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PubMed1998

Activation of hsr203, a plant gene expressed during incompatible plant-pathogen interactions, is correlated with programmed cell death.

hsr203J is a tobacco gene whose activation is rapid, highly localized, and specific for incompatible interactions between tobacco and the bacterial pathogen Ralstonia solanacearum. The effect of other hypersensitive response (HR)-inducing pathogens and elicitors has been tested with transgenic plants containing the hsr203J promoter-GUS reporter gene fusion, and confirms the generality of the preferential inducibility of the hsr203J gene promoter during incompatible interactions: bacterial and viral pathogens inducing an HR in tobacco were able to induce the promoter fusion, as were inducers of HR-like responses such as harpin, elicitins, and PopA1 proteins. A tomato hsr203 homologous cDNA was isolated (Lehsr203) and used to examine the effect of avr gene products on the expression of such genes. Lehsr203 was shown to be rapidly and transiently induced in leaves of the tomato Cf-9 line, following Avr9 product infiltration, but not in those of the Cf-0 line. Among potential effectors of HR or resistance such as H2O2, salicylic acid, methyl jasmonate, and 2,6-dichloro-isonicotinic acid (INA), none is able to induce a significant increase in promoter activation. In contrast, heavy metals that cause leaf necrosis can trigger such an activation. In addition, hsr203-GUS fusion expression is detected in transgenic tobacco lines expressing the bO gene and exhibiting spontaneous HR-like lesions. Taken together, these results demonstrate a strong correlation between hsr203 and genetically controlled cell death in tobacco and tomato. The expression of this gene should be a useful marker for programmed cell death occurring in response not only to diverse pathogens, but also to diverse death-triggering extracellular agents.

Amino Acid Sequence↗

PubMed2000

Positive and negative regulation of salicylic acid-dependent cell death and pathogen resistance in Arabidopsis lsd6 and ssi1 mutants.

Salicylic acid (SA) is a key defense molecule in higher plants that is required for resistance to diverse pathogens. A number of mutants of Arabidopsis with elevated resistance to pathogens and constitutive activation of defense-related genes and cell death have been shown to require SA for all of their phenotypes. These mutants potentially identify interesting regulatory genes that control diverse SA responses. When dominant mutations confer SA-dependent phenotypes, it is important to know the genetic basis of dominance in order to draw conclusions on the possible mechanisms of action of the genes identified. Here I characterize the basis of the dominant phenotypes conferred by the ssi1 and lsd6 mutations. I show that ssi1 is haploinsufficient, while lsd6 is a gain-of-function mutation. Thus, SA-dependent responses are under both negative and positive regulation.

Arabidopsis↗

PubMed1998

A nonessential African swine fever virus gene UK is a significant virulence determinant in domestic swine.

Sequence analysis of the right variable genomic region of the pathogenic African swine fever virus (ASFV) isolate E70 revealed a novel gene, UK, that is immediately upstream from the previously described ASFV virulence-associated gene NL-S (L. Zsak, Z. Lu, G. F. Kutish, J. G. Neilan, and D. L. Rock, J. Virol. 70:8865-8871, 1996). UK, transcriptionally oriented toward the right end of the genome, predicts a protein of 96 amino acids with a molecular mass of 10.7 kDa. Searches of genetic databases did not find significant similarity between UK and other known genes. Sequence analysis of the UK genes from several pathogenic ASFVs from Europe, the Caribbean, and Africa demonstrated that this gene was highly conserved among diverse pathogenic isolates, including those from both tick and pig sources. Polyclonal antibodies raised against the UK protein specifically precipitated a 15-kDa protein from ASFV-infected macrophage cell cultures as early as 2 h postinfection. A recombinant UK gene deletion mutant, deltaUK, and its revertant, UK-R, were constructed from the E70 isolate to study gene function. Although deletion of UK did not affect the growth characteristics of the virus in macrophage cell cultures, deltaUK exhibited reduced virulence in infected pigs. While mortality among parental E70- or UK-R-infected animals was 100%, all deltaUK-infected pigs survived infection. Fever responses were comparable in E70-, UK-R-, and deltaUK-infected groups; however, deltaUK-infected animals exhibited significant, 100- to 1,000-fold, reductions in viremia titers. These data indicate that the highly conserved UK gene of ASFV, while being nonessential for growth in macrophages in vitro, is an important viral virulence determinant for domestic pigs.

African Swine Fever Virus↗

PubMed2006

Host gene expression profiling in pathogen-host interactions.

Microarray technology is a powerful high-throughput tool for the analysis of host-pathogen interactions that permits simultaneous interrogation of the transcriptional status of thousands of genes. Emerging topics from microarray-based studies employing diverse pathogens and cell types suggest an initial common host response largely characterised by features of the innate immune response. However, specific host gene expression patterns that reflect differences between bacteria of related genera, different species of a particular genus, as well as strains within a single species can also be discerned. These differences are indicative of virulence determinant functions and suggest adaptive survival strategies. These studies have led to a more comprehensive understanding of the host response and identified new avenues of research for potential control strategies against pathogens.

Animals↗

PubMed1999

Transmission bottlenecks as determinants of virulence in rapidly evolving pathogens.

Transmission bottlenecks occur in pathogen populations when only a few individual pathogens are transmitted from one infected host to another in the initiation of a new infection. Transmission bottlenecks can dramatically affect the evolution of virulence in rapidly evolving pathogens such as RNA viruses. Characterizing pathogen diversity with the quasispecies concept, we use analytical and simulation methods to demonstrate that severe bottlenecks are likely to drive down the virulence of a pathogen because of stochastic loss of the most virulent pathotypes, through a process analogous to Muller's ratchet. We investigate in this process the roles of host population size, duration of within-host viral replication, and transmission bottleneck size. We argue that the patterns of accumulation of deleterious mutation may explain differing levels of virulence in vertically and horizontally transmitted diseases.

Evolution, Molecular↗

PubMed2003

Plant disease resistance genes: recent insights and potential applications.

Plant disease resistance genes (R genes) encode proteins that detect pathogens. R genes have been used in resistance breeding programs for decades, with varying degrees of success. Recent molecular research on R proteins and downstream signal transduction networks has provided exciting insights, which will enhance the use of R genes for disease control. Definition of conserved structural motifs in R proteins has facilitated the cloning of useful R genes, including several that are functional in multiple crop species and/or provide resistance to a relatively wide range of pathogens. Numerous signal transduction components in the defense network have been defined, and several are being exploited as switches by which resistance can be activated against diverse pathogens.

Gene Expression Regulation, Plant↗

PubMed2002

Cellular and cytokine immunoregulation in patients with chronic obstructive pulmonary disease and bronchial asthma.

BACKGROUND: Different forms of chronic airway inflammation may involve diverse pathogenic elements. In general, deficient defence response is a feature of chronic obstructive pulmonary disease (COPD), whereas distorted immunoregulatory mechanisms lead to development of asthmatic symptoms. In addition to diverse effector mechanisms, the cellular and humoral elements participating in the development of immune response may appear to be different in COPD and bronchial asthma (BA) patients. AIMS: To evaluate the immunoregulatory properties of T cells and monocytes in cultures of peripheral blood mononuclear cells (PBMC) and to determine the chosen cytokine profiles in COPD and BA patients. METHODS: The microcultures of PBMC from COPD and BA patients were assessed for the T-cell response to mitogens, saturation of interleukin (IL)-2 receptors, T-cell suppressive activity and monokine influence on lymphocyte proliferation. Concomitantly, the cytokine (IL-1beta, interleukin-1 receptor antagonist, tumour necrosis factor-alpha, IL-4, IL-6, IL-8) concentrations were determined in the serum, the broncho-alveolar lavage fluid and in the culture supernatants. RESULTS: The T-lymphocyte reactions (response to phytohaemagglutinin, IL-2 receptor saturation, suppressive activity) were lower in BA patients than in COPD patients. Reversely, the immunogenic activity of monocytes (IL-1beta versus IL-1ra production) was higher in BA patients than in COPD patients. The highest values of cytokine concentrations were found in the culture supernatants. The concentrations of tumour necrosis factor-alpha, IL-4, IL-6 and IL-8 were significantly higher and the concentration of IL-1ra was lower in BA patients than in COPD patients. CONCLUSION: The assessments of cellular immunoregulatory properties and cytokine profiles in the cultures of blood mononuclear cells may prove helpful for diagnostic and therapeutic discrimination between BA and COPD patients.

Adult↗

PubMed2003

Induction of H2O2 in transgenic rice leads to cell death and enhanced resistance to both bacterial and fungal pathogens.

Oxidative burst, mediated by hydrogen peroxide (H2O2), has been recognized as a key component of plant defense response during an incompatible interaction. To determine if elevated levels of H2O2 lead to cell death, activation of defense genes and enhanced resistance to diverse pathogens, transgenic rice plants expressing a fungal glucose oxidase gene (GOX) were generated using both constitutive and inducible expression systems. Constitutive or wound/pathogen-induced expression of GOX also allowed us to determine the effectiveness of these systems in conferring long lasting resistance to various pathogens. Both constitutive and wound/pathogen-induced expression of GOX lead to increases in the endogenous levels of H2O2, which in turn caused cell death. Elevated levels of H2O2 also activated the expression of several defense genes and these transgenic plants showed enhanced resistance to both bacterial and fungal pathogens. In comparison to inducible expression, constitutive expression of GOX resulted in 3-10-fold higher levels of the GOX transcript and the corresponding enzymatic activity. Such increased levels of GOX, which would result in elevated levels of H2O2, caused improper seed set and decreased seed viability in transgenic plants constitutively expressing GOX. Our results suggest that pathogen inducible expression of heterologous genes may be a practical and robust way of generating broad spectrum disease resistance.

Apoptosis↗

PubMed2006

The cell biology of acute childhood respiratory disease: therapeutic implications.

Respiratory syncytial virus (RSV), the recently identified human metapneumovirus (HMPV), and the human parainfluenza viruses (HPIVs), cause most cases of childhood croup, bronchiolitis, and pneumonia. Influenza virus also causes a significant burden of disease in young children, although its significance in children was not fully recognized until recently. This article discusses pathogens that have been studied for several decades, including RSV and HPIVs, and also explores the newly identified viral pathogens HMPV and human coronavirus NL63. The escalating rate of emergence of new infectious agents, fortunately meeting with equally rapid advancements in molecular methods of surveillance and pathogen discovery, means that new organisms will soon be added to the list. A section on therapies for bronchiolitis addresses the final common pathways that can result from infection with diverse pathogens, highlighting the mechanisms that may be amenable to therapeutic approaches. The article concludes with a discussion of the overarching impact of new diagnostic strategies.

Acute Disease↗

PubMed2005

Role of mitogen-activated protein kinases in plant immunity.

Studies of the early events that follow pathogen recognition have established the importance of mitogen-activated protein kinase (MAPK) cascades in plant defense signaling. Specific MAPK cascade components have now been identified in several species, and so it has become possible to compare defense responses to diverse pathogens and to elucidate downstream events that are initiated by these key signaling molecules. Recent work utilizing post-transcriptional gene silencing techniques and the development of stable transgenic lines for both gain- and loss-of-function analysis have further advanced our understanding of the role of MAPK cascades in plant immunity.

Mitogen-Activated Protein Kinases↗

PubMed1998

Heterogeneity of phenotypic and genotypic traits including organic-acid resistance in Escherichia coli O157 isolates.

We undertook an epidemiologic study for the sensitivity of both Shiga-like toxin (Slt)-producing Escherichia coli (STEC) O157 and non-STEC O157 strains isolated from different patients with diarrhea to hydrochloric acid (HCl) and organic acids such as acetate, propionate, butyrate and lactate, and other pathogenic factors. The E. coli O157 isolates examined showed a wide variety of organic-acid susceptibility patterns. E. coli O157 isolates resistant to HCl or acetate were found more frequently than those resistant to other organic acids. These isolates also showed diverse pathogenicity patterns for the presence of the virulence genes, antibiotic susceptibility and plasmid profile.

Acids, Acyclic↗

PubMed2000

Characterizing rice lesion mimic mutants and identifying a mutant with broad-spectrum resistance to rice blast and bacterial blight.

Many plant mutants develop spontaneous lesions that resemble disease symptoms in the absence of pathogen attack. In several pathosystems, lesion mimic mutations have been shown to be involved in programmed cell death, which in some instances leads to enhanced disease resistance to multiple pathogens. We investigated the relationship between spontaneous cell death and disease resistance in rice with nine mutants with a range of lesion mimic phenotypes. All nine mutations are controlled by recessive genes and some of these mutants have stunted growth and other abnormal characteristics. The lesion mimics that appeared on the leaves of these mutants were caused by cell death as measured by trypan blue staining. Activation of six defense-related genes was observed in most of the mutants when the mimic lesions developed. Four mutants exhibited significant enhanced resistance to rice blast. One of the mutants, spl11, confers non-race-specific resistance not only to blast but also to bacterial blight. The level of resistance in the spl11 mutant to the two pathogens correlates with the defense-related gene expression and lesion development on the leaves. The results suggest that some lesion mimic mutations in rice may be involved in disease resistance, and cloning of these genes may provide a clue to developing broad-spectrum resistance to diverse pathogens.

Bacteria↗

PubMed2004

Molecular genotyping of a large, multicentric collection of tubercle bacilli indicates geographical partitioning of strain variation and has implications for global epidemiology of Mycobacterium tuberculosis.

Tuberculosis continues to be a major killer disease, despite an all-out effort launched against it in the postgenomic era. We describe here the population structure of Mycobacterium tuberculosis strains, as revealed by a chromosome-wide scan of fluorescent amplified fragment length polymorphisms (FAFLPs), for more than 1,100 independent isolates from 11 different countries. The bacterial strains were genotyped based on a total of 136 +/- 1 different FAFLP markers at the genome sequence interface, with details on IS6110 profiles, drug resistance status, clinicopathological observations, and host status integrated into the analysis process. The strains were found to cluster with possible geographic affinities, including the parameters of host species type, IS6110 profile, and drug susceptibility status. Of the five most commonly amplified fragment sets (or amplitypes), type A predominated in strains of mixed origin, deposited in The Netherlands; type B was exclusively observed for Indian isolates; type C was found mainly in strains from Peru and Australia; and types D and E predominated in European strains from France and Italy. The amplitypes were independent of certain large sequence polymorphisms representing two important deletions, TbD1 and Rd9. It appears that M. tuberculosis has a high genomic diversity with a possible geographic evolution. This may have occurred due to specific genomic deletions and synonymous substitutions selected rigorously against host defenses and environmental stresses on an evolutionary timescale. The genotypic data reported here are additionally significant for genotype-phenotype correlations and for determining whether pathogen diversity is a reflection f the host population diversity.

DNA Transposable Elements↗

PubMed2000

How the host 'sees' pathogens: global gene expression responses to infection.

Innate immune responses to pathogens are believed to be patterned and stereotyped. Adaptive responses display variety but in relatively few types of products and with limited numbers of mechanisms. Is this apparent disparity between microbial pathogen diversity and a restricted set of host responses an accurate picture of infection or is it the result of a limited collection of analytic tools? DNA microarray technology permits one to address simple descriptive questions about global gene expression inside cells. In particular, it offers an opportunity to examine the relationship between host and pathogen in much greater detail than has been possible previously. One can now ask, firstly, how a host cell or organism 'sees' a microbial pathogen from the viewpoint of gene expression responses and, secondly, at what level it is able to discriminate between different agents. Other potential insights to be reaped include the identification of microbial determinants of the host response, the temporal features of the 'conversation' between host and pathogen, novel strategies for therapeutic and prophylactic intervention and prognostic markers of outcome.

Animals↗

PubMed2002

CD8(+) T-cell homeostasis after infection: setting the 'curve'.

Antigen (Ag)-specific CD8(+) T-cell responses exhibit remarkably similar kinetics after different types of infection. Starting from levels that are virtually undetectable in vivo, pathogen-specific naïve CD8(+) T cells are precisely regulated to go through rapid expansion and contraction (death) phases, achieving memory levels of Ag-specific CD8(+) T cells that are maintained for the life of the host. However, the exact mechanisms used to achieve appropriate and reproducible CD8(+) T-cell homeostasis in response to diverse pathogens remain to be determined. The possibility that early events after infection regulate major features of Ag-specific CD8(+) T-cell homeostasis will be discussed here.

Animals↗

PubMed2006

The DARC conspiracy--virus invasion tactics.

Is there a "conspiracy" at work among viral pathogens? Apparently, yes. Rabies virus, lenti- and retroviruses, and herpesviruses, the "co-conspirators", target select members of the tumor necrosis factor (TNF) receptor superfamily to invade the cells of their host. The intrigue deepens, as several reports have revealed that the viral envelope proteins interact with the cellular TNF receptor in a highly conserved region of previously unknown function. Targeting of this region by diverse pathogens suggests that a selective advantage is acquired. This advantage might involve regulation of the immune response, because recent investigations of the herpesvirus entry receptor demonstrated that this conserved region engages an inhibitory co-receptor governing T-cell activation.

Amino Acid Sequence↗

PubMed2025

A major trade-off between growth and defense in Arabidopsis thaliana can vanish in field conditions.

When wild plants defend themselves from pathogens, this often comes with a trade-off: the same genes that protect a plant from disease can also reduce its growth and fecundity in the absence of pathogens. One protein implicated in a major growth-defense trade-off is ACCELERATED CELL DEATH 6 (ACD6), an ion channel that modulates salicylic acid (SA) synthesis to potentiate a wide range of defenses. Wild Arabidopsis thaliana populations maintain significant functional variation at the ACD6 locus, with some alleles making the protein hyperactive. In the greenhouse, plants with hyperactive ACD6 alleles are resistant to diverse pathogens, yet they are of smaller stature, their leaves senesce earlier, and they set fewer seeds compared to plants with the standard allele. We hypothesized that ACD6 hyperactivity would not only affect the growth of microbial pathogens but also more generally change leaf microbiome assembly. To test this in an ecologically meaningful context, we compared plants with hyperactive, standard, and defective ACD6 alleles in the same field-collected soil, both outdoors and in naturally lit and climate-controlled indoor conditions, taking advantage of near-isogenic lines as well as a natural accession and a CRISPR-edited derivative. We surveyed visual phenotypes, gene expression, hormone levels, seed production, and the microbiome in each environment. The genetic precision of CRISPR-edited plants allowed us to conclude that ACD6 genotype had no effect on mature field plants in our setting, despite reproducibly dramatic effects on greenhouse plants. We conclude that additional abiotic and/or microbial signals present outdoors-but not in the greenhouse-greatly modulate ACD6 activity. This raises the possibility that the fitness costs of other commonly studied immune system genes may be grossly misjudged without field studies.

Arabidopsis↗

PubMed2025

Temporal and geographical lineage dynamics of invasive Streptococcus pyogenes in Australia from 2011 to 2023: a retrospective, multicentre, clinical and genomic epidemiology study.

BACKGROUND: Defining the temporal dynamics of invasive Streptococcus pyogenes (group A Streptococcus) and differences between hyperendemic and lower-incidence regions provides crucial insights into pathogen evolution and, in turn, informs preventive measures. We aimed to examine the clinical and temporal lineage dynamics of S pyogenes across different disease settings in Australia to improve understanding of drivers of pathogen diversity. METHODS: In this retrospective, multicentre, clinical and genomic epidemiology study, we identified cases of invasive S pyogenes infection from normally sterile sites between Jan 1, 2011, and Feb 28, 2023. Data were collected from five hospital networks across low-incidence regions in temperate southeast Australia and the hyperendemic, tropical, and largely remote Top End of the Northern Territory of Australia. The crude incidence rate ratio (IRR) of bloodstream S pyogenes infection comparing the Top End and southeast Australia and in First Nations people compared with non-First Nations people was estimated by quasi-Poisson regression. We estimated odds ratios (ORs) of intensive care unit (ICU) admission, in-hospital mortality, and 30-day mortality for the Top End versus southeast Australia using logistic regression. Retrieved and successfully sequenced isolates were assigned lineages at whole-genome resolution. Temporal trends in the composition of co-circulating lineages were compared between the two regions. We used an S pyogenes-specific multistrain simulated transmission model to examine the relationship between host population-specific parameters and observed pathogen lineage dynamics. The prevalence of accessory genes (those present in 5-95% of all genomes) was compared across geographies and temporal periods to investigate genomic drivers of diversity. FINDINGS: We identified 500 cases of invasive S pyogenes infection in patients in the Top End and 495 cases in patients in southeast Australia. The crude IRR of bloodstream infection for the Top End compared with southeast Australia was 5·97 (95% CI 4·61-7·73) across the entire study period; in the Top End, infection disproportionately affected First Nations people compared with non-First Nations people (5·41, 4·28-6·89). The odds of in-hospital mortality (OR 0·43, 95% CI 0·26-0·70), 30-day mortality (0·38, 0·23-0·63), and ICU admission (0·42, 0·30-0·59) were lower in the Top End than in southeast Australia. Longitudinal lineage analysis of 642 S pyogenes genomes identified waves of replacement with distinct lineages in the Top End, whereas southeast Australia had a small number of dominant lineages that persisted and cycled in frequency. The transmission model qualitatively reproduced a similar pattern of replacement with distinct lineages when using a high transmission rate, small population size, and high levels of human movement-characteristics similar to those of communities in the hyperendemic Top End. Using a lower transmission rate, larger population size, and lower levels of migration similar to those of communities in urbanised southeast Australia, the transmission model qualitatively reproduced a pattern of dominant lineages that cycled in frequency. Despite distinct circulating lineages, the prevalence of accessory genes in the bacterial population was maintained across geographies and temporal periods. INTERPRETATION: In a hyperendemic setting, the replacement of distinct S pyogenes lineages occurred in waves, which could be linked to the disproportionate burden of disease and sparse human population in this setting. The maintenance of bacterial gene frequency could be consistent with multilocus selection. These findings suggest that lineage-specific interventions-such as vaccines under development-should consider disease setting and, without broad cross-protection, might lead to lineage replacement. FUNDING: National Health and Medical Research Council, and Leducq Foundation.

Humans↗