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1.
Sci Total Environ ; 857(Pt 3): 159378, 2023 Jan 20.
Article in English | MEDLINE | ID: mdl-36272475

ABSTRACT

This study aimed to investigate the bacterial diversity and the background level of antibiotic resistance in two freshwater ecosystems with low anthropogenic impact in order to evaluate the presence of natural antimicrobial resistance in these areas and its potential to spread downstream. Water samples from a pre-Alpine and an Apennine river (Variola and Tiber, respectively) were collected in three different sampling campaigns and bacterial diversity was assessed by 16S sequencing, while the presence of bacteria resistant to five antibiotics was screened using a culturable approach. Overall bacterial load was higher in the Tiber River compared with the Variola River. Furthermore, the study revealed the presence of resistant bacteria, especially the Tiber River showed, for each sampling, the presence of resistance to all antibiotics tested, while for the Variola River, the detected resistance was variable, comprising two or more antibiotics. Screening of two resistance genes on a total of one hundred eighteen bacterial isolates from the two rivers showed that blaTEM, conferring resistance to ß-lactam antibiotics, was dominant and present in ~58 % of isolates compared to only ~9 % for mefA/E conferring resistance to macrolides. Moreover, ß-lactam resistance was detected in various isolates showing also resistance to additional antibiotics such as macrolides, aminoglycosides and tetracyclines. These observations would suggest the presence of co-resistant bacteria even in non-anthropogenic environments and this resistance may spread from the environment to humans and/or animals.


Subject(s)
Genes, Bacterial , Smallpox , Humans , Animals , Ecosystem , Smallpox/genetics , Anthropogenic Effects , Drug Resistance, Microbial/genetics , Anti-Bacterial Agents/pharmacology , Fresh Water , Bacteria/genetics , Macrolides
2.
J Int Med Res ; 46(10): 4032-4038, 2018 Oct.
Article in English | MEDLINE | ID: mdl-30088790

ABSTRACT

It is generally accepted that human immunodeficiency virus (HIV) is the etiological agent of acquired immune deficiency syndrome. According to this claim, HIV was transferred to humans from contact with monkeys around 35-50 years ago. However, this claim has not been sufficiently confirmed epidemiologically. The spread and incubation period of the plague epidemic has led to the theory that the Black Death was caused by hemorrhagic viruses. Having examined detailed historical data, we have concluded that the bacterium Yersenia pestis was an infectious agent in the epidemic, together with another agent which we suggest was HIV. Our considerations were mainly based on the existence of the CCR5 delta 32 mutation, which protects against HIV infection and has been present in the Caucasian population for over 2000 years. The combination of two infectious agents led to the devastation of the Black Death, the removal of HIV carriers, and an increase in the number of CCR5Δ32 mutations in the Caucasian population. In sub-Saharan Africa, this epidemic and subsequent sanitation process did not occur, which explains the much higher level of HIV genetic information in this part of the world.


Subject(s)
Epidemics/statistics & numerical data , HIV Infections , Receptors, CCR5/genetics , Acquired Immunodeficiency Syndrome/epidemiology , Acquired Immunodeficiency Syndrome/genetics , Acquired Immunodeficiency Syndrome/history , Africa South of the Sahara/epidemiology , Asia/epidemiology , Biological Evolution , Black People/genetics , Epidemics/history , Europe/epidemiology , Evolution, Molecular , HIV Infections/epidemiology , HIV Infections/genetics , HIV Infections/history , Hemorrhagic Fevers, Viral/epidemiology , Hemorrhagic Fevers, Viral/genetics , Hemorrhagic Fevers, Viral/history , Heterozygote , History, 15th Century , History, 16th Century , History, 17th Century , History, 20th Century , History, 21st Century , History, Ancient , History, Medieval , Humans , Plague/epidemiology , Plague/genetics , Plague/history , Smallpox/epidemiology , Smallpox/genetics , Smallpox/history , White People/genetics
3.
PLoS One ; 11(8): e0158016, 2016.
Article in English | MEDLINE | ID: mdl-27513748

ABSTRACT

Although many diseases and traits show large heritability, few genetic variants have been found to strongly separate phenotype groups by genotype. Complex regulatory networks of variants and expression of multiple genes lead to small individual-variant effects and difficulty replicating the effect of any single variant in an affected pathway. Interaction network modeling of GWAS identifies effects ignored by univariate models, but population differences may still cause specific genes to not replicate. Integrative network models may help detect indirect effects of variants in the underlying biological pathway. In this study, we used gene-level functional interaction information from the Integrative Multi-species Prediction (IMP) tool to reveal important genes associated with a complex phenotype through evidence from epistasis networks and pathway enrichment. We test this method for augmenting variant-based network analyses with functional interactions by applying it to a smallpox vaccine immune response GWAS. The integrative analysis spotlights the role of genes related to retinoid X receptor alpha (RXRA), which has been implicated in a previous epistasis network analysis of smallpox vaccine.


Subject(s)
Epistasis, Genetic/genetics , Gene Regulatory Networks , Immune System Phenomena/genetics , Polymorphism, Single Nucleotide/genetics , Retinoid X Receptors/genetics , Smallpox Vaccine/immunology , Smallpox/genetics , Adolescent , Adult , Algorithms , Computational Biology , Female , Genome-Wide Association Study , Genotype , Humans , Male , Phenotype , Signal Transduction , Smallpox/immunology , Smallpox/prevention & control , Smallpox Vaccine/genetics , Young Adult
4.
Genes Immun ; 17(4): 244-50, 2016 06.
Article in English | MEDLINE | ID: mdl-27052692

ABSTRACT

Expression quantitative trait loci (eQTL) studies have functionalized nucleic acid variants through the regulation of gene expression. Although most eQTL studies only examine the effects of single variants on transcription, a more complex process of variant-variant interaction (epistasis) may regulate transcription. Herein, we describe a tool called interaction QTL (iQTL) designed to efficiently detect epistatic interactions that regulate gene expression. To maximize biological relevance and minimize the computational and hypothesis testing burden, iQTL restricts interactions such that one variant is within a user-defined proximity of the transcript (cis-regulatory). We apply iQTL to a data set of 183 smallpox vaccine study participants with genome-wide association study and gene expression data from unstimulated samples and samples stimulated by inactivated vaccinia virus. While computing only 0.15% of possible interactions, we identify 11 probe sets whose expression is regulated through a variant-variant interaction. We highlight the functional epistatic interactions among apoptosis-related genes, DIABLO, TRAPPC4 and FADD, in the context of smallpox vaccination. We also use an integrative network approach to characterize these iQTL interactions in a posterior network of known prior functional interactions. iQTL is an efficient, open-source tool to analyze variant interactions in eQTL studies, providing better understanding of the function of epistasis in immune response and other complex phenotypes.


Subject(s)
Apoptosis/genetics , Epistasis, Genetic , Quantitative Trait Loci , Smallpox/genetics , Software , Adolescent , Adult , Apoptosis Regulatory Proteins , Fas-Associated Death Domain Protein/genetics , Fas-Associated Death Domain Protein/metabolism , Female , Gene Regulatory Networks , Humans , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Male , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Smallpox/immunology , Smallpox Vaccine/immunology , Vesicular Transport Proteins/genetics , Vesicular Transport Proteins/metabolism
5.
Mod Healthc ; suppl: 24-26, 2016 Aug.
Article in English | MEDLINE | ID: mdl-30398801

ABSTRACT

The sequencing of the human genome represents the most significant breakthrough in healthcare over the past 40 years, according to Modern Healthcare readers. That achievement, capping a 13-year, $3 billion international effort funded by the federal government, drew the most votes from the 728 respondents to a survey that listed 60 healthcare milestones achieved since Modern Healthcare was founded in 1976. The survey asked readers to pick their top five choices from each of three categories: science and technology; healthcare delivery; and politics and policy.


Subject(s)
Awards and Prizes , Inventions/history , Whole Genome Sequencing , Financing, Government , Health Care Reform , History, 20th Century , History, 21st Century , Smallpox/genetics
6.
Anal Chem ; 86(22): 11326-33, 2014 Nov 18.
Article in English | MEDLINE | ID: mdl-25369533

ABSTRACT

The progressive development of amplified DNA sensors using nucleic acid-based machineries, involving the isothermal autonomous synthesis of the Mg(2+)-dependent DNAzyme, is used for the amplified, multiplexed analysis of genes (Smallpox, TP53) and metal ions (Ag(+), Hg(2+)). The DNA sensing machineries are based on the assembly of two sensing modules consisting of two nucleic acid scaffolds that include recognition sites for the two genes and replication tracks that yield the nicking domains for Nt.BbvCI and two different Mg(2+)-dependent DNAzyme sequences. In the presence of any of the genes or the genes together, their binding to the respective recognition sequences triggers the nicking/polymerization machineries, leading to the synthesis of two different Mg(2+)-dependent DNAzyme sequences. The cleavage of two different fluorophore/quencher-modified substrates by the respective DNAzymes leads to the fluorescence of F1 and/or F2 as readout signals for the detection of the genes. The detection limits for analyzing the Smallpox and TP53 genes correspond to 0.1 nM. Similarly, two different nucleic acid scaffolds that include Ag(+)-ions or Hg(2+)-ions recognition sequences and the replication tracks that yield the Nt.BbvCI nicking domains and the respective Mg(2+)-dependent DNAzyme sequences are implemented as nicking/replication machineries for the amplified, multiplexed analysis of the two ions, with detection limits corresponding to 1 nM. The ions sensing modules reveal selectivities dominated by the respective recognition sequences associated with the scaffolds.


Subject(s)
DNA, Catalytic/metabolism , Mercury/analysis , Silver/analysis , Smallpox/genetics , Tumor Suppressor Protein p53/genetics , Humans , Nucleic Acid Amplification Techniques
7.
Vaccine ; 31(39): 4241-6, 2013 Sep 06.
Article in English | MEDLINE | ID: mdl-23523410

ABSTRACT

The smallpox vaccine Vaccinia was successfully used to eradicate smallpox, but although very effective, it was a very reactogenic vaccine and responsible for the deaths of one or two people per million vaccinated. Modified Vaccinia virus Ankara (MVA) is a replication-deficient and attenuated derivative, also used in the smallpox eradication campaign and now being developed as a recombinant viral vector to produce vaccines against infectious diseases and cancer. Many clinical trials of these new vaccines have been conducted, and the findings of these trials are reviewed here. The safety of MVA is now well documented, immunogenicity is influenced by the dose and vaccination regimen, and information on the efficacy of MVA-vectored vaccines is now beginning to accumulate.


Subject(s)
Genetic Vectors , Smallpox Vaccine/immunology , Viral Vaccines/immunology , Animals , Humans , Malaria/immunology , Malaria/prevention & control , Smallpox/genetics , Smallpox/prevention & control , Smallpox Vaccine/genetics , Vaccination , Vaccines, Attenuated , Vaccines, DNA , Vaccinia virus/genetics , Vaccinia virus/immunology , Viral Vaccines/genetics
8.
J Comp Pathol ; 148(1): 6-21, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22884034

ABSTRACT

In the three decades since the eradication of smallpox and cessation of routine vaccination, the collective memory of the devastating epidemics caused by this orthopoxvirus has waned, and the human population has become increasingly susceptible to a disease that remains high on the list of possible bioterrorism agents. Research using surrogate orthopoxviruses in their natural hosts, as well as limited variola virus research in animal models, continues worldwide; however, interpretation of findings is often limited by our relative lack of knowledge about the naturally occurring disease. For modern comparative pathologists, many of whom have no first-hand knowledge of naturally occurring smallpox, this work provides a contemporary review of this historical disease, as well as discussion of how it compares with human monkeypox and the corresponding diseases in macaques.


Subject(s)
Macaca mulatta , Mpox (monkeypox)/pathology , Smallpox/pathology , Animals , Gene Expression Regulation, Viral , Humans , Mpox (monkeypox)/genetics , Poxviridae/pathogenicity , Poxviridae/physiology , Smallpox/genetics , Species Specificity
9.
J Biol Chem ; 287(47): 39470-9, 2012 Nov 16.
Article in English | MEDLINE | ID: mdl-23012361

ABSTRACT

The K7L gene product of the smallpox virus is a protease implicated in the maturation of viral proteins. K7L belongs to protease Clan CE, which includes distantly related cysteine proteases from eukaryotes, pathogenic bacteria, and viruses. Here, we describe its recombinant high level expression, biochemical mechanism, substrate preference, and regulation. Earlier studies inferred that the orthologous I7L vaccinia protease cleaves at an AG-X motif in six viral proteins. Our data for K7L suggest that the AG-X motif is necessary but not sufficient for optimal cleavage activity. Thus, K7L requires peptides extended into the P7 and P8 positions for efficient substrate cleavage. Catalytic activity of K7L is substantially enhanced by homodimerization, by the substrate protein P25K as well as by glycerol. RNA and DNA also enhance cleavage of the P25K protein but not of synthetic peptides, suggesting that nucleic acids augment the interaction of K7L with its protein substrate. Library-based peptide preference analyses enabled us to design an activity-based probe that covalently and selectively labels K7L in lysates of transfected and infected cells. Our study thus provides proof-of-concept for the design of inhibitors and probes that may contribute both to a better understanding of the role of K7L in the virus life cycle and the design of novel anti-virals.


Subject(s)
Antiviral Agents/chemistry , Molecular Probes/chemistry , Peptide Hydrolases/chemistry , Peptide Library , Protease Inhibitors/chemistry , Variola virus/enzymology , Viral Proteins/antagonists & inhibitors , Amino Acid Motifs , Animals , Cell Line , Cricetinae , Drug Design , Peptide Hydrolases/genetics , Peptide Hydrolases/metabolism , Smallpox/drug therapy , Smallpox/enzymology , Smallpox/genetics , Variola virus/genetics , Viral Proteins/chemistry , Viral Proteins/genetics , Viral Proteins/metabolism
10.
J Exp Med ; 207(11): 2369-81, 2010 Oct 25.
Article in English | MEDLINE | ID: mdl-20876312

ABSTRACT

Although it is well known that aged hosts are generally more susceptible to viral diseases than the young, specific dysfunctions of the immune system directly responsible for this increased susceptibility have yet to be identified. We show that mice genetically resistant to mousepox (the mouse parallel of human smallpox) lose resistance at mid-age. Surprisingly, this loss of resistance is not a result of intrinsically defective T cell responses. Instead, the primary reason for the loss of resistance results from a decreased number of total and mature natural killer (NK) cells in the blood and an intrinsic impairment in their ability to migrate to the lymph node draining the site of infection, which is essential to curb systemic virus spread. Hence, our work links the age-dependent increase in susceptibility to a viral disease to a specific defect of NK cells, opening the possibility of exploring treatments to improve NK cell function in the aged with the goal of enhancing their resistance to viral diseases.


Subject(s)
Aging/immunology , Cell Movement/immunology , Disease Susceptibility/immunology , Ectromelia, Infectious/immunology , Immunity, Innate/immunology , Killer Cells, Natural/immunology , Aging/genetics , Animals , Cell Movement/genetics , Ectromelia, Infectious/genetics , Humans , Immunity, Innate/genetics , Mice , Mice, Mutant Strains , Smallpox/genetics , Smallpox/immunology
12.
Vopr Virusol ; 54(6): 28-33, 2009.
Article in Russian | MEDLINE | ID: mdl-20030279

ABSTRACT

A kit of specific oligonucleotide primers and hybridization probes has been proposed to detect orthopoxviruses (OPV) and to discriminate human pathogenic viruses, such as variola virus and monkey virus by real-time polymerase chain reaction (PCR). For real-time PCR, the following pairs of fluorophore and a fluorescence quencher were used: TAMRA-BHQ2 for genus-specific probes and FAM-BHQ1 for species-specific ones (variola virus, monkeypox virus, ectomelia virus). The specificity of this assay was tested on 38 strains of 6 OPV species and it was 100%.


Subject(s)
Monkeypox virus/isolation & purification , Mpox (monkeypox)/diagnosis , Polymerase Chain Reaction/methods , Smallpox/diagnosis , Variola virus/isolation & purification , Animals , DNA Primers/genetics , DNA, Viral/analysis , Humans , Mpox (monkeypox)/genetics , Monkeypox virus/genetics , Smallpox/genetics , Variola virus/genetics
14.
J Am Chem Soc ; 131(26): 9368-77, 2009 Jul 08.
Article in English | MEDLINE | ID: mdl-19566101

ABSTRACT

Defined broadly, molecular translators are constructs that can convert any designated molecular input into a unique output molecule. In particular, the development of universal nucleic acid translators would be of significant practical value in view of the expanding biomedical importance of gene diagnostics. Currently, diagnostic assays for nucleic acids must be individually developed and optimized for each new sequence because inputs for one assay are sequence-specific and are therefore incompatible with any other assay designed for the detection of a different nucleic acid. However, if a desired nucleic acid sequence could be translated in vitro into a predetermined nucleic acid output for which there is already a known diagnostic assay, then that single assay could be easily adapted to detect nearly any strand. Here we investigate PCR-independent isothermal molecular translation strategies that function without the need for post-translation purification and can be implemented with commercially available components. Translation yields up to 96% are obtained in 5 min at room temperature with minimal background reaction (<1%) and with discrimination of single nucleotide polymorphisms in the input sequence. Furthermore, we apply these translators to adapt a high-gain HIV diagnostic system for high-throughput detection of hepatitis C, avian influenza (H5N1), and smallpox without making changes to the underlying assay. Finally, we show the feasibility of translating small-molecule interactions into nucleic acid outputs by demonstrating the utility of a DNA aptamer for translating adenosine into a readily detectable output DNA sequence. Additionally, equilibrium expressions are described in order to facilitate rational engineering of aptameric translators for label-free detection of any molecule that an aptamer can recognize.


Subject(s)
Hepatitis C/diagnosis , Influenza in Birds/diagnosis , Nucleic Acid Amplification Techniques/methods , Smallpox/diagnosis , Adenosine/genetics , Animals , Aptamers, Nucleotide/genetics , Base Sequence , Birds , DNA/analysis , DNA/genetics , Hepatitis C/genetics , Humans , Influenza A Virus, H5N1 Subtype/genetics , Influenza in Birds/genetics , Polymorphism, Single Nucleotide , RNA, Viral/analysis , RNA, Viral/genetics , Smallpox/genetics
15.
Mol Cell Probes ; 23(3-4): 166-70, 2009.
Article in English | MEDLINE | ID: mdl-19345728

ABSTRACT

Smallpox, caused by the Variola major virus, is considered to be one of the most lethal of all potential biological weapons and has far-reaching consequences. Real-time polymerase chain reaction (PCR) assays are available as a reliable diagnostic tool to detect members of the genus Orthopoxvirus. In addition real-time PCR assays specific for the variola virus have been developed that distinguish it from other orthopoxviruses. However, a positive identification of variola spp. does not classify the virus as the one that causes smallpox (V. major) or as the variant (Variola minor) that causes a much less severe form of the disease. This study reports the development of a real-time PCR minor groove binder (MGB)-Eclipse probe assay utilizing a sequence within the variola B9R/B10R gene complex that reliably differentiates V. major from V. minor by specific probe melting temperatures (T(m)s) and genotyping analysis. The MGB-Eclipse probe assay is an important step beyond the standard TaqMan-MGB assay and we feel this is a significant addition to our current variola species identification algorithm with TaqMan-MGB assays that target the B9R and B10R genes. The probe T(m)s for V. major and V. minor were 62.71 (+/-0.05) and 53.97 (+/-0.44) degrees C, respectively (P=<0.001). We also used the identical sequence to develop a TaqMan((R))-MGB assay that specifically detected V. minor but not V. major variants by qualitative analysis.


Subject(s)
DNA Probes/genetics , Genes, Viral/genetics , Smallpox/genetics , Genotype , Polymerase Chain Reaction , Smallpox/virology , Transition Temperature
16.
J Immunol ; 181(11): 7969-76, 2008 Dec 01.
Article in English | MEDLINE | ID: mdl-19017988

ABSTRACT

Vaccinia virus (VACV) affords long-lasting protection against variola virus, the agent of smallpox. VACV-reactive CD8 T cells contribute to protection but their molecular control is unknown. We show that the TNFR molecule OX40 (CD134) controls primary VACV-specific CD8 T cell expansion and antiviral cytokine production and dictates development of strong memory to both dominant and subdominant VACV epitopes. Using adoptive transfer of OX40-deficient CD8 TCR-transgenic T cells responding to Ag in the context of VACV infection, we found that this reflects a direct action of OX40 expressed by CD8 T cells. Furthermore, CD8 T cells that can protect against lethal VACV challenge do not develop in mice deficient in OX40. Thus, OX40, which has been found to play little if any role in the generation of CD8 T cells to several viruses, including lymphocytic choriomeningitis virus and influenza, plays a dominant role in shaping the CD8 T cell response to VACV. These data suggest that unique costimulatory pathways might control alternate antiviral CD8 responses, demonstrating the plasticity of the immune response in utilizing different mechanisms to achieve similar ultimate goals.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cytokines/immunology , Immunologic Memory , Receptors, OX40/immunology , Vaccinia virus/immunology , Adoptive Transfer , Animals , CD8-Positive T-Lymphocytes/transplantation , Female , Immunologic Memory/genetics , Mice , Mice, Transgenic , Receptors, OX40/genetics , Smallpox/genetics , Smallpox/immunology , Smallpox/prevention & control , Variola virus/immunology
17.
Pac Symp Biocomput ; : 100-11, 2007.
Article in English | MEDLINE | ID: mdl-17992748

ABSTRACT

Smallpox is a deadly disease that can be intentionally reintroduced into the human population as a bioweapon. While host gene expression microarray profiling can be used to detect infection, the analysis of this information using unsupervised and supervised classification techniques can produce contradictory results. Here, we present a novel computational approach to incorporate molecular genome annotation features that are key for identifying early infection biomarkers (EIB). Our analysis identified 58 EIBs expressed in peripheral blood mononuclear cells (PBMCs) collected from 21 cynomolgus macaques (Macaca fascicularis) infected with two variola strains via aerosol and intravenous exposure. The level of expression of these EIBs was correlated with disease progression and severity. No overlap between the EIBs co-expression and protein interaction data reported in public databases was found. This suggests that a pathogen-specific re-organization of the gene expression and protein interaction networks occurs during infection. To identify potential genome-wide protein interactions between variola and humans, we performed a protein domain analysis of all smallpox and human proteins. We found that only 55 of the 161 protein domains in smallpox are also present in the human genome. These co-occurring domains are mostly represented in proteins involved in blood coagulation, complement activation, angiogenesis, inflammation, and hormone transport. Several of these proteins are within the EIBs category and suggest potential new targets for the development of therapeutic countermeasures.


Subject(s)
Smallpox/diagnosis , Animals , Biomarkers , Computational Biology , Gene Expression Profiling , Genome, Human , Genome, Viral , Humans , Macaca fascicularis , Protein Interaction Mapping/statistics & numerical data , Smallpox/genetics , Smallpox/virology , Transcription, Genetic , Variola virus/genetics
18.
BMC Syst Biol ; 1: 38, 2007 Aug 24.
Article in English | MEDLINE | ID: mdl-17718913

ABSTRACT

BACKGROUND: Smallpox is a lethal disease that was endemic in many parts of the world until eradicated by massive immunization. Due to its lethality, there are serious concerns about its use as a bioweapon. Here we analyze publicly available microarray data to further understand survival of smallpox infected macaques, using systems biology approaches. Our goal is to improve the knowledge about the progression of this disease. RESULTS: We used KEGG pathways annotations to define groups of genes (or modules), and subsequently compared them to macaque survival times. This technique provided additional insights about the host response to this disease, such as increased expression of the cytokines and ECM receptors in the individuals with higher survival times. These results could indicate that these gene groups could influence an effective response from the host to smallpox. CONCLUSION: Macaques with higher survival times clearly express some specific pathways previously unidentified using regular gene-by-gene approaches. Our work also shows how third party analysis of public datasets can be important to support new hypotheses to relevant biological problems.


Subject(s)
Gene Expression Profiling , Macaca/genetics , Macaca/virology , Oligonucleotide Array Sequence Analysis , Smallpox/genetics , Systems Biology , Animals , Cell Adhesion Molecules/genetics , Computer Simulation , Cytokines/genetics , Gene Regulatory Networks , Humans , Killer Cells, Natural/immunology , Models, Genetic , Smallpox/immunology , Smallpox/mortality , Smallpox/virology , Survival Rate
19.
Novartis Found Symp ; 281: 129-36; discussion 136-40, 208-9, 2007.
Article in English | MEDLINE | ID: mdl-17534070

ABSTRACT

There is increased interest in understanding protective immunity to smallpox for two principal reasons. First, it is the only disease that has been successfully eradicated using a live virus vaccine and, second, there exists a potential threat of intentional or unintentional release of variola virus, the causative agent of smallpox. Although mortality rates associated with smallpox were as high as 40%, a significant subset of those infected recovered. The basis of susceptibility or resistance, and the immune parameters associated with recovery, are still unknown. Animal models of poxvirus infections are being employed to understand what constitutes an effective host response. Ectromelia virus is closely related to variola virus and it causes a disease similar to smallpox in mice. This model is well established, resistant and susceptible strains of mice are defined and four genetic loci associated with resistance have been identified. Susceptibility to infec tion and disease severity is also influenced by virus immune evasion strategies. The outcome of infection is clearly dictated by several factors including host and viral genes, both of which influence the immune response. Here we present data on one virus-encoded immune modifier and its effect on the functions of two host genetic loci associ ated with resistance.


Subject(s)
Disease Models, Animal , Ectromelia virus/immunology , Ectromelia, Infectious/immunology , Genetic Predisposition to Disease/genetics , Smallpox/immunology , Animals , Ectromelia, Infectious/genetics , Humans , Mice , Mice, Inbred C57BL , Smallpox/genetics
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