Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “viral pathogenesis”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 289 records · Page 16Linked to original sources
PubMed2006

Attachment and cell entry of mammalian orthoreovirus.

Mammalian orthoreoviruses (reoviruses) serve as a tractable model system for studies of viral pathogenesis. Reoviruses infect virtually all mammals, but cause disease only in the very young. Prototype strains of the three reovirus serotypes differ in pathogenesis following infection of newborn mice. Reoviruses are nonenveloped, icosahedral particles that consist of ten segments of double-stranded RNA encapsidated within two protein shells, the inner core and outer capsid. High-resolution structures of individual components of the reovirus outer capsid and a single viral receptor have been solved and provide insight into the functions of these molecules in viral attachment, entry, and pathogenesis. Attachment of reovirus to target cells is mediated by the reovirus sigma1 protein, a filamentous trimer that projects from the outer capsid. Junctional adhesion molecule-A is a serotype-independent receptor for reovirus, and sialic acid is a coreceptor for serotype 3 strains. After binding to receptors on the cell surface, reovirus is internalized via receptor-mediated endocytosis. Internalization is followed by stepwise disassembly of the viral outer capsid in the endocytic compartment. Uncoating events, which require acidic pH and endocytic proteases, lead to removal of major outer-capsid protein sigma3, resulting in exposure of membrane-penetration mediator micro1 and a conformational change in attachment protein sigma1. After penetration of endosomes by uncoated particles, the transcriptionally active viral core is released into the cytoplasm, where replication proceeds. Despite major advances in defining reovirus attachment and entry mechanisms, many questions remain. Ongoing research is aimed at understanding serotype-dependent differences in reovirus tropism, viral cell-entry pathways, the individual and corporate roles of acidic pH and proteases in viral entry, and micro1 function in membrane penetration.

Amino Acid Sequence↗
PubMed2006

Patterns of evolution of host proteins involved in retroviral pathogenesis.

BACKGROUND: Evolutionary analysis may serve as a useful approach to identify and characterize host defense and viral proteins involved in genetic conflicts. We analyzed patterns of coding sequence evolution of genes with known (TRIM5alpha and APOBEC3G) or suspected (TRIM19/PML) roles in virus restriction, or in viral pathogenesis (PPIA, encoding Cyclophilin A), in the same set of human and non-human primate species. RESULTS AND CONCLUSION: This analysis revealed previously unidentified clusters of positively selected sites in APOBEC3G and TRIM5alpha that may delineate new virus-interaction domains. In contrast, our evolutionary analyses suggest that PPIA is not under diversifying selection in primates, consistent with the interaction of Cyclophilin A being limited to the HIV-1M/SIVcpz lineage. The strong sequence conservation of the TRIM19/PML sequences among primates suggests that this gene does not play a role in antiretroviral defense.

Animals↗
PubMed2006

Defective interfering RNAs of Japanese encephalitis virus found in mosquito cells and correlation with persistent infection.

Defective interfering (DI) RNAs are deletion mutants of viral genomes that are known in many cases to contribute to persistent infection and modification of viral pathogenesis. Cell type also plays a critical role in the establishment of viral persistence. In this study we have identified for the first time the generation of DI RNAs of Japanese encephalitis virus in C6/36 mosquito cells. A persistent infection was established by replacing growth medium on surviving cells and continued cell passaging. Persistent infection was demonstrated by a continual release of infectious virus, fluorescent antibody staining, and Northern analysis. A population of DI RNAs of approximately 8.2-9.7 kb, not detectable in acutely infected cells, became apparent in the persistently infected cells by 25 days postinfection. Sequence analyses revealed a population of DI RNAs that contained in-frame deletions of 1.3-2.8 kb covering the region of the E gene and some flanking C or prM and NS1 gene sequences. Transcripts from one cDNA clone of a DI RNA replicated in uninfected mosquito cells as demonstrated by RT-PCR. DI RNA-containing virions in supernatant fluids from persistently infected mosquito cells could be used to establish persistent infection in BHK-21 cells. The correlation of DI RNA presence with cell survival suggests that DI RNAs are contributing mechanistically to the establishment of persistent infection in both the mosquito and mammalian cells.

Animals↗
PubMed2006

hsp72, a host determinant of measles virus neurovirulence.

Transient hyperthermia such as that experienced during febrile episodes increases expression of the major inducible 70-kDa heat shock protein (hsp72). Despite the relevance of febrile episodes to viral pathogenesis and the multiple in vitro roles of heat shock proteins in viral replication and gene expression, the in vivo significance of virus-heat shock protein interactions is unknown. The present work determined the in vivo relationship between hsp72 levels and neurovirulence of an hsp72-responsive virus using the mouse model of measles virus (MV) encephalitis. Transgenic C57BL/6 mice were created to constitutively overexpress hsp72 in neurons, and these mice were inoculated intracranially with Edmonston MV (Ed MV) at 42 h of age. The mean viral RNA burden in brain was approximately 2 orders of magnitude higher in transgenic animals than in nontransgenic animals 2 to 4 weeks postinfection, and this increased burden was associated with a fivefold increase in mortality. Mice were also challenged with an Ed MV variant exhibiting an attenuated in vitro response to hsp72-dependent stimulation of viral transcription (Ed N-522D). This virus exhibited an attenuated neuropathogenicity in transgenic mice, where mortality and viral RNA burdens were not significantly different from nontransgenic mice infected with either Ed N-522D or parent Ed MV. Collectively, these results indicate that hsp72 levels can serve as a host determinant of viral neurovirulence in C57BL/6 mice, reflecting the direct influence of hsp72 on viral gene expression.

Animals↗
PubMed2002

Infection of macaques with a molecular clone, SHIVSF33A2, provides evidence for tissue specific variants.

Infection of rhesus macaques with chimeric simian-human immunodeficiency viruses (SHIV) is an established model to study acquired immunodeficiency syndrome (AIDS) pathogenesis. Such a controlled system allows for detailed analysis of the molecular determinants of viral pathogenesis in addition to studying host-specific immune responses that modulate disease progression. Furthermore, the use of a pathogenic molecular clone affords the opportunity to study both viral evolution within a host and to examine the generation of tissue specific variants. In this report we describe viral diversification within tissues of two rhesus macaques infected intravenously with the CXCR4-specific molecular clone SHIVSF33A2. Heteroduplex tracking analysis (HTA) was used to determine the complexity of viral DNA within distinct lymphoid tissues. Not surprising, heterogeneity of the proviral quasispecies in tissues obtained during the acute infection was limited. However, tissues obtained at necropsy harbored a more diverse and often different population of env variants. As the inoculating virus is a molecular clone, the variants generated are likely due to the presence of tissue specific selective forces rather than a founder's effect.

Animals↗
PubMed1995

Comparative pathogenesis of Autographa californica M nuclear polyhedrosis virus in larvae of Trichoplusia ni and Heliothis virescens.

We compared early viral pathogenesis and dose-mortality relationships for larvae of two highly susceptible hosts, Trichoplusia ni and Heliothis virescens, using a construct of AcMNPV containing the lacZ reporter gene. Larvae were inoculated either as newly molted fourth instars (4(0)) or 15 hr after the molt (4(15)). In 4(0)-inoculated larvae, first lacZ expression was detected in the midgut epithelium of T. ni at 4 hr postinoculation (hpi) compared to 18 hpi in H. virescens, and systemic infections were initiated from tracheole cells servicing the midgut epithelia beginning at 12 and 20 hpi, respectively. The longer viral tenure within the midgut and the slower progression of systemic infections within H. virescens ultimately contributed to its longer time to death. For 4(0)-inoculated H. virescens, proportions of lacZ-expressing larvae increased from 18 hpi until the onset of the molt to the fifth instar at 36 hpi; at this time point, the proportion of signaling insects equaled the final larval mortality. Viral infections within the midgut epithelium of H. virescens were lost during the molt to the fifth instar. Dose-mortality relationships suggested that the peritrophic membrane provided little protection from AcMNPV infections for either species.

Analysis of Variance↗
PubMed1995

Serial passage of microglial SIV results in selection of homogeneous env quasispecies in the brain.

The pathogenic effects of HIV include infection of the central nervous system (CNS) which can result in cognitive and motor dysfunction. Simian immunodeficiency virus (SIV) infection of rhesus macaques provides an excellent model of HIV-induced disease. We have achieved a reproducible infection of the CNS using a stock of virus obtained by serial passage of microglia-associated SIV. Since the envelope genes of both HIV and SIV encode determinants important in viral pathogenesis, and the variability inherent in these viruses provides a molecular footprint of viral quasispecies, we analyzed the viral env sequences resulting from this serial passage. SIV env sequences were analyzed by direct PCR amplification of DNA isolated from microglia from infected animals. Nucleotide sequence comparison reveals that serial passage of microglia-associated SIV resulted in divergence from the donor stock of virus. Furthermore, an enrichment of unique env quasispecies which is maintained through the serial passage was found in the diseased brains.

Amino Acid Sequence↗
PubMed1989

RNA virus evolution and the control of viral disease.

RNA viruses and other RNA genetic elements must be viewed as organized distributions of sequences termed quasi-species. This means that the viral genome is statistically defined but individually indeterminate. Stable distributions may be maintained for extremely long time periods under conditions of population equilibrium. Perturbation of equilibrium results in rapid distribution shifts. This genomic organization has many implications for viral pathogenesis and disease control. This review has emphasized the problem of selection of viral mutants resistant to antiviral drugs and the current difficulties encountered in the design of novel synthetic vaccines. Possible strategies for antiviral therapy and vaccine development have been discussed.

Animals↗
PubMed2001

Influenza virus ns1 protein induces apoptosis in cultured cells.

The importance of influenza viruses as worldwide pathogens in humans, domestic animals, and poultry is well recognized. Discerning how influenza viruses interact with the host at a cellular level is crucial for a better understanding of viral pathogenesis. Influenza viruses induce apoptosis through mechanisms involving the interplay of cellular and viral factors that may depend on the cell type. However, it is unclear which viral genes induce apoptosis. In these studies, we show that the expression of the nonstructural (NS) gene of influenza A virus is sufficient to induce apoptosis in MDCK and HeLa cells. Further studies showed that the multimerization domain of the NS1 protein but not the effector domain is required for apoptosis. However, this mutation is not sufficient to inhibit apoptosis using whole virus.

Animals↗
PubMed2006

Toll-like receptors, innate immunity and HSV pathogenesis.

In the last decade, substantial progress has been made in understanding the molecular mechanisms involved in initial host responses to viral infections, and how viral recognition leads to the innate responses that ultimately shape the adaptive immune response. Viruses, including herpes simplex virus (HSV) types 1 and 2, trigger toll-like receptors (TLRs) that elicit cytokine and chemokine production. In turn, this can create local resistance and modulate T- and B-cell-mediated immunity. TLR activation by HSV-produced molecules (or other synthetic agonists) leads to the remodelling of draining lymph nodes. This enhances the screening of naive T-cells, from which antigen-specific lymphocytes can be selected and expanded. The innate response thereby serves to direct a timely and effective acquired immune response, through the initial TLR recognition of viral pathogen-associated molecular patterns that can limit or possibly exacerbate viral pathogenesis. Recently, these findings have been exploited by strategies that utilize synthetic TLR agonists as prophylactic or therapeutic devices. Such devices prime innate immune responses, enhancing host resistance to viral infections, including experimental HSV infections.

Herpes Simplex↗
PubMed2005

Nonstructural protein sigma1s is a determinant of reovirus virulence and influences the kinetics and severity of apoptosis induction in the heart and central nervous system.

The mechanisms by which viruses kill susceptible cells in target organs and ultimately produce disease in the infected host remain poorly understood. Dependent upon the site of inoculation and strain of virus, experimental infection of neonatal mice with reoviruses can induce fatal encephalitis or myocarditis. Reovirus-induced apoptosis is a major mechanism of tissue injury, leading to disease development in both the brain and heart. In cultured cells, differences in the capacity of reovirus strains to induce apoptosis are determined by the S1 gene segment, which also plays a major role as a determinant of viral pathogenesis in both the heart and the central nervous system (CNS) in vivo. The S1 gene is bicistronic, encoding both the viral attachment protein sigma-1 and the nonstructural protein sigma-1-small (sigma1s). Although sigma1s is dispensable for viral replication in vitro, we wished to investigate the expression of sigma1s in the infected heart and brain and its potential role in reovirus pathogenesis in vivo. Two-day-old mice were inoculated intramuscularly or intracerebrally with either sigma1s(-) or sigma1s(+) reovirus strains. While viral replication in target organs did not differ between sigma1s(-) and sigma1s(+) viral strains, virus-induced caspase-3 activation and resultant histological tissue injury in both the heart and brain were significantly reduced in sigma1s(-) reovirus-infected animals. These results demonstrate that sigma1s is a determinant of the magnitude and extent of reovirus-induced apoptosis in both the heart and CNS and thereby contributes to reovirus pathogenesis and virulence.

Animals↗
PubMed2004

Inhibition of PKR by vaccinia virus: role of the N- and C-terminal domains of E3L.

The process of eukaryotic translation initiation can be regulated by a highly conserved mechanism involving the phosphorylation of the translation initiation factor eIF2 on the alpha subunit. This mechanism is recognized as an efficient step in the host antiviral response. Vaccinia virus (VV), like many other viruses, encodes proteins to overcome this inhibitory process. The C-terminus of the vaccinia virus E3L is known to bind to double-stranded RNA (dsRNA) thereby sequestering the activator of this antiviral response. In this report, the N-terminus of E3L was found to be required for the additional regulation of eIF2alpha phosphorylation. This phosphorylation event did not lead to a global shutdown in protein synthesis. Because the N-terminus of E3L is required for full viral pathogenesis in mice, these results suggest an alternative role of eIF2alpha phosphorylation in regulating viral replication.

Animals↗
PubMed2006

Emerging respiratory viruses: challenges and vaccine strategies.

The current threat of avian influenza to the human population, the potential for the reemergence of severe acute respiratory syndrome (SARS)-associated coronavirus, and the identification of multiple novel respiratory viruses underline the necessity for the development of therapeutic and preventive strategies to combat viral infection. Vaccine development is a key component in the prevention of widespread viral infection and in the reduction of morbidity and mortality associated with many viral infections. In this review we describe the different approaches currently being evaluated in the development of vaccines against SARS-associated coronavirus and avian influenza viruses and also highlight the many obstacles encountered in the development of these vaccines. Lessons learned from current vaccine studies, coupled with our increasing knowledge of the host and viral factors involved in viral pathogenesis, will help to increase the speed with which efficacious vaccines targeting newly emerging viral pathogens can be developed.

Animals↗
PubMed1989

Nucleic acid amplification in vitro: detection of sequences with low copy numbers and application to diagnosis of human immunodeficiency virus type 1 infection.

The enzymatic amplification of specific nucleic acid sequences in vitro has revolutionized the use of nucleic acid hybridization assays for viral detection. With this method, the copy number of a pathogen-specific sequence is increased several orders of magnitude before detection is attempted. The sensitivity and specificity of detection are thus markedly improved. Mullis and Faloona devised the first method of sequence amplification in vitro, the polymerase chain reaction (K.B. Mullis and F.A. Faloona, Methods Enzymol. 155:355-350, 1987). By this method, synthetic oligonucleotide primers direct repeated, target-specific, deoxyribonucleic acid-synthetic reactions, resulting in an exponential increase in the amount of the specific target sequence. The application of sequence amplification to viral detection was initially performed with human immunodeficiency virus type 1 and human T-cell lymphoma virus type I. In principle, however, this approach can be applied to the detection of any deoxyribonucleic or ribonucleic acid virus; the only requirement is that sufficient nucleotide sequence data exist to allow the synthesis of target-specific oligonucleotide primers. The use of target amplification in vitro will permit a variety of studies of viral pathogenesis which have not been feasible because of the low copy number of the viral nucleic acids in infected material. This approach is particularly applicable to the study of human retroviral infections, which are chronic and persistent and are characterized by low titers of virus in tissues. In addition, target amplification in vitro will facilitate the development of new methods of sequence detection, which will be useful for rapid viral diagnosis in the clinical laboratory.

Acquired Immunodeficiency Syndrome↗
PubMed2026

Application of emerging technologies in the antiviral field.

Viral diseases pose a serious threat to global public health, agriculture, and biosecurity. Conventional antiviral strategies are often limited by an incomplete understanding of disease mechanisms, poor targeting precision, and slow response times. Emerging technologies are now reshaping the landscape of antiviral research. This review examines the roles of four key frontiers, including organoid models, gene editing, AI-driven molecular design, and synthetic biology. Organoids provide physiologically relevant platforms that model virus-host interactions and disease progression. Viral infections remain a major challenge to human and animal health, agriculture, and biosecurity. Progress in antiviral research is constrained by the complexity of viral pathogenesis, the diversity and rapid evolution of viruses, and the limited translational relevance of some traditional model systems. Recent advances in organoid technology, gene editing, artificial intelligence, and synthetic biology are expanding the toolkit available for antiviral research and development. In this review, we discuss how these four technological frontiers contribute to disease modeling, target discovery, molecular design, and translational innovation. Organoids, in particular, provide physiologically relevant systems for investigating viral infection, tissue tropism, host responses, and pathogenesis. Gene editing tools, such as CRISPR, enable precise manipulation of host and viral genomes, facilitating the development of resistant organisms and next-generation vaccine platforms. AI technologies, including AlphaFold for structure prediction and platforms for de novo protein design, address long-standing bottlenecks in structural biology and offer powerful means to engineer antiviral proteins, antibodies, and vaccine antigens. Synthetic biology, guided by the Design-Build-Test-Learn cycle, integrates computational design, genetic assembly, and functional validation into a cohesive pipeline. Together, these technologies form a synergistic workflow that spans disease modeling, target discovery, molecular design, construction, testing, and iterative optimization. This integrated approach is shifting antiviral development from traditional empirical methods toward more precise, intelligent strategies. The review also highlights ongoing challenges in integration and scalability, stressing that high-quality biological datasets and stronger interdisciplinary collaboration are essential for realizing translational potential. By presenting a cohesive view of these converging methodologies, this review offers a framework to guide the intelligent evolution of antiviral strategies in both human and animal health.

Antiviral↗
PubMed2003

The double-stranded RNA-activated protein kinase mediates viral-induced encephalitis.

The double-stranded (ds) RNA-activated protein kinase (PKR) plays an important role in control of viral infections and cell growth. We have studied the role of PKR in viral infection in mice that are defective in the PKR signaling pathway. Transgenic mice were derived that constitutively express a trans-dominant-negative kinase-defective mutant PKR under control of the beta-actin promoter. The trans-dominant-negative PKR mutant expressing transgenic mice do not have a detectable phenotype, similar to observations with PKR knock-out mice. The requirement for PKR in viral pathogenesis was studied by intracerebral infection of mice with a mouse-adapted poliovirus. Histopathological analysis revealed diffuse encephalomyelitis with severe inflammatory lesions throughout the central nervous system (CNS) in infected wild-type mice. In contrast, histopathological evaluation of virus-injected trans-dominant-negative PKR transgenic mice as well as PKR knock-out mice yielded no signs of tissue damage associated with inflammatory host responses. However, the virus did replicate in both models of PKR-deficient mice at a level equal to that observed in wild-type infected mice. Although the results indicate a clear difference in susceptibility to poliovirus-induced encephalitis, this difference manifests clinically as a slight delay in fatal neuropathy in trans-dominant-negative PKR transgenic and PKR knock-out animals. Our observations support the finding that viral-induced PKR activation may play a significant role in pathogenesis by mediating the host response to viral CNS infection. They support PKR to be an effective target to control tissue damage due to deleterious host responses to viral infection.

Animals↗
PubMed1995

Expression of the chemokine receptor BLR2/EBI1 is specifically transactivated by Epstein-Barr virus nuclear antigen 2.

In our attempt to identify chemokine receptors that are related to Burkitt's lymphoma receptor 1 (BLR1) and are expressed in activated lymphocytes we used RT-PCR resulting in the isolation of a cDNA encoding a seven transmembrane receptor termed BLR2. The protein shows significant sequence similarities to the family of G-protein coupled chemokine receptors and turned out to be identical to the recently described receptor EBI1. Northern blot analysis revealed that BLR2 mRNA could be highly stimulated in mitogen- and anti-CD3-treated peripheral blood lymphocytes. BLR2-specific mRNA could be detected in all Epstein-Barr virus positive B cell lines. We show that transcription of the BLR2 gene could be specifically induced in Epstein-Barr virus negative BL 41 cells via estrogen-mediated activation of Epstein-Barr virus nuclear antigen 2, a key regulator of viral and cellular genes in immortalized B cells. Our data suggest an involvement of BLR2 in the regulation of migration in activated lymphocytes and in viral pathogenesis.

Antigens, Viral↗
PubMed2005

Baculovirus-mediated promoter assay and transcriptional analysis of white spot syndrome virus orf427 gene.

BACKGROUND: White spot syndrome virus (WSSV) is an important pathogen of the penaeid shrimp with high mortalities. In previous reports, Orf427 of WSSV is characterized as one of the three major latency-associated genes of WSSV. Here, we were interested to analyze the promoter of orf427 and its expression during viral pathogenesis. RESULTS: in situ hybridization revealed that orf427 was transcribed in all the infected tissues during viral lytic infection and the translational product can be detected from the infected shrimp. A time-course RT-PCR analysis indicated that transcriptional products of orf427 could only be detected after 6 h post virus inoculation. Furthermore, a baculovirus-mediated promoter analysis indicated that the promoter of orf427 failed to express the EGFP reporter gene in both insect SF9 cells and primary shrimp cells. CONCLUSION: Our data suggested that latency-related orf427 might not play an important role in activating virus replication from latent phase due to its late transcription during the lytic infection.

Journal Article↗