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PubMed1996

Space, time and persistence of virulent pathogens.

Epidemiological theory predicts that pathogens of high virulence should not become endemic. We show, using an empirically based lattice map model, that a pathogen that is too virulent to persist if its host population is spatially well mixed, can persist if the host population is spatially distributed, because of internally generated complex spatial dynamics, provided that the area occupied by the host population is sufficiently large. The dynamics are not an artefact of spatial or temporal discretization. The results uncover a mechanism for the persistence of virulent pathogens, suggesting a means by which pathogens of high virulence could achieve sustained as well as short-term biological pest control.

Animals↗

PubMed2004

Major histocompatibility complex controls the trajectory but not host-specific adaptation during virulence evolution of the pathogenic fungus Cryptococcus neoformans.

Genes of the major histocompatibility complex (MHC) play a critical role in immune recognition and are the most genetically diverse loci known. One hypothesis to explain this diversity postulates that pathogens adapt to common MHC haplotypes and thus favour selection of new or rare alleles. To determine whether the pathogenic yeast Cryptococcus neoformans adapts to MHC-dependent immune responses, it was serially passaged in two independent replicate lines of five B10 MHC-congenic strains and Balb/c mice. All passaged lines increased in virulence as measured by reduced host survival. MHC influenced the rate (trajectory) of virulence increase during passages as measured by significant differences in mortality rate (p < 0.001). However, when the post-passage strains were tested, no MHC differences in mortality rate remained and only minor differences in titres were observed. Also contrary to expectations, increased virulence in three lines passaged in B10 mice had a larger effect in Balb/c mice, and the evolution of virulence in lines passaged in alternating hosts was not retarded. To our knowledge, these data represent the first experimental test of MHC-specific adaptation in a non-viral pathogen. The failure to observe MHC effects despite dramatically increased virulence and host-genotype-specific adaptation to non-MHC genes suggests that escape of MHC-dependent immune recognition may be difficult for pathogens with unlimited epitopes or that other virulence factors can swamp MHC effects.

Adaptation, Biological↗

PubMed2004

The impact of cross-immunity, mutation and stochastic extinction on pathogen diversity.

We examine the dynamics of antigenically diverse infectious agents using a mathematical model describing the transmission dynamics of arbitrary numbers of pathogen strains, interacting via cross-immunity, and in the presence of mutations generating new strains and stochastic extinctions of existing ones. Equilibrium dynamics fall into three classes depending on cross-immunity, transmissibility and host population size: systems where global extinction is likely, stable single-strain persistence, and multiple-strain persistence with stable diversity. Where multi-strain dynamics are stable, a diversity threshold region separates a low-prevalence, low-diversity region of parameter space from a high-diversity, high-prevalence region. The location of the threshold region is determined by the reproduction number of the pathogen and the intensity of cross-immunity, with the sharpness of the transition being determined by the manner in which immunity accrues with repeated infections. Host population size and cross-immunity are found to be the most decisive factors in determining pathogen diversity. While the model framework developed is simplified, we show that it can capture essential aspects of the complex evolutionary dynamics of pathogens such as influenza.

Antigenic Variation↗

PubMed2006

Integrating life history and cross-immunity into the evolutionary dynamics of pathogens.

Models for the diversity and evolution of pathogens have branched into two main directions: the adaptive dynamics of quantitative life-history traits (notably virulence) and the maintenance and invasion of multiple, antigenically diverse strains that interact with the host's immune memory. In a first attempt to reconcile these two approaches, we developed a simple modelling framework where two strains of pathogens, defined by a pair of life-history traits (infectious period and infectivity), interfere through a given level of cross-immunity. We used whooping cough as a potential example, but the framework proposed here could be applied to other acute infectious diseases. Specifically, we analysed the effects of these parameters on the invasion dynamics of one strain into a population, where the second strain is endemic. Whereas the deterministic version of the model converges towards stable coexistence of the two strains in most cases, stochastic simulations showed that transient epidemic dynamics can cause the extinction of either strain. Thus ecological dynamics, modulated by the immune parameters, eventually determine the adaptive value of different pathogen genotypes. We advocate an integrative view of pathogen dynamics at the crossroads of immunology, epidemiology and evolution, as a way towards efficient control of infectious diseases.

Antigenic Variation↗

PubMed2006

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.

Adaptation, Biological↗

PubMed1980

Genetic determinants for infectivity and pathogenicity of influenza viruses.

The objective of the studies presented was to define a molecular basis for infectivity and pathogenicity of influenza virus. It is demonstrated that activation of the HA glycoprotein by post-translational proteolytic cleavage is indispensable for the formation of infectious influenza virus. There are two preconditions for influenza virus to be pathogenic: (1) the presence on the virus particle of a cleaved HA molecule essential for the infectivity, and (2) an optimal genome composition. In naturally occurring avian influenza viruses there is a direct correlation between the cleavability of the haemagglutinin, the potential of the virus to be produced in infectious form in a wide range of host cells, and the viruses' pathogenicity for chicken. It is concluded that Nature selects an optimal gene constellation for each individual field strain. In these viruses the structure of the haemagglutinin is the determining factor for pathogenicity.

Animals↗

PubMed1997

Evolutionary pattern of intra-host pathogen antigenic drift: effect of cross-reactivity in immune response.

Several viruses are known to change their surface antigen types after infecting a host, thereby escaping the immune defence and ensuring persistent infection. In this paper, we theoretically study the pattern of intra-host micro-evolution of pathogen antigen variants under the antigen specific immune response. We assume that the antigen types of the pathogen can be indexed in one-dimensional space, and that a mutation can produce a new antigen variant that is one step distant from the parental type. We also assume that antibodies directed to a specific antigen can also neutralize similar antigen types with a decreased efficiency (cross-reactivity). The model reveals that the pattern of intra-host antigen evolution critically depends on the width of cross-reactivity. If the width of cross-reactivity is narrower than a certain threshold, antigen variants gradually evolve in antigen space as a travelling wave with a constant wave speed, and the total pathogen density approaches a constant. In contrast, if the width of cross-reactivity exceeds the threshold, the travelling wave loses stability and the distribution of antigen variants fluctuates both in time and in genotype space. In the latter case, the expected episodes after infection are a series of intermittent outbreaks of pathogen density, caused by distantly separated antigen types. The implication of the model to intra-host evolution of equine infectious anaemia virus and human immunodeficiency virus is discussed.

Animals↗

PubMed1995

Random amplified polymorphic DNA fingerprinting of mosquito-pathogenic and nonpathogenic strains of Bacillus sphaericus.

Random amplified polymorphic DNA fingerprinting was used to examine 31 mosquito-pathogenic and 14 nonpathogenic strains of Bacillus sphaericus. We verified that DNA bands that migrated the same distance in an agarose gel were homologous by using PCR-generated probes made from the random amplified polymorphic DNA bands. The band patterns obtained with eight primers were analyzed by using the Jaccard coefficient and unweighted pair group with arithmetic average clustering. Pathogenic strains belonging to DNA homology group IIA were similar to strains belonging to nonpathogenic homology groups at an average level of similarity of 6.3%. Individual serotypes were clearly identified among the pathogenic strains. This suggests that there is overall genetic homogeneity among strains within serotypes. It is also consistent with the uniform toxicity pattern found for each serotype (unlike the toxin diversity found in Bacillus thuringiensis serotypes). These results, together with DNA homology data, support the proposal that a new species should be described for the pathogenic strains.

Animals↗

PubMed1999

Erwinia pyrifoliae sp. nov., a novel pathogen that affects Asian pear trees (Pyrus pyrifolia Nakai)

A novel pathogen from Asian pears (Pyrus pyrifolia Nakai) was analysed by sequencing the 16S rDNA and the adjacent intergenic region, and the data were compared to related Enterobacteriaceae. The 16S rDNA of the Asian pear pathogen was almost identical with the sequence of Erwinia amylovora, in contrast to the 16S-23S rRNA intergenic transcribed spacer region of both species. A dendrogram was deduced from determined sequences of the spacer regions including those of several related species such as Erwinia amylovora, Enterobacter pyrinus, Pantoea stewartii subsp. stewartii and Escherichia coli. Dendrograms derived from 121 biochemical characteristics including Biotype 100 data placed the Asian pear pathogen close to Erwinia amylovora and more distantly to other members of the species Erwinia and to the species Pantoea and Enterobacter. Another DNA relatedness study was performed by DNA hybridizations and estimation of delta Tm values. The Asian pear strains constituted a tight DNA hybridization group (89-100%) and were barely related to strains of Erwinia amylovora (40-50%) with a delta Tm in the range of 5.2-6.8. The G + C content of DNA from the novel pathogen is 52 mol%. Therefore, it is proposed that strains isolated from Asian pears constitute a new species and the name Erwinia pyrifoliae is suggested; the type strain is strain Ep 16/96T (= CFBP 4172T = DSM 12163T).

Base Composition↗

PubMed1985

Recombinants between vaccinia and ectromelia viruses bearing the specific pathogenicity markers of both parents.

Nineteen recombinants between vaccinia virus (VV) DNA-temperature-sensitive mutants and ectromelia virus (EMV) were characterized with respect to their biological properties and genome structure. Four of these recombinants acquired the pathogenicity for mice characteristic of EMV, while the pathogenicity for rabbits characteristic of VV was not only preserved, but even enhanced. Most unexpectedly, these recombinants with 'double pathogenicity', as well as four other recombinants, acquired a stable genetic trait which was not typical of the parental viruses, i.e., the ability to form haemorrhagic lesions on the chorioallantoic membrane of chick embryos. Approximate mapping of the genomes of these recombinants with restriction endonucleases showed that their DNA contained mostly VV sequences with a single detected insert of EMV DNA. In the 'double pathogenicity' recombinants, this insert was located in the central part of the genome, and its minimal size was about 16 Mdal.

Chromosome Mapping↗

PubMed1986

Restoration of wild-type pathogenicity to an attenuated DNA polymerase mutant of herpes simplex virus type 1.

The drug-resistant variant, RSC-26, which was derived from the herpes simplex virus type 1 wild-type strain SC16, expresses an altered DNA polymerase and has reduced pathogenicity in animal models. To determine whether the attenuation in pathogenicity was due solely to mutation in the polymerase gene, a fragment of the wild-type gene was cloned, transferred into the genome of RSC-26 and recombinants were isolated. Three recombinants examined had similar properties to wild-type virus with respect to their sensitivity to antiviral drugs, DNA polymerase activities and their pathogenicity for mice. These results strongly suggest that expression of the altered polymerase of RSC-26 results in attenuated pathogenicity.

Animals↗

PubMed1999

Secretion of beta-chemokines by bronchoalveolar lavage cells during primary infection of macaques inoculated with attenuated nef-deleted or pathogenic simian immunodeficiency virus strain mac251.

Primary infection of macaques with simian immunodeficiency virus (SIV) as a model of human immunodeficiency virus (HIV) infection represents a unique opportunity to investigate early lentivirus-host interactions. In order to gain insight into immunopathogenic events taking place in the lung during lentiviral infection, we analysed lymphocyte expansion in the lung and chemokine secretion by mononuclear cells obtained by bronchoalveolar lavage (BALMCs) during primary infection by a pathogenic and a non-pathogenic SIV. Two groups of cynomolgus macaques were inoculated intravenously with a fully pathogenic isolate of SIVmac251 or with an attenuated, nef-deleted, molecular clone of SIVmac251. Spontaneous MIP-1alpha, MIP-1beta and RANTES production was assessed by ELISA in supernatants of short-term cultured BALMCs. Kinetics of haematological, virological and immunological parameters were investigated simultaneously. All 11 inoculated animals became infected. Monkeys inoculated with the nef-deleted SIV clone exhibited a significantly reduced plasma virus load and a less pronounced accumulation of lymphocytes in the lung compared to monkeys infected with the pathogenic SIVmac251 isolate. Compared to pre-infection levels, we observed an increase in the levels of RANTES, MIP1-alpha and MIP1-beta production in the two groups of monkeys, by the time of peak viraemia. Strikingly, a greater enhancement of RANTES and MIP-1alpha production was detected in monkeys infected with the attenuated virus. Given the potential influence of beta-chemokines on the immune response and virus replication, such results suggest that RANTES, MIP1-alpha and MIP1-beta could contribute to the singular features of the immune response elicited during infection of macaques with an attenuated SIV.

Animals↗

PubMed1990

Numerical classification and identification of Bacillus sphaericus including some strains pathogenic for mosquito larvae.

Ninety-one strains of Bacillus sphaericus, including representatives of all the established DNA homology groups, related round-spored and oval-spored species, and six strains pathogenic for mosquito larvae, were examined for 155 characters. Numerical analyses (Jaccard coefficient/average linkage clustering) based on the 88 variable features revealed 14 clusters at the 79% similarity level that contained more than one strain and 17 single member clusters. All insect pathogenic strains were recovered in a single cluster and the classification was in accord with an established classification based on DNA sequence homology. Two frequency matrices for probabilistic identification were constructed and tested. A comprehensive matrix comprising 14 mesophilic, round-spored taxa and 27 tests gave good results for identification of hypothetical median organisms, cluster overlap and identifications of representative strains (based on data generated in the classification study). Reference strains for the 14 taxa and eight additional insect pathogenic strains were examined for the 27 tests and were correctly identified with high scores using this matrix. A second matrix comprising seven taxa and 13 tests also performed well in the theoretical evaluation and correctly identified the reference strains and insect pathogenic strains.

Animals↗

PubMed1999

Expression of cytotoxicity by potential pathogens in the standard Escherichia coli collection of reference (ECOR) strains.

The standard Escherichia coli collection of reference (ECOR) strains was examined for ability to exert cytotoxicity towards mammalian cells. A group of strains with functional haemolysin expression caused strong cytotoxicity and detachment in J774 macrophage cells as measured by lactate dehydrogenase release and as observed under a microscope. The expression of haemolysin was monitored by using antisera recognizing the E. coli alpha-haemolysin, the HlyA protein, and by quantitative haemolysis assays. The presence of the hlyA gene, which may be part of a pathogenicity island, was also confirmed. These analyses revealed that different ECOR strains express quantitatively different levels of haemolysin. One putative enteroaggregative E. coli (EAEC) strain was also found in the ECOR collection. The EAEC strain was characterized by the clump formation assay, PCR amplification of the EAEC DNA probe sequence and confirmative sequence analysis of the amplified fragment. The EAEC heat-stable enterotoxin 1 gene, astA, was found in 14% (10/72) of the ECOR strains and a consensus sequence for astA was proposed by comparing these sequences with those from pathogens. The astA gene appeared to be plasmid-located. Based on evidence from the work of other laboratories and from the present findings, it is concluded that the ECOR collection contains strains that may represent pathogenic E. coli. It is noted that caution is necessary when handling or disposing of those potentially pathogenic ECOR strains.

Amino Acid Sequence↗

PubMed1981

The pathogenicity of Bacteroides fragilis and related species estimated by intracutaneous infection in the guinea-pig.

The pathogenicity of 42 strains of Bacteroides of human origins was estimated by intracutaneous injection of bacterial suspensions into guinea-pig skin. Comparisons of living and heat-killed suspensions revealed that B. fragilis strains maintained themselves and possibly multiplied in the skin, whereas the lesions induced by non-fragilis strains appeared to be due mainly to toxicity. Measurement of skin pathogenicity in terms of the number of viable organisms in the inoculum that produced a lesion 10 mm in diameter showed that B. fragilis was, on average, 17 times as pathogenic as non-fragilis strains. Skin tests of pathogens may be of value in the analysis of virulence factors of Bacteroides and possibly of other anaerobic organisms.

Animals↗

PubMed1986

Role of endotoxin in the pathogenicity of Neisseria gonorrhoeae colonial types 1, 4 and 5 determined by chicken embryo model.

The pathogenicity of Neisseria gonorrhoeae is a subject of considerable interest. It is believed that N. gonorrhoeae of colonial type 1 are pathogenic while those of type 4 are not. This is based on experimentation in human volunteers. The object of this study was to determine the reasons for the differences of susceptibility of chicken embryos to N. gonorrhoeae strains of colonial types 1, 4, 5 and 1R (a type-1 revertant from a non-pathogenic type 4 strain originally tested in human volunteers). Colonial types 1, 5, 1R and 4 caused mortality rates of 80, 70, 85 and 20% respectively. This variation in lethality appeared to depend upon the availability of free extra-cellular endotoxin and this was confirmed by chicken-embryo inoculation results and electronmicroscopy of normal and heated colonial types 1, 4 and 5. Similar results were obtained by inoculating purified endotoxins from these types into chicken embryos. The results of this study suggest that endotoxins play a major role in the pathogenicity of N. gonorrhoeae and that the variations in virulence of the colonial types depends on the stability of their cell walls.

Animals↗

PubMed1986

The prevalence of bacterial intestinal pathogens in a healthy rural population in southern India.

In a one-year prospective survey bacterial intestinal pathogens unassociated with diarrhoeal episodes were isolated from 20.5% of stool samples from 48.5% of a stratified random sample of the population of a village in southern India. Campylobacter jejuni was the pathogen most frequently isolated, followed by enteropathogenic serotypes of Escherichia coli. The incidence of diarrhoea in the study population was lower than the frequency of isolation of bacterial intestinal pathogens. It is necessary to understand the prevalence of intestinal pathogens in this ecosystem to know the dynamics of intestinal infection and the pathogenesis of diarrhoea.

Adolescent↗

PubMed1995

An alpha 5 beta 1-like integrin receptor mediates the binding of less pathogenic Candida species to fibronectin.

The present study was undertaken to investigate whether less pathogenic Candida species (C. tropicalis, C. stellatoidea, C. krusei and C. glabrata) express a fibronectin receptor (FNr) antigenically related to alpha 5 beta 1 integrin, which mediates their binding to fibronectin (FN). By flow cytometric analysis, a monoclonal antibody (MAb) directed against human alpha 5 integrin subunit (clone SAM-1) and two different antisera to FNr positively stained C. tropicalis, C. stellatoidea and C. glabrata, with the greatest expression observed for C. tropicalis. No or only marginal immunoreactivity was found on C. krusei. C. tropicalis, C. stellatoidea, C. glabrata, but not C. krusei yeasts specifically adhered to FN; higher levels of adhesion were found for C. tropicalis and C. stellatoidea with respect to C. glabrata. Less pathogenic Candida spp. bound to the Arg-Gly-Asp (RGD) containing 120-kDa fragment of FN and adhesion to intact FN was markedly inhibited by Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP), but not by Gly-Arg-Gly-Glu-Ser-Pro (GRGESP) peptides. In addition, anti-alpha 5 SAM-1 MAb and both anti-FNr antisera strongly blocked binding of less pathogenic Candida spp. to FN. Overall, these results indicate that less pathogenic Candida spp., including C. tropicalis, C. stellatoidea and C. glabrata, express a receptor antigenically related to alpha 5 beta 1 integrin which mediates their adhesion to FN.

Amino Acid Sequence↗