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[Integrative processes in modern epidemiology].

The integration of achievements in population ecology and the molecular genetics of pathogenic microorganisms into nowadays epidemiology of infectious diseases and the formation of its corresponding trends are discussed. The decisive role of highly complicated key problems of general epidemiology, such as the regularities of the autochthonous existence of pathogenic bacteria in the environment, the mechanisms of the pathogenicity regulation of infective agents and the formation of their epidemic variants, the mechanisms of the prolonged reservation of pathogenic bacteria at interepidemic (interepizootic) periods, the mechanisms of transformation of active (vegetative) and dormant forms in bacterial populations at different stages of epidemic and epizootic cycles, is demonstrated. The detection and analysis of such processes, and especially their latent mechanisms, become possible with the use of new concepts and methodological approaches, highly productive for the progress of epidemiology.

Adaptation, Physiological↗
PubMed1995

Deletions and duplication in internal inverted repeat sequence of long region/unique sequence of long region (IRL/UL) of herpes simplex virus type-1 (HSV-1) genome are not evidently associated with intracranial and foot-pad pathogenicity in mouse model.

The biological properties of three deletion variants (1704, 1705 and 1706) of herpes simplex virus type-1 (HSV-1) strain 17 syn+, were studied by establishing a base line pathogenicity of nine individual plaques from the parental 17 syn+ elite stock. Restriction enzyme analysis of deoxyribonucleic acid (DNA) from each of the nine plaque stocks and intracranial inoculation into three weeks old BALB/c mice showed no difference in the size of fragments and distribution of the sites or their 50% lethal dose (LD50) values [plaque forming units (pfu)/mouse] as compared to the parental 17 syn+ stock. Inoculation of the variants into three weeks old BALB/c mice showed that 1705 was not different in pathogenicity from the wild type following intracranial and footpad inoculations. On the other hand variants 1704 and 1706, when compared to the wild type virus were less virulent on intracranial inoculation i.e. the difference in LD50 values was approximately one log and two logs respectively and both the variants failed to kill any of the animals following footpad inoculation even at the dose of 1 x 10(7) pfu/mouse. During in vivo replication experiment in the peripheral nervous system of mice, 1704 and 1706 grew very poorly.

Amino Acid Sequence↗
PubMed2003

From immunome to vaccine: epitope mapping and vaccine design tools.

Since the publication of the complete genome of a pathogenic bacterium in 1995, more than 50 bacterial pathogens have been sequenced and at least 120 additional projects are currently underway. Faced with the expanding volume of information now available from genome databases, vaccinologists are turning to epitope mapping tools to screen vaccine candidates. Bioinformatics tools such as EpiMatrix and Conservatrix, which search for unique or multi-HLA-restricted (promiscuous) T cell epitopes and can find epitopes that are conserved across variant strains of the same pathogen, have accelerated the process of epitope mapping. Additional tools for screening epitopes for similarity to 'self' (BlastiMer) and for assembling putative epitopes into strings if they overlap (EpiAssembler) have been developed at EpiVax. Tools that map proteasome cleavage sires are available on the Internet. When used together, these bioinformatics tools offer a significant advantage over traditional methods of vaccine design since high throughput screening and design is performed in silico, followed by confirmatory studies in vitro. These new tools are being used to develop novel vaccines and therapeutics for the prevention and treatment of infectious diseases such as HIV, hepatitis C, tuberculosis, and some cancers. More recent applications of the tools involve deriving novel vaccine candidates directly from whole genomes, an approach that has been named 'genome to vaccine'.

Allergy and Immunology↗
PubMed2007

Germline MYH mutations in a clinic-based series of Canadian multiple colorectal adenoma patients.

OBJECTIVES: MYH is a member of the DNA base excision repair (BER) pathway and mutations of this gene predispose to the development of colorectal neoplasia in an autosomal recessive transmission pattern. Our objective was to determine the significance of MYH mutations in a series of Canadian patients with multiple adenomas. METHODS: We screened for germline MYH mutations (by dHPLCO) in 20 clinic-based multiple adenoma patients who were adenomatous polyposis coli (APC) mutation-negative. Suspected mutations were confirmed by sequence analysis. RESULTS: Six of 20 (30%) patients carried pathogenic biallelic MYH mutations, 1 Y165C homozygote and 5 compound heterozygotes of other sequence variants. We identified three novel variants, Q377X, 1314delA, and P281L, which are likely pathogenic. Twenty-nine relatives of the Y90X/1103delC compound heterozygous carrier were also screened for germline MYH mutations, and 1 homozygous and 14 heterozygous carriers were identified. CONCLUSIONS: Among patients with multiple adenomas, biallelic MYH mutations account for approximately 30% of APC mutation negative cases and two thirds of these carry mutations other than the "common" Y165C and G382D variants. Clinical screening algorithms which focus only on the Y165C and G382D alleles are inadequate since additional pathogenic mutations may be identified by screening the entire gene.

Adenocarcinoma↗
PubMed1999

Emergence of Anaplasma marginale antigenic variants during persistent rickettsemia.

Anaplasma marginale is an ehrlichial pathogen of cattle, in the order Rickettsiales, that establishes persistent cyclic rickettsemia in the infected host. Within each rickettsemic cycle, A. marginale expressing antigenically variant major surface protein 2 (MSP2) emerge. By cloning 17 full-length msp2 transcripts expressed during cyclic rickettsemia, we determined that emergent variants have a single, central hypervariable region encoding variant B-cell epitopes. The N- and C-terminal regions are highly conserved among the expressed A. marginale variants, and similar sequences define the MSP2 homologues in the agent of human granulocytic ehrlichiosis (HGE). This is in contrast to the MSP2 homologues in ehrlichial genogroup I pathogens, Ehrlichia chaffeensis, Ehrlichia canis, and Cowdria ruminantium, that have multiple hypervariable regions. By defining the variable and conserved regions, we were able to show that the single hypervariable region of A. marginale MSP2 encodes epitopes that are immunogenic and induce variant-specific antibody responses during persistent infection. These findings demonstrate that the MSP2 structural variants that emerge during each cycle of persistent rickettsemia are true antigenic variants, consistent with MSP2 antigenic variation as a mechanism of A. marginale persistence.

Amino Acid Sequence↗
PubMed2024

Delayed diagnosis of mild mucopolysaccharidosis type IVA.

BACKGROUND: Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease caused by biallelic variants in the N-acetylgalactosamine-6-sulfatase (GALNS) gene and is characterized by progressive and multi-system involvements, dominantly with skeletal deformities. A mild form of MPS IVA often presents with atypical symptoms and can go unrecognized for years. METHODS: The diagnosis of MPS IVA was confirmed via GALNS enzyme activity testing in leukocytes. Clinical features were collected. Molecular analysis was performed by next generation sequence and Sanger sequencing of the GALNS gene. The pathogenicity of the deep intron variant was verified by mRNA analyses. RESULTS: Thirteen patients with mild MPS IVA from six families were included. All probands first visit pediatric orthopedists and it took 5.6 years to be diagnosed after the disease onset. The most common symptoms in our series were waddling gait (85%), short neck (69%) and flat feet (62%). Radiologic findings indicated skeletal abnormalities in all patients, especially modification of the vertebral bodies (100%) and acetabular and femoral head dysplasia (100%). Five novel GALNS variants, including c.121-2_121-1insTTTGCTGGCATATGCA, E2 deletion, c.569 A > G, c.898 + 2 T > A, and c.1139 + 2 T > C, were identified. The most common variant, a deep intron variant NM_000512.5: c.121-210 C > T (NM_001323544.2: c.129 C > T, p.G43G), was revealed to result in an 11 bp deletion (c.128_138delGCGATGCTGAG, p.Gly43Aspfs*5) on GALNS mRNA in the GALNS transcript of NM_001323544.2. CONCLUSIONS: This study provides significant insights into the clinical features and molecular characteristics that contribute to the early diagnosis of mild MPS IVA. On the basis of our cohort, orthopedists need to be able to recognize signs and symptoms of mild MPS IVA as well as the molecular and biochemical diagnosis so that an early diagnosis and treatment can be instituted.

Humans↗
PubMed2001

Fatal primary infection due to human herpesvirus 6 variant A in a renal transplant recipient.

We describe a fatal primary human herpesvirus 6 (HHV-6) variant A infection in a kidney transplanted adult woman. On day 20 post transplantation (TX), after rejection therapy, the patient presented an acute hemophagocytic syndrome with hepatitis and central nervous system involvement. HHV-6 IgG and IgM antibodies seroconversion was demonstrated. HHV-6 variant A was the sole pathogen detected by nested PCR and/or culture in blood, bone marrow aspiration, liver biopsy, cerebrospinal fluid and bronchoalveolar lavage. The graft was HHV-6 seropositive and the patient was not transfused before day 28 post TX, suggesting that the virus was transmitted by the graft. Despite immunoglobulins, ganciclovir and foscarnet therapy, the HHV-6 infection progressed and led to severe aplasia. The patient developed Aspergillus fumigatus pneumonia and died from fulminant candidemia. This case demonstrated for the first time that HHV-6 variant A primary infection can cause life-threatening disseminated infection in immunosuppressed patients.

Adult↗
PubMed2000

[Development of blunt Tilletia caries (D.C.) Tul. pathogen on embryogenic wheat callus].

The development of Tilletia caries on embryogenic and morphogenic wheat calluses from germination of spores up to sorus formation have been investigated. Pathogene growth was similar in variants with wheat calluses of susceptible species Triticum aestivum and resistant species T. timopheevii, but intensity of its development of embryogenic calluses of both species was lower, than on morphogenic. Necrosis of parenchyma-like cells was more distinct in the embryogenic than in morphogenic calluses. It was combined with low accumulation rate of infected cells in embryogenic calluses. Necrosis reduced the healthy cell reproduction in meristem-like cells of morphogenic calluses and thereby additionally decreased resistance of morphogenic calluses to pathogene.

Basidiomycota↗
PubMed2006

DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls.

Mutations in GJB2 are associated with hereditary hearing loss. DNA sequencing of GJB2 in a cohort of hearing impaired patients and a multi-ethnic control group is reported. Among 610 hearing impaired cases, 43 DNA sequence variations were identified in the coding region of GJB2 including 24 mutations, 8 polymorphisms, 3 unclassified variants (G4D, R127C, M163V), 1 controversial variant (V37I), and 7 novel variants (G12C, N14D, V63A, T86M, L132V, D159, 592_600delinsCAGTGTTCATGACATTC). Sixteen non-coding sequence variations were also identified among cases including the IVS1+1A>G mutation, 2 polymorphisms, and 13 novel variants. A diagnosis of GJB2-associated hearing loss was confirmed for 63 cases (10.3%). Heterozygous mutations were found in 39 cases (6.4%). Eleven cases carrying novel or unclassified variants (1.8 %) and 18 cases carrying the controversial V37I variant were identified (3%). In addition, 294 control subjects from 4 ethnic groups were sequenced for GJB2. Thirteen sequence variations in the coding region of GJB2 were identified among controls including 2 mutations, 6 polymorphisms, 2 unclassified variants (G4D, T123N), 1 controversial variant (V37I), and 2 novel variants (R127L, V207L). Nine sequence variations were identified among controls in the non-coding regions in and around GJB2 exon 2. Of particular interest among controls were the variability in carrier rates and ethnic stratification of alleles, and the complex genotypes among Asians, 47% of whom carried two to four sequence variations in the coding region of GJB2. These data provide new information about carrier rates for GJB2-based hearing loss in various ethnic groups and contribute to evaluation of the pathogenicity of the controversial V37I variant.

Alleles↗
PubMed2005

Genotypic and phenotypic diversity of a baculovirus population within an individual insect host.

It is becoming increasingly apparent that many pathogen populations, including those of insects, show high levels of genotypic variation. Baculoviruses are known to be highly variable, with isolates collected from the same species in different geographical locations frequently showing genetic variation and differences in their biology. More recent studies at smaller scales have also shown that virus DNA profiles from individual larvae can show polymorphisms within and between populations of the same species. Here, we investigate the genotypic and phenotypic variation of an insect baculovirus infection within a single insect host. Twenty four genotypically distinct nucleopolyhedrovirus (NPV) variants were isolated from an individual pine beauty moth, Panolis flammea, caterpillar by in vivo cloning techniques. No variant appeared to be dominant in the population. The PaflNPV variants have been mapped using three restriction endonucleases and shown to contain three hypervariable regions containing insertions of 70-750 bp. Comparison of seven of these variants in an alternative host, Mamestra brassicae, demonstrated that the variants differed significantly in both pathogenicity and speed of kill. The generation and maintenance of pathogen heterogeneity are discussed.

Animals↗
PubMed2000

Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain.

More than 500 unrelated patients with neurofibromatosis type 1 (NF1) were screened for mutations in the NF1 gene. For each patient, the whole coding sequence and all splice sites were studied for aberrations, either by the protein truncation test (PTT), temperature-gradient gel electrophoresis (TGGE) of genomic PCR products, or, most often, by direct genomic sequencing (DGS) of all individual exons. A total of 301 sequence variants, including 278 bona fide pathogenic mutations, were identified. As many as 216 or 183 of the genuine mutations, comprising 179 or 161 different ones, can be considered novel when compared to the recent findings of Upadhyaya and Cooper, or to the NNFF mutation database. Mutation-detection efficiencies of the various screening methods were similar: 47.1% for PTT, 53.7% for TGGE, and 54.9% for DGS. Some 224 mutations (80.2%) yielded directly or indirectly premature termination codons. These mutations showed even distribution over the whole gene from exon 1 to exon 47. Of all sequence variants determined in our study, <20% represent C-->T or G-->A transitions within a CpG dinucleotide, and only six different mutations also occur in NF1 pseudogenes, with five being typical C-->T transitions in a CpG. Thus, neither frequent deamination of 5-methylcytosines nor interchromosomal gene conversion may account for the high mutation rate of the NF1 gene. As opposed to the truncating mutations, the 28 (10.1%) missense or single-amino-acid-deletion mutations identified clustered in two distinct regions, the GAP-related domain (GRD) and an upstream gene segment comprising exons 11-17. The latter forms a so-called cysteine/serine-rich domain with three cysteine pairs suggestive of ATP binding, as well as three potential cAMP-dependent protein kinase (PKA) recognition sites obviously phosphorylated by PKA. Coincidence of mutated amino acids and those conserved between human and Drosophila strongly suggest significant functional relevance of this region, with major roles played by exons 12a and 15 and part of exon 16.

Cohort Studies↗
PubMed2003

Bioinformatics tools for identifying class I-restricted epitopes.

The lack of simple methods to identify relevant T-cell epitopes, the high mutation rate of many pathogens, and restriction of T-cell response to epitopes due to human lymphocyte antigen (HLA) polymorphism have significantly hindered the development of cytotoxic T-lymphocyte (CTL) epitope-based or "epitope-driven" vaccines. Previously, CTL epitopes were mapped using large arrays of overlapping synthetic peptides. The large number of protein sequences available for mapping is now making this method prohibitively expensive and time-consuming. Bioinformatics tools such as EpiMatrix and Conservatrix, which search for unique or multi-HLA-restricted (promiscuous) T-cell epitopes and identify epitopes that are conserved across variant strains of the same pathogen, accelerate epitope mapping. These tools offer a significant advantage over other methods of epitope selection because high-throughput screening can be performed in silico, followed by confirmatory studies in vitro. CTL epitopes discovered using these tools might be used to develop novel vaccines and therapeutics for the prevention and treatment of infectious diseases such as human immunodeficiency virus, hepatitis C, tuberculosis, and some cancers.

Algorithms↗
PubMed1999

In vivo cell and tissue tropism of SIVsmmPBj14-bcl.3.

To gain insight into the unique pathogenicity of simian immunodeficiency virus (SIV) variant PBj14, which produces an acutely lethal enteropathic syndrome in infected pigtail macaques, we investigated the cell and tissue tropisms of a highly pathogenic biologic clone (bcl.3) of SIVsmmPBj14. To compare the relative amount of viral antigen in lymphoid organs of infected macaques we used an objective semiquantitative immunohistochemistry (sQIHC) assay. We found that in all animals viral antigen load was greater in alimentary-associated lymphoid tissues (gut-associated lymphoid tissue [GALT], tonsil, mesenteric and retropharyngeal lymph nodes) than in non-alimentary-associated lymphoid tissues (spleen, thymus, inguinal and axillary lymph nodes). Moreover, in six of nine animals examined, virus load in GALT was greater than that in any other lymphoid tissue. To determine whether the acute pathogenicity and prolific replication of SIVsmmPBj14 might be explained by a broader in vivo cell tropism than is typical of SIVs, we used cell subset separation and nested PCR. We found that the primary target cells in mesenteric lymph node for SIVsmmPBj14 were CD4+ T lymphocytes. However, the virus also infected macrophages, as well as CD8+ T cells and B cells, albeit at low frequencies. These results suggest that alimentary lymphoid tissue localization rather than unusual cell phenotype tropism distinguishes the singular pathogenesis of SIVsmmPBj14.

Animals↗
PubMed2001

The flexibility of the TCR allows recognition of a large set of naturally occurring epitope variants by HIV-specific cytotoxic T lymphocytes.

Pathogens attempt to evade immune recognition by expressing mutated antigens. The present study shows that two mechanisms happen in vivo during the course of HIV infection to limit the escape of antigenic variants from cytotoxic T lymphocyte (CTL) recognition: recognition of several epitope variants by the same TCR and generation of several CTL populations specific for a single epitope but recognizing different variant sequences. We have studied two CTL populations directed towards the HIV-p24gag amino acids 176--184 QASQEVKNW epitope, presented by HLA-B5301. Both CTL populations were derived from a long-term asymptomatic HIV-infected child and they express different TCR. Each of the two CTL recognizes five of the 10 naturally occurring variants. These variants are distinct for both CTL and thus a total of eight variants are recognized. Thus, polyclonality of CTL specific for the same epitope but differing in variant sequences recognized may improve the control of variant viruses' replication in vivo. In addition to cross-recognition of several variant epitopes, promiscuous recognition of exogenous peptides complexed to allogeneic HLA-B molecules occurs, showing that the TCR can tolerate amino acid changes on both the peptide and the MHC molecule. This flexibility of the TCR is probably of great importance for control of viruses with high genetic variability, such as HIV.

Alleles↗
PubMed1993

Surface expression of alpha 4 integrin by CD4 T cells is required for their entry into brain parenchyma.

Cloned CD4 T cell lines that recognize the Ac1-16 peptide of myelin basic protein bound to I-Au were isolated and used to analyze the immunopathogenesis of experimental autoimmune encephalomyelitis (EAE). T helper type 1 (Th1) clones induced disease, while Th2 clones did not. Using variants of a single cloned Th1 line, the surface expression of alpha 4 integrins (very late antigen 4 [VLA-4]) was identified as a major pathogenic factor. Encephalitogenic clones and nonencephalitogenic variants differ by 10-fold in their level of surface expression of alpha 4 integrin and in their ability to bind to endothelial cells and recombinant vascular cell adhesion molecule 1 (VCAM-1). The alpha 4 integrin-high, disease-inducing cloned Th1 T cells enter brain parenchyma in abundance, while alpha 4 integrin-low, nonencephalitogenic Th1 cells do not. Moreover, antibodies to alpha 4 integrin, its ligand VCAM-1, and intercellular adhesion molecule 1 all influence the pathogenicity of this encephalitogenic clone in vivo. The importance of the expression of VLA-4 for encephalitogenicity is not unique to cloned T cell lines, as similar results were obtained using myelin basic protein-primed lymph node T cells. alpha 4 integrin levels did not affect antigen responsiveness or production of the Th1 cytokines interleukin 2, interferon gamma, and lymphotoxin/tumor necrosis factor beta; and antibodies against alpha 4 integrin did not block antigen recognition in vitro. Thus, we conclude that surface expression of alpha 4 integrin is important in CD4 T cell entry into brain parenchyma. A general conclusion of these studies is that alpha 4 integrins may be crucial in allowing activated effector T cells to leave blood and enter the brain and other tissues to clear infections.

Animals↗
PubMed1999

Rapid generation of genetic heterogeneity in progenies from individual cDNA clones of peach latent mosaic viroid in its natural host.

Viroids, small single-stranded circular RNAs endowed with autonomous replication, are unique systems to conduct evolutionary studies of complete RNA genomes. The primary structure of 36 progeny variants of peach latent mosaic viroid (PLMVd), evolved from inoculations of the peach indicator GF-305 with four individual PLMVd cDNAs differing in their pathogenicity, has been determined. Most progeny variants had unique sequences, revealing that the extremely heterogeneous character of PLMVd natural isolates most probably results from the intrinsic ability of this RNA to accumulate changes, rather than from repeated inoculations of the same individual trees under field conditions. The structure of the populations derived from single PLMVd sequences differed according to the observed phenotype. Variant gds6 induced a reproducible symptomatic infection and gave rise to a more uniform progeny that preserves some parental features, whereas variant gds15, which induced a variable phenotype, showed a more complex behaviour, generating two distinct progenies in symptomatic and asymptomatic individual plants. Progenies derived from variants esc10 and Is11, which incited latent infections, followed a similar evolutionary pattern, leading to a population structure consisting of two main groups of variants, one of which was formed by variants closely related to the parental sequence. The evolution rate exhibited by PLMVd, considerably higher than that reported for potato spindle tuber viroid, may contribute to the fluctuating symptomatology of the severe PLMVd natural isolates. However, the polymorphism observed in PLMVd progenies does preserve some structural and functional elements previously proposed for this viroid, supporting the fact that they act as constraints limiting the genetic divergence of PLMVd quasispecies generated de novo.

Base Sequence↗
PubMed1999

Recombinant feline leukemia virus (FeLV) variants establish a limited infection with altered cell tropism in specific-pathogen-free cats in the absence of FeLV subgroup A helper virus.

Feline leukemia virus subgroup B (FeLV-B) is commonly associated with feline lymphosarcoma and arises through recombination between endogenous retroviral elements inherited in the cat genome and corresponding regions of the envelope (env) gene from FeLV subgroup A (FeLV-A). In vivo infectivity for FeLV-B is thought to be inefficient in the absence of FeLV-A. Proposed FeLV-A helper functions include enhanced replication efficiency, immune evasion, and replication rescue for defective FeLV-B virions. In vitro analysis of the recombinant FeLV-B-like viruses (rFeLVs) employed in this study confirmed these viruses were replication competent prior to their use in an in vivo study without FeLV-A helper virus. Eight specific-pathogen-free kittens were inoculated with the rFeLVs alone. Subsequent hematology and histology results were within normal limits, however, in the absence of detectable viremia, virus expression, or significant seroconversion, rFeLV proviral DNA was detected in bone marrow tissue of 4/4 (100%) cats at 45 weeks postinoculation (pi), indicating these rFeLVs established a limited but persistent infection in the absence of FeLV-A. Altered cell tropism was also noted. Focal infection was seen in T-cell areas of the splenic follicles in 3/4 (75%) rFeLV-infected cats analyzed, while an FeLV-A-infected cat showed focal infection in B-cell areas of the splenic follicles. Nucleotide sequence analysis of the surface glycoprotein portion of the rFeLV env gene amplified from bone marrow tissue collected at 45 weeks pi showed no sequence alterations from the original rFeLV inocula.

Animals↗