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PubMed1996

Host-bacteria interactions in foreign body infections.

Persistent staphylococcal infections are a major medical problem, especially when they occur on implanted materials or intravascular catheters. This review describes some of the recently discovered molecular mechanisms of Staphylococcus aureus attachment to host proteins coating biomedical implants. These interactions involve specific surface proteins, called bacterial adhesins, that recognize specific domains of host proteins deposited on indwelling devices, such as fibronectin, fibrinogen, or fibrin. Elucidation of molecular mechanisms of S aureus adhesion to the different host proteins may lead to the development of specific inhibitors blocking attachment of S aureus, which may decrease the risk of bacterial colonization of indwelling devices.

Adhesins, Bacterial↗
PubMed1997

Chlamydia psittaci infection in sheep: a paradigm for human reproductive tract infection.

Chlamydiae are important reproductive tract pathogens in a wide variety of animals. In humans, chronic or repeated infection of the female genital tract with Chlamydia trachomatis has been identified as a significant factor in the development of occlusive infertility or increased risk of ectopic pregnancy. The spectrum of reproductive disease recognized in sheep to be caused by Chlamydia psittaci has been primarily restricted to pregnant animals because the organism was clearly identified as a major cause of infectious abortion. However, following pregnancy failure, a chronic chlamydial infection can become established in the reproductive tracts of experimentally infected ewes. Persistent infection of the ewe's reproductive tract may eventually result in pathology, similar to that observed in women infected with C. trachomatis, thus decreasing the breeding life of affected ewes. Furthermore, ewes that experienced C. psittaci induced abortion provide a unique opportunity to study the host: parasite dynamic as it relates to persistent infection. This natural model of persistent infection may, in some ways, be superior to more contrived models in which the chlamydial isolate is not a normal reproductive pathogen of the study animal. Thus, the study of persistent chlamydial infection in sheep may be used for the benefit of both human and veterinary medicine.

Abortion, Veterinary↗
PubMed2003

Molecular mechanisms regulating persistent Mycobacterium tuberculosis infection.

Establishing persistent infection and resisting elimination by the host's immune system are key factors contributing to latent infection by Mycobacterium tuberculosis. Recently, bacterial determinants regulating these processes have been identified. Here, we review molecular mechanisms regulating persistent infection and discuss the highly dynamic interaction of M. tuberculosis with the host.

Animals↗
PubMed1989

Persistent poliovirus infection of human neuroblastoma cells.

Two human neuroblastoma cell lines were persistently infected with poliovirus strains of all three serotypes. In persistently infected IMR-32 cells, which were studied in greatest detail, viral antigens were present in most cells, and over a 9-month period virions were found in the medium at high titers. Persistently infected cells were resistant to superinfection by Sabin 1, 2, and 3 poliovirus but sensitive to coxsackievirus B3. The viruses recovered from persistently infected cells were studied for conservation of epitopes, host cell specificity, and temperature resistance phenotype. The antigenic site 1 carried by the major capsid protein VP1 was modified on the persistent viruses of all three serotypes. This was confirmed for one virus by sequencing the corresponding genomic region in which two mutations were detected. The titers of persistent viruses were 1-3 log10 units higher on IMR-32 cells than on nonneuronal HEp-2 cells, while parental viruses had similar titers on both lines. When thermosensitive viruses were used to initiate the infection, the persistent viruses were found to be thermoresistant at 39 degrees C. Together the results indicate that the persistent infection correlated with the selection of highly mutated viral strains. Poliovirus-infected neuroblastoma cell lines thus constitute an in vitro model of chronic viral infections, which are increasingly implicated in human neural diseases.

Cell Line↗
PubMed1982

Role of the S4 gene in the establishment of persistent reovirus infection in L cells.

We have studied the viral genes playing a role in persistence of reovirus in L cells. We established persistent infections by coinfecting L cells using wild-type reovirus type 2 and defective reovirus type 3. An analysis of the genomic double-stranded RNA pattern of the virus population selected during persistent infection revealed that the S4 gene was derived from the defective parent in three independently established lines, suggesting that the S4 gene plays an essential role in the establishment of persistent infection. The selection of recombinant viruses containing the S4 gene derived from the defective virus was specific for persistent infection, since it was not selected in lytic infections. Following the establishment of persistent infection, mutations in the S1 gene appeared in two of three cell lines. Thus mutations in the S4 gene play a critical role in the establishment of persistent infection, while mutations in the S1 gene play a role in the maintenance of the persistent infection.

Animals↗
PubMed1980

Host response to Treponema pallidum in intradermally-infected rabbits: evidence for persistence of infection at local and distant sites.

Intradermal infection of rabbits with Treponema pallidum imitiates rapid and active cellular response at the site of injection. During the first 2 weeks following infection, there is a marked increase in the numbers of organisms at the site of infection. Systemic dissemination of treponemes occurs during the early stage of infection, presumably before the immune response is fully mobilized. The mononuclear infiltration, which is apparent at the lesion site one week postinfection, becomes more pronounced at 2 weeks. The infiltrating cells are predominantly T lymphocytes and macrophages. By 4 weeks postinfection, most of the organisms have been cleared from the primary site; however, low numbers of treponemes survive locally and in distant tissues. Thus, whereas infection with T. pallidum appears to activate immune mechanisms which are capable of clearing most of the organisms from the primary lesion, some organisms are able to evade these mechanisms and persist in vivo.

Animals↗
PubMed2006

Reprogramming of antiviral T cells prevents inactivation and restores T cell activity during persistent viral infection.

Failure to clear persistent viral infections results from the early loss of T cell activity. A pertinent question is whether the immune response is programmed to fail or if nonresponsive T cells can specifically be fixed to eliminate infection. Although evidence indicates that T cell expansion is permanently programmed during the initial priming events, the mechanisms that determine the acquisition of T cell function are less clear. Herein we show that in contrast to expansion, the functional programming of T cell effector and memory responses in vivo in mice is not hardwired during priming but is alterable and responsive to continuous instruction from the antigenic environment. As a direct consequence, dysfunctional T cells can be functionally reactivated during persistent infection even after an initial program of inactivation has been instituted. We also show that early therapeutic reductions in viral replication facilitate the preservation of antiviral CD4+ T cell activity, enabling the long-term control of viral replication. Thus, dysfunctional antiviral T cells can regain activity, providing a basis for future therapeutic strategies to treat persistent viral infections.

Adoptive Transfer↗
PubMed1994

Virus-induced immunosuppression: kinetic analysis of the selection of a mutation associated with viral persistence.

Infection of neonatal mice with lymphocytic choriomeningitis virus (LCMV) strain Armstrong (ARM) results in a lifelong persistent infection. Viral variants (cytotoxic T lymphocyte [CTL] negative, persistence positive [CTL- P+]) can be isolated from the lymphoid tissues of such mice. Adult mice inoculated with these CTL- P+ viruses fail to generate sufficient cytotoxic T lymphocytes to clear the acute infection and become persistently infected. By contrast, inoculation of a similar dose of the parental ARM virus (CTL+ P-) into adult mice leads to the generation of a vigorous virus-specific CTL response that clears the infection. Sequence analysis revealed a phenylalanine (Phe)-to-Leucine (Leu) change at amino acid 260 of the viral glycoprotein (GP) as a marker for variant viruses with the CTL- P+ phenotype. An RNA PCR assay that detects the variant GP sequence and thus allows kinetic studies of the selection of the Leu at position 260 was developed. We found that although CTL- P+ viruses are known to be lymphotropic, mature T and B cells were not required for the generation and selection of the Leu at GP amino acid 260. Kinetically, in mice infected at birth with LCMV ARM, as early as 3 weeks postinfection the Phe-to-Leu change was found in virus in the serum. By 5 weeks, viral nucleic acid obtained from peritoneal macrophages, spleen, lymph nodes, and liver showed the Phe-to-Leu change. At 2 months postinfection, the Leu change was detected in virus from the thymus, heart, lung, and kidney. By contrast, virus replicating in the central nervous system showed only minimal levels of the Leu change by 4 months and as long as 1 year postinfection. In vitro studies showed that the parental LCMV ARM CTL+ P- virus replicates more efficiently and outcompetes CTL- P+ virus in a cultured neuronal cell line, indicating that differential growth properties in neurons are likely the basis for the selection of the parental virus over the CTL- P+ variant in the brain.

Amino Acid Sequence↗
PubMed2006

Plus- and minus-stranded foot-and-mouth disease virus RNA quantified simultaneously using a novel real-time RT-PCR.

Even though tagged RT-PCR and rTth RT-PCR have been developed to improve strand-specific detection of RNA virus, these assays are not quantitative. In this study, a novel real-time RT-PCR assay, which combines the benefits of both the tagged and rTth RT-PCR has been developed to quantify the strand-specific RNA of foot-and-mouth disease virus (FMDV). The tagged-primers plus a TaqMan probe located within the highly conserved viral 3D region were used. The in vitro synthesized minus-and plus-stranded RNA templates were used as a dual control along with the copy number of viral RNA molecules, which is more reliable than reported RT-PCR employing a DNA-based standard. This assay was used to quantify FMDV RNA from 10(9) to 10(1) copies with a maximum sensitivity of between ten and five copies and was shown to be highly reproducible with low intra-and inter-assay variation. Coefficients of variation (CV) values were 0.70-1.39% and 0.98-2.1%, respectively. Importantly, the method was applied to simultaneously quantify both plus-stranded and minus-stranded FMDV RNA using tagged-RT and tagged-FP primer during a high-temperature reverse transcription. Highly sensitive and strand-specific real-time RT-PCR assay has been established. We tested the ratio of viral plus-stranded to minus-stranded RNA in acutely infected and persistently infected BHK-21 cells, for which the values ranged from 22/1 to 143/1 and from 287/1 to 334/1, respectively, suggesting different replication patterns of plus-and minus-stranded RNA in acutely infected and persistently infected cells. This value ranged from 83/1 to 93/1 in enriched FMDV virions, indicating that FMDV encapsidation is highly specific for plus-stranded RNAs. In addition, the method was applied to surveille the FMDV replication at animal level.

Animals↗
PubMed1978

Susceptibility of mice to acute and persistent measles infection.

Intracerebral inoculation of neonatal mice with the Edmonston strain of measles virus produced an acute, lethal encephalitis and thymic dysplasia in susceptible mice. There was an age-related development of resistance to infection. This resistance was strain-dependent and appeared to be associated with the extent of virus growth in the brain. Studies on the genetic basis for susceptibility, using hybrid and backcross mice, revealed that the principal determinant of host resistance to acute infection was a dominant gene or genes which segregated independently of the H-2 complex. A small number of survivors of the acute infection showed persistence of measles virus antigens in the cerebellum and spleen for up to 2 months after inoculation. However, the low frequency of this persistence indicated that, at this time, intracerebral inoculation of neonatal mice with the Edmonston strain of measles virus constitutes a difficult model for the study of persistant measles infection.

Acute Disease↗
PubMed1999

Protection against establishment of retroviral persistence by vaccination with a live attenuated virus.

Many human viruses not only cause acute diseases but also establish persistent infections. Such persistent viruses can cause chronic diseases or can reactivate to cause acute diseases in AIDS patients or patients receiving immunosuppressive therapies. While the prevention of persistent infections is an important consideration in the design of modern vaccines, surprisingly little is known about this aspect of protection. In the current study, we tested the feasibility of vaccine prevention of retroviral persistence by using a Friend virus model that we recently developed. In this model, persistent virus can be detected at very low levels by immunosuppressing the host to reactivate virus or by transferring persistently infected spleen cells into highly susceptible mice. Two vaccines were analyzed, a recombinant vaccinia virus vector expressing Friend virus envelope protein and a live attenuated Friend virus. Both vaccines reduced pathogenic virus loads to levels undetectable by infectious center assays. However, only the live, attenuated vaccine prevented immunosuppression-induced reactivation of persistent virus. Thus, even very low levels of persistent Friend virus posed a significant threat during immunosuppression. Our results demonstrate that vaccine protection against establishment of retroviral persistence is attainable.

Animals↗
PubMed1996

Persistent reovirus infections of L cells select mutations in viral attachment protein sigma1 that alter oligomer stability.

During maintenance of L-cell cultures persistently infected with reovirus, mutations are selected in viruses and cells. Cells cured of persistent infection support growth of viruses isolated from persistently infected cultures (PI viruses) significantly better than that of wild-type (wt) viruses. In a previous study, the capacity of PI virus strain L/C to grow better than wt strain type 1 Lang (T1L) in cured cells was mapped genetically to the S1 gene (R. S. Kauffman, R. Ahmed, and B. N. Fields, Virology 131:79-87, 1983), which encodes viral attachment protein sigma1. To investigate mechanisms by which mutations in S1 confer growth of PI viruses in cured cells, we determined the S1 gene nucleotide sequences of L/C virus and six additional PI viruses isolated from independent persistently infected L-cell cultures. The S1 sequences of these viruses contained from one to three mutations, and with the exception of PI 2A1 mutations in each S1 gene resulted in changes in the deduced amino acid sequence of sigma1 protein. Using electrophoresis conditions that favor migration of sigma1 oligomers, we found that sigma1 proteins of L/C, PI 1A1, PI 3-1, and PI 5-1 migrated as monomers, whereas sigma1 proteins of wt reovirus and PI 2A1 migrated as oligomers. These findings suggest that mutations in sigma1 protein affecting stability of sigma1 oligomers are important for the capacity of PI viruses to infect mutant cells selected during persistent infection. Since no mutation was found in the deduced amino acid sequence of PI 2A1 sigma1 protein, we used T1L X PI 2A1 reassortant viruses to identify viral genes associated with the capacity of this PI virus to grow better than wt in cured cells. The capacity of PI 2A1 to grow better than T1L in cured cells was mapped to the S4 gene, which encodes outer-capsid protein sigma3. This finding suggests that in some cases, mutations in sigma3 protein in the absence of sigma1 mutations confer growth of PI viruses in mutant cells. To confirm the importance of the S1 gene in PI virus growth in cured cells, we used T1L X PI 3-1 reassortant viruses to genetically map the capacity of this PI virus to grow better than wt in cured cells. In contrast to our results using PI 2A1, we found that growth of PI 3-1 in cured cells was determined by the sigma1-encoding S1 gene. Given that the sigma1 and sigma3 proteins play important roles in reovirus disassembly, findings made in this study suggest that stability of the viral outer capsid is an important determinant of the capacity of reoviruses to adapt to host cells during persistent infection.

Animals↗
PubMed1981

Characteristics of a persistent rubella infection in a human cell line.

A persistent infection of the human MCF-7 cell line (MCF-7RV) was established with the DBS strain of rubella virus at a low multiplicity of infections. Fluorescent antibody staining revealed that 100% of the cells were positive for rubella antigens. The infected cells were refractory to superinfection with vesicular stomatitis virus (VSV) but were susceptible to herpes simplex virus type 2 (HSV-2). No interferon could be detected in infected cell culture fluid, and continuous passage in the presence of antibody did not lead to a decrease in the percentage of infected cells. Virus production in the persistently infected cells represented a 5- to 10-fold increase over primary infection. Plaque assays at 30 and 39 degree C of the virus produced at 37 degree C revealed the presence of temperature-sensitive (ts) mutants. If MCF-7RV cells were maintained at 30 degree C, significant increases in virus production were observed, leading to cytopathic effect and destruction of the monolayer. If maintained at 39 degree C, MCF-7RV cells produced less virus and demonstrated normal morphology. These data suggest that the naturally selected population of ts mutants being produced by these cells represents the mechanism by which persistence is maintained.

Breast↗
PubMed1995

Eradication of persistent reovirus infection from a B-cell hybridoma.

The 2G10 B-cell hybridoma was found to be persistently infected with reovirus serotype 3 (RV3). The persistently infected 2G10 culture produced approximately 1 x 10(8) plaque-forming units of virus per milliliter of culture lysate, and a majority of cells in the culture were infected, as determined by infectious center assay and immunocytochemistry. Cure of the persistent infection was achieved by passaging 2G10 cells for 33 days (12 passages) in medium containing polyclonal anti-RV3 antiserum and a monoclonal antibody specific for the RV3 attachment protein. After several passages in antibody-free medium, cured 2G10 cells had (1) nondetectable levels of RV3 in cell-culture lysates, (2) no infectious centers per 3 x 10(5) cells, (3) no immunocytochemically detectable RV3 antigen, and (4) no detectable reovirus-specific RNA by reverse transcription-polymerase chain reaction amplification. Additionally, mice inoculated with cured 2G10 cell lysates did not generate antibodies directed against RV3. These observations demonstrate that persistent reovirus infection of a B-cell hybridoma can be cured by passage in medium containing anti-reovirus antibodies and suggest that the maintenance of this persistent infection is dependent on horizontal cell-to-cell transmission of virus in the culture.

Animals↗
PubMed1998

Viruses and cells with mutations affecting viral entry are selected during persistent rotavirus infections of MA104 cells.

To better understand mechanisms of persistent rotavirus infections of cultured cells, we established independent, persistently infected cultures of MA104 cells, using rotavirus strain SA11. The cultures were either passaged when the cells reached confluence or supplemented with fresh medium every 7 days. Viral titers in culture lysates varied from 10(4) to 10(7) PFU per ml during 350 days of culture maintenance. Trypan blue staining indicated that 72 to 100% of cells in the cultures were viable, and immunocytochemical staining using a monoclonal antibody directed against viral protein VP6 demonstrated that 38 to 63% of the cells contained rotavirus antigen. We tested the capacity of rotaviruses isolated from the persistently infected cultures (PI viruses) to infect cells cured of persistent infection. Although wild-type (wt) and PI viruses produced equivalent yields in parental MA104 cells, PI viruses produced greater yields than wt virus in cured cells, which indicates that viruses and cells coevolve during persistent rotavirus infections of MA104 cells. To determine whether mutations in viruses and cells selected during these persistent infections affect viral entry, we tested the effect of trypsin treatment of the viral inoculum on growth of wt and PI viruses. Trypsin pretreatment is required for postattachment penetration of rotavirus virions into cells. In contrast to the case with wt virus, PI viruses produced equivalent yields with and without trypsin pretreatment in parental MA104 cells. However, PI viruses required trypsin pretreatment for efficient growth in cured cells. These results indicate that mutant viruses and cells are selected during maintenance of persistent rotavirus infections of MA104 cells and suggest that mutations in each affect trypsin-dependent steps in rotavirus entry.

Biological Evolution↗
PubMedDate not supplied

Cytoimmunotherapy for persistent virus infection reveals a unique clearance pattern from the central nervous system.

The mechanism(s) by which infectious or malignant material is cleared by the host has long been an area of intensive study. We have used the murine model of infection with lymphocytic choriomeningitis virus (LCMV) to look at immune clearance during persistent infection. LCMV was selected because the mouse is its natural host, it easily induces acute or persistent infection in vivo, and the mechanism by which it is cleared in vivo during acute infection is now well understood. Clearance, although associated with several antiviral immune effector mechanisms, is primarily dependent on the activity of virus-specific cytotoxic T lymphocytes (CTL) restricted by H-2 molecules of the mouse major histocompatibility complex (MHC). If these cells fail to generate or are depleted, progression from acute to persistent infection occurs. Here, using molecular probes, we show that viral nucleic acid sequences, viral proteins and infectious materials can be efficiently and effectively cleared by adoptive transfer of antiviral H-2-restricted lymphocytes bearing the Lyt 2+ phenotype. Viral materials are cleared from a wide variety of tissues and organs where they normally lodge during persistent infection. Unexpectedly, the mode by which viral materials are removed from the central nervous system (CNS) differed markedly from the mechanism of clearance occurring at other sites. These observations indicate the possible use of adoptive lymphocyte therapy for treatment of persistent infections and suggest that immune clearance of products from the CNS probably occurs by a process distinct from those in other organs.

Animals↗
PubMed2003

Poliovirus-induced apoptosis is reduced in cells expressing a mutant CD155 selected during persistent poliovirus infection in neuroblastoma cells.

Poliovirus (PV) can establish persistent infections in human neuroblastoma IMR-32 cells. We previously showed that during persistent infection, specific mutations were selected in the first extracellular domain of the PV receptor (CD155) of these cells (N. Pavio, T. Couderc, S. Girard, J. Y. Sgro, B. Blondel, and F. Colbère-Garapin, Virology 274:331-342, 2000). These mutations included the Ala 67 --> Thr substitution, corresponding to a previously described allelic form of the PV receptor. The mutated CD155(Thr67) and the nonmutated IMR-32 CD155 (CD155(IMR)) were expressed independently in murine LM cells lacking the CD155 gene. Following infection of the cells with PV, we analyzed the death of cells expressing these two forms of CD155. Levels of DNA fragmentation, caspase activity, and cytochrome c release were lower in LM-CD155(Thr67) cells than in LM-CD155(IMR) cells. Thus, the level of apoptosis was lower in cells expressing mutated CD155 selected during persistent PV infection in IMR-32 than in cells expressing the wild-type receptor.

Apoptosis↗