deleterious Mutations

Replicators such as parasites invading a new host species, species invading a new ecological niche, or cancer cells invading a new tissue often must mutate to adapt to a new environment. It is often argued that a higher mutation rate will favor evolutionary invasion and escape from extinction. However, most mutations are deleterious, and even lethal. We study the probability that the lineage will survive and invade successfully as a function of the mutation rate when both the initial strain and an adaptive mutant strain are threatened by lethal mutations. We show that mutations are beneficial, i.e. a non-zero mutation rate increases survival compared to the limit of no mutations, if in the no-mutation limit the survival probability of the initial strain is smaller than the average survival probability of the strains which are one mutation away. The mutation rate that maximizes survival depends on the characteristics of both the initial strain and the adaptive mutant, but if one strain is closer to the threshold governing survival then its properties will have greater influence. These conclusions are robust for more realistic or mechanistic depictions of the fitness landscapes such as a more detailed viral life history, or non-lethal deleterious mutations.     

Flagellin from an incompatible strain of Pseudomonas avenae induces a resistance response in cultured rice cells

The host range of Pseudomonas avenae is wide among monocotyledonous plants, but individual strains can infect only one or a few host species. The resistance response of rice cells to pathogens has been previously shown to be induced by a rice-incompatible strain, N1141, but not by a rice-compatible strain, H8301. To clarify the molecular mechanism of the host specificity in P. avenae, a strain-specific antibody that was raised against N1141 cells and then absorbed with H8301 cells was prepared. When a cell extract of strain N1141 was separated by SDS-polyacrylamide gel electrophoresis and immunostained with the N1141 strain-specific antibody, only a flagellin protein was detected. Purified N1141 flagellin induced the hypersensitive cell death in cultured rice cells within 6 h of treatment, whereas the H8301 flagellin did not. The hypersensitive cell death could be blocked by pretreatment with anti-N1141 flagellin antibody. Furthermore, a flagellin-deficient N1141 strain lost not only the induction ability of hypersensitive cell death but also the expression ability of the EL2 gene, which is thought to be one of the defense-related genes. These results demonstrated that the resistance response in cultured rice cells is induced by the flagellin existing in the incompatible strain of P. avenae but not in the flagellin of the compatible strain.     

Influenza emergence in the face of evolutionary constraints

Different influenza subtypes can evolve at very different rates, but the causes are not well understood. In this paper, we explore whether differences in transmissibility between subtypes can play a role if there are fitness constraints on antigenic evolution. We investigate the problem using a mathematical model that separates the interaction of strains through cross-immunity from the process of emergence for new antigenic variants. Evolutionary constraints are also included with antigenic mutation incurring a fitness cost. We show that the transmissibility of a strain can become disproportionately important in dictating the rate of antigenic drift: strains that spread only slightly more easily can have a much higher rate of emergence. Further, we see that the effect continues when vaccination is considered; a small increase in the rate of transmission can make it much harder to control the frequency at which new strains emerge. Our results not only highlight the importance of considering both transmission and fitness constraints when modelling influenza evolution, but may also help in understanding the differences between the emergence of H1N1 and H3N2 subtypes.     

辽宁省2016‒2017年H3N2亚型流感病毒 HA1基因特征分析

摘要：目的 了解2016?2017年辽宁省H3N2亚型流感病毒基因变异情况及流行株与疫苗株的匹配情况。方法 采用逆转录聚合酶链反应（RT-PCR）对分离得到的H3N2亚型流感毒株的HA1基因进行扩增,扩增片段经测序与近年来WHO推荐的北半球疫苗株进行比对和基因特征分析。结果 进化分析表明,2016?2017年H3N2亚型流感病毒与近三年的疫苗株均不在同一分支上;基因特性分析中,所有病毒均在A、B抗原决定簇上发生了两处以上的变异;19株病毒的受体结合位点131位氨基酸发生了新的变异;20株病毒中有1株突变产生了新的半胱氨酸,提示可能有新的二硫键产生;糖基化位点并未检测到新的突变。结论 2016?2017年辽宁省H3N2亚型流感病毒的抗原性及基因特性均发生了一定的变化,但变异程度不大,应密切关注疫苗株对流感病毒的免疫效果及流感毒株的变异情况。