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PubMed2004

Structural differences among hemagglutinins of influenza A virus subtypes are reflected in their antigenic architecture: analysis of H9 escape mutants.

We used a panel of monoclonal antibodies to H9 hemagglutinin to select 18 escape mutants of mouse-adapted influenza A/Swine/Hong Kong/9/98 (H9N2) virus. Cross-reactions of the mutants with the antibodies and the sequencing of hemagglutinin genes revealed two minimally overlapping epitopes. We mapped the amino acid changes to two areas of the recently reported three-dimensional structure of A/Swine/Hong Kong/9/98 hemagglutinin. The grouping of the antigenically relevant amino acid positions in H9 hemagglutinin differs from the pattern observed in H3 and H5 hemagglutinins. Several positions in site B of H3 hemagglutinin are distributed in two sites of H9 hemagglutinin. Unlike any subtype analyzed so far, H9 hemagglutinin does not contain an antigenic site corresponding to site A in H3 hemagglutinin. Positions 145 and 193 (H3 numbering), which in H3 hemagglutinin belong to sites A and B, respectively, are within one site in H9 hemagglutinin. This finding is consistent with the peculiarity of the three-dimensional structure of the H9 molecule, that is, the absence from H9 hemagglutinin of the lateral loop that forms site A in H3 and the equivalent site in H5 hemagglutinins. The escape mutants analyzed displayed phenotypic variations, including decreased virulence for mice and changes in affinity for sialyl substrates. Our results demonstrate a correlation between intersubtype differences in three-dimensional structure and variations among subtypes in the distribution of antigenic areas. Our findings also suggest that covariation and pleiotropic effects of antibody-selected mutations may be important in the evolution of H9 influenza virus, a possible causative agent of a future pandemic.

Amino Acid Substitution↗
PubMed2006

The role of immune-mediated apparent competition in genetically diverse malaria infections.

Competitive interactions between coinfecting genotypes of the same pathogen can impose selection on virulence, but the direction of this selection depends on the mechanisms behind the interactions. Here, we investigate how host immune responses contribute to competition between clones in mixed infections of the rodent malaria parasite Plasmodium chabaudi. We studied single and mixed infections of a virulent and an avirulent clone and compared the extent of competition in immunodeficient and immunocompetent mice (nude mice and T cell-reconstituted nude mice, respectively). In immunocompetent mice, the avirulent clone suffered more from competition than did the virulent clone. The competitive suppression of the avirulent clone was alleviated in immunodeficient mice. Moreover, the relative density of the avirulent clone in mixed infections was higher in immunodeficient than in immunocompetent mice. We conclude that immune-mediated interactions contributed to competitive suppression of the avirulent clone, although other mechanisms, presumably competition for resources such as red blood cells, must also be important. Because only the avirulent clone suffered from immune-mediated competition, this mechanism should contribute to selection for increased virulence in mixed infections in this host-parasite system. As far as we are aware, this is the first direct experimental evidence of immune-mediated apparent competition in any host-parasite system.

Animals↗
PubMed1995

The molecular genetics of feline coronaviruses: comparative sequence analysis of the ORF7a/7b transcription unit of different biotypes.

Feline coronaviruses (FCoVs) have been subdivided into feline enteric coronaviruses (FECVs) and feline infectious peritonitis viruses (FIPVs) on the basis of pathogenic properties. Serologically, a distinction has been made between type I and II FCoVs, the latter of which more closely resemble canine coronavirus (CCV). To gain more insight into the genetic relationships between different FCoV biotypes, we determined the nucleotide sequences of the ORF7a/7b transcription unit of nine strains. The following observations were made: (i) The sequences are 87-100% identical. In this part of the genome, type I and II FCoVs are more closely related to each other than to CCV. To explain the genetic and antigenic differences between the spike genes of type I and II FCoVs, we postulate that type II FcoVs have arisen by an RNA recombination event between a type I FCoV and CCV. (ii) The avirulent "FECV" strains UCD and 79-1683 are more similar to virulent "FIPV" strains than to each other. Our findings thus support the notion that FECV and FIPV are not different species but merely virulence variants. (iii) In contrast to FECV 79-1683, FECV UCD contains an intact ORF7b, indicating that ORF7b deletions are not a universal distinguishing property of FECVs. (iv) ORF7b deletions readily occur in vitro, correlating with loss of virulence. By reverse transcription-polymerase chain reaction analysis, we show that in naturally occurring FCoVs ORF7b is maintained. Thus, ORF7b seems to provide a distinct selective advantage during natural infection.

Amino Acid Sequence↗
PubMed1996

Salmonellosis: host immune responses and bacterial virulence determinants.

The lifestyle of bacterial pathogens requires them to establish infection in the face of host immunity. Upon entering a potential host, a variety of interactions are initiated, the outcome of which depends upon a myriad of attributes of each of the participants. In this review we discuss the interactions that occur between pathogenic Salmonella species and the host immune systems, but when appropriate to broaden perspective, we have provided a general overview of the interactions between bacterial pathogens and animal hosts. Pathogenic Salmonella species possess an array of invasion genes that produce proteins secreted by a specialized type III secretion apparatus. These proteins are used by the bacteria to penetrate the intestinal mucosa by invading and destroying specialized epithelial M cells of the Peyer's patches. This maneuver deposits the bacteria directly within the confines of the reticuloendothelial system. The host responds to these actions with nonspecific phagocytic cells and an inflammatory response as well as by activating specific cellular and humoral immune responses. Salmonella responds to this show of force directly. It appears that the bacteria invade and establish a niche within the very cells that have been sent to destroy them. Efforts are underway to characterize the factors that allow these intracellular bacteria to customize intracellular vacuoles for their own purposes. It is the constant play between these interactions that determines the outcome of the host infection, and clearly they will also shape the evolution of new survival strategies for both the bacterium and the host.

Animals↗
PubMed2005

Origins of host-specific populations of the blast pathogen Magnaporthe oryzae in crop domestication with subsequent expansion of pandemic clones on rice and weeds of rice.

Rice, as a widely and intensively cultivated crop, should be a target for parasite host shifts and a source for shifts to co-occurring weeds. Magnaporthe oryzae, of the M. grisea species complex, is the most important fungal pathogen of rice, with a high degree of host specificity. On the basis of 10 loci from six of its seven linkage groups, 37 multilocus haplotypes among 497 isolates of M. oryzae from rice and other grasses were identified. Phylogenetic relationships among isolates from rice (Oryza sativa), millet (Setaria spp.), cutgrass (Leersia hexandra), and torpedo grass (Panicum repens) were predominantly tree like, consistent with a lack of recombination, but from other hosts were reticulate, consistent with recombination. The single origin of rice-infecting M. oryzae followed a host shift from a Setaria millet and was closely followed by additional shifts to weeds of rice, cutgrass, and torpedo grass. Two independent estimators of divergence time indicate that these host shifts predate the Green Revolution and could be associated with rice domestication. The rice-infecting lineage is characterized by high copy number of the transposable element MGR586 (Pot3) and, except in two haplotypes, by a loss of AVR-Co39. Both mating types have been retained in ancestral, well-distributed rice-infecting haplotypes 10 (mainly temperate) and 14 (mainly tropical), but only one mating type was recovered from several derived, geographically restricted haplotypes. There is evidence of a common origin of both ACE1 virulence genotypes in haplotype 14. Host-haplotype association is evidenced by low pathogenicity on hosts associated with other haplotypes.

Bayes Theorem↗
PubMed2025

Genomic insights into a diarrheal outbreak in Bangladesh reveal novel ETEC lineages and expansion of CS23 colonization factor.

Enterotoxigenic Escherichia coli (ETEC), a leading cause of diarrhea, is defined by heat-stable (ST) and/or heat-labile (LT) toxins and associated colonization factors (CFs). However, there is still a knowledge gap in understanding ETEC's evolution, particularly in endemic regions like Bangladesh. This study investigates the genomic attributes contributing to the rise of ETEC-associated diarrhea in Bangladesh during 2022-2023. Whole genome sequencing of 325 ETEC isolates (2022-2023), compared with historical strains (1980-2021), revealed significant evolutionary changes. Our findings showed a significant shift in ETEC toxin from LT to ST over the period 2013-2023. The most frequent virulence profile during this period was CFA/I + CS21 compared with previous years (1980-2021). The emergence of CS23-positive ETEC was reported for the first time in Bangladesh, which was considered a less common CF in previous studies. Notably, we report the four novel lineages "L26-L29" in this study through phylogenetic analysis, partly encompassing emergent CS23-positive ETEC strains. Additionally, the high prevalence of multi-drug-resistant ETEC strains and the presence of ESBL-CTX-M-resistant gene during 2022-2023 are a matter of great concern, underscoring the need for preventive measures. The switch of distinct toxin and CF combinations, the rapid emergence of CS23, ESBL-CTX-M resistance, and novel lineages may be the reason behind the increased number of ETEC diarrheal cases between 2022 and 2023. These findings highlight the rapid ETEC evolution that underscores the necessity of continued genomic surveillance to track ongoing changes.IMPORTANCEThis study expands on previous evidence, demonstrating a remarkable genomic diversity in ETEC strains from 2022 to 2023, particularly in virulence factors and AMR genes. The combined findings from these studies will be important for mitigating future diarrheal outbreaks by informing preventive measures, including future vaccine targets, and implementing antibiotic stewardship programs against ETEC infection. Importantly, this research underscores the necessity of continued genomic surveillance to track ongoing changes in ETEC. Such monitoring is essential for understanding the pathogen's evolving population structure, transmission dynamics, and resistance mechanisms.

Bangladesh↗
PubMed1997

Wolbachia, normally a symbiont of Drosophila, can be virulent, causing degeneration and early death.

Wolbachia, a maternally transmitted microorganism of the Rickettsial family, is known to cause cytoplasmic incompatibility, parthenogenesis, or feminization in various insect species. The bacterium-host relationship is usually symbiotic: incompatibility between infected males and uninfected females can enhance reproductive isolation and evolution, whereas the other mechanisms enhance progeny production. We have discovered a variant Wolbachia carried by Drosophila melanogaster in which this cozy relationship is abrogated. Although quiescent during the fly's development, it begins massive proliferation in the adult, causing widespread degeneration of tissues, including brain, retina, and muscle, culminating in early death. Tetracycline treatment of carrier flies eliminates both the bacteria and the degeneration, restoring normal life-span. The 16s rDNA sequence is over 98% identical to Wolbachia known from other insects. Examination of laboratory strains of D. melanogaster commonly used in genetic experiments reveals that a large proportion actually carry Wolbachia in a nonvirulent form, which might affect their longevity and behavior.

Animals↗
PubMed2001

A Streptococcus pneumoniae pathogenicity island encoding an ABC transporter involved in iron uptake and virulence.

Restricted iron availability is a major obstacle to growth and survival of pathogenic bacteria during infection. In contrast to Gram-negative pathogens, little is known about how Gram-positive pathogens obtain this essential metal. We have identified two Streptococcus pneumoniae genetic loci, pit1 and pit2, encoding homologues of ABC iron transporters that are required for iron uptake by this organism. S. pneumoniae strains containing disrupted copies of either pit1 or pit2 had decreased sensitivity to the iron-dependent antibiotic streptonigrin, and a strain containing disrupted copies of both pit1 and pit2 was unable to use haemoglobin as an iron source and had a reduced rate of iron uptake. The pit2- strain was moderately and the pit1-/pit2- strain strongly attenuated in virulence in mouse models of pulmonary and systemic infection, showing that the pit loci play a critical role during in vivo growth of S. pneumoniae. The pit2 locus is contained within a 27 kb region of chromosomal DNA that has several features of Gram-negative bacterial pathogenicity islands. This probable pathogenicity island (PPI-1) is the first to be described for S. pneumoniae, and its acquisition is likely to have played a significant role in the evolution of this important human pathogen.

ATP-Binding Cassette Transporters↗
PubMed2005

Evolution of antifungal-drug resistance: mechanisms and pathogen fitness.

Like other microorganisms, fungi exist in populations that are adaptable. Under the selection imposed by antifungal drugs, drug-sensitive fungal pathogens frequently evolve resistance. Although the molecular mechanisms of resistance are well-characterized, there are few measurements of the impact of these mechanisms on pathogen fitness in different environments. To predict resistance before a new drug is prescribed in the clinic, the full spectrum of potential resistance mutations and the interactions among combinations of divergent mechanisms can be determined in evolution experiments. In the search for new strategies to manage drug resistance, measuring the limits of adaptation might reveal methods for trapping fungal pathogens in evolutionary dead ends.

Antifungal Agents↗
PubMed2003

The Leopoldina international symposium on parasitism, commensalism and symbiosis--common themes, different outcome.

The development of new methods, including genomics, which can even be applied to unculturable microorganisms, has significantly increased our knowledge about bacterial pathogenesis and symbiosis and, in consequence, is profoundly modifying our views on the evolution and the genetic and physiological basis of bacteria-host interactions. The presentations at this symposium revealed conceptual links between bacterial pathogenesis and symbiosis. The close co-operation of experts in both fields will result in significant synergy and new insights into basic mechanisms of bacteria-host interactions and their evolution. The meeting provided fascinating news about the genetic and metabolic consequences that the change in their lifestyle had for bacteria that developed from free-living to permanent host-associated organisms exemplified by intracellular pathogens or symbionts. In addition, surprising similarities but also striking differences between the strategies involved in the establishment of a symbiotic versus a parasitic lifestyle can be noted. In the long run, the characterization of such differences might lead to lifestyle prediction or to an evaluation of the pathogenic potential of newly isolated bacteria via the definition of genetic and/or metabolic signatures characteristic for pathogenic or symbiotic organisms. Moreover, it is expected that these investigations will lead to new strategies for the treatment or prevention of bacterial infections, or the avoidance of pathogen transmission.

Animals↗
PubMed2003

Prokaryotic chromosomes and disease.

Recent insights into bacterial genome organization and function have improved our understanding of the nature of pathogenic bacteria and their ability to cause disease. It is becoming increasingly clear that the bacterial chromosome constantly undergoes structural changes due to gene acquisition and loss, recombination, and mutational events that have an impact on the pathogenic potential of the bacterium. Even though the bacterial genome includes additional genetic elements, the chromosome represents the most important entity in this context. Here, we will show that various processes of genomic instability have an influence on the many manifestations of infectious disease.

Adaptation, Physiological↗
PubMed1999

Sequence and organization of pXO1, the large Bacillus anthracis plasmid harboring the anthrax toxin genes.

The Bacillus anthracis Sterne plasmid pXO1 was sequenced by random, "shotgun" cloning. A circular sequence of 181,654 bp was generated. One hundred forty-three open reading frames (ORFs) were predicted using GeneMark and GeneMark.hmm, comprising only 61% (110,817 bp) of the pXO1 DNA sequence. The overall guanine-plus-cytosine content of the plasmid is 32.5%. The most recognizable feature of the plasmid is a "pathogenicity island," defined by a 44.8-kb region that is bordered by inverted IS1627 elements at each end. This region contains the three toxin genes (cya, lef, and pagA), regulatory elements controlling the toxin genes, three germination response genes, and 19 additional ORFs. Nearly 70% of the ORFs on pXO1 do not have significant similarity to sequences available in open databases. Absent from the pXO1 sequence are homologs to genes that are typically required to drive theta replication and to maintain stability of large plasmids in Bacillus spp. Among the ORFs with a high degree of similarity to known sequences are a collection of putative transposases, resolvases, and integrases, suggesting an evolution involving lateral movement of DNA among species. Among the remaining ORFs, there are three sequences that may encode enzymes responsible for the synthesis of a polysaccharide capsule usually associated with serotype-specific virulent streptococci.

Antigens, Bacterial↗
PubMed2005

Helicobacter pylori and gastroduodenal pathology: new threats of the old friend.

The human gastric pathogen Helicobacter pylori causes chronic gastritis, peptic ulcer disease, gastric carcinoma, and mucosa-associated lymphoid tissue (MALT) lymphoma. It infects over 50% of the worlds' population, however, only a small subset of infected people experience H. pylori-associated illnesses. Associations with disease-specific factors remain enigmatic years after the genome sequences were deciphered. Infection with strains of Helicobacter pylori that carry the cytotoxin-associated antigen A (cagA) gene is associated with gastric carcinoma. Recent studies revealed mechanisms through which the cagA protein triggers oncopathogenic activities. Other candidate genes such as some members of the so-called plasticity region cluster are also implicated to be associated with carcinoma of stomach. Study of the evolution of polymorphisms and sequence variation in H. pylori populations on a global basis has provided a window into the history of human population migration and co-evolution of this pathogen with its host. Possible symbiotic relationships were debated since the discovery of this pathogen. The debate has been further intensified as some studies have posed the possibility that H. pylori infection may be beneficial in some humans. This assumption is based on increased incidence of gastro-oesophageal reflux disease (GERD), Barrett's oesophagus and adenocarcinoma of the oesophagus following H. pylori eradication in some countries. The contribution of comparative genomics to our understanding of the genome organisation and diversity of H. pylori and its pathophysiological importance to human healthcare is exemplified in this review.

Antigens, Bacterial↗