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PubMed2002

Persistent infections and immunity in cystic fibrosis.

Cystic fibrosis (CF) is the most common autosomal recessive lethal disease in the Caucasian population. Chronic respiratory infections with Pseudomonas aeruginosa, neutrophil-dominated airway inflammation and progressive lung damage are the major causes of morbidity and mortality in CF. Two persistent infection phenotypes expressed by this bacterium are biofilm and mucoidy. Biofilm, also called the microcolony mode of growth is the surface-associated adherent bacterial community, while mucoidy refers to a phenotype conducive to copious amounts of mucoid exopolysaccharide (MEP)/alginate that provides a matrix for mature biofilms conferring resistance to host defenses and antibiotics. Recent completion of the whole genomic sequence of the standard reference strain P. aeruginosa PAO1 has led to discoveries that many clinical isolates of this species possess unique genomic sequences (genomic islands) due to horizontal gene transfer. We propose this type of genetic exchange may play an important role in causing intrinsic genomic diversity of this organism. Therefore, the diversity, as revealed through profiles of restriction fragment length polymorphism (RFLP), may be linked to an array of novel and unexplored pathogenic mechanisms in P. aeruginosa. CF mouse models, while displaying many clinical similarities to human CF, have yet to demonstrate a chronic pulmonary disease phenotype. This review is intended to provide an overview of P. aeruginosa persistent infection phenotypes (biofilm and mucoidy) and an aerosol infection mouse model for CF. Genomic diversity of P. aeruginosa and its implications in the pathogenesis in CF will also be discussed.

Animals↗
PubMed1997

Persistent infection of human vascular endothelial cells by group B coxsackieviruses.

Group B coxsackieviruses (CVBs) cause >20% of the cases of myocarditis and dilated cardiomyopathy. Information on the permissiveness of vascular cells to CVBs is scant. Interactions of CVBs with human vascular endothelial cells (ECs) were investigated in vitro. All 6 CVBs (CVB-1 to -6) consistently infected primary EC cultures and an immortalized EC line without producing cytopathology. Whereas replication of types 1, 2, 4, and 6 ceased within 30-60 days after infection, CVB-3 and -5 caused a persistent infection. Replication of CVB-3 and -5 continued for >260 days. In ECs, the constitutive production of interferon-beta, but not of other cytokines, appeared to confer resistance to CVBs. Persistence of CVB-3 and -5 was associated with the chronic release of tumor necrosis factor-alpha, a cytotoxic cytokine that also has a negative inotropic effect on myocardial cells. The results suggest that chronic endothelial CVB infections may play a role in vascular disease.

Cells, Cultured↗
PubMed1993

Molecular analysis of neurovirulent strains of Sindbis virus that evolve during persistent infection of scid mice.

To understand the role of tissue-specific adaptation and antibody-induced selectional pressures in the evolution of neurovirulent viruses, we analyzed three strains of Sindbis virus isolated from the brains of persistently infected scid mice and four strains of Sindbis virus isolated from the brains of scid mice with viral reactivation following immune serum treatment. For each viral isolate, we tested neurovirulence in weanling BALB/c mice and sequenced regions of the E2 and E1 envelope glycoprotein genes that are known to contain important determinants of Sindbis virus neurovirulence. One strain isolated from a persistently infected scid mouse and two strains isolated from scid mice with viral reactivation were neurovirulent, resulting in mortality in 80 to 100% of weanling BALB/c mice. All three neurovirulent strains contained an A-->U change at nucleotide 8795, which predicts a Gln-->His substitution at E2 amino acid position 55. No nucleotide changes were detected in the other sequenced regions of the E2 and E1 envelope glycoprotein genes or in the avirulent isolates. Our findings indicate that tissue-specific adaptations, rather than antibody-induced selectional pressures, are a critical determinant of the evolution of neurovirulent strains of Sindbis virus and provide evidence that E2 His-55 is an important neuroadaptive mutation that confers neurovirulence properties on Sindbis virus.

Alphavirus Infections↗
PubMed1995

Prevalence of cattle persistently infected with bovine viral diarrhea virus in 20 dairy herds in two counties in central Michigan and comparison of prevalence of antibody-positive cattle among herds with different infection and vaccination status.

All cattle in 20 dairy herds randomly selected from herds participating in the Dairy Herd Improvement Association program in 2 counties in central Michigan were tested for the presence of bovine viral diarrhea virus (BVDV). Virus-positive animals were retested to ascertain persistent infection with the virus. A total of 5,481 animals were tested for presence of BVDV. In 9 of the herds, all animals were also tested for virus neutralizing antibody titer. Based on infection and vaccination status, these 9 herds were divided into 3 different herd categories: A, 5 herds with currently no cattle persistently infected (PI) with BVDV and without any vaccination program against BVDV in recent years; B, 2 herds with no current PI cattle but using killed BVDV vaccines; and C, 2 herds with PI cattle. PI cattle were detected in 3 out of 20 herds (15%). A total of 7 of 5,481 animals (0.13%) were PI. The mean prevalences of antibody carriers in herd categories A, B, and C were 28.8%, 76.4% and 90.6%, respectively. For one herd in category A, antibody analyses indicated that mostly young stock was seropositive, suggested recent BVDV infection in a previously closed and naive herd. Cattle in category B herds were vaccinated with killed vaccine from the age of 15 months. These herds had several antibody negative animals among the younger cows, suggesting incomplete protection against BVDV infection. In the 3 herds in which PI animals were detected, all cattle had been vaccinated with killed vaccine. The antibody-positive animals had antibody titers that were significantly different both among herds and among herd categories.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1981

Persistent infection of human lymphoid cells with poliovirus and development of temperature-sensitive mutants.

Exposure of several spontaneously transformed human lymphoid cell lines to attenuated and virulent types 1 and 2 poliovirus strains led to an initial sharp increase in virus titer followed by a persistent infection. Virus was present as late as 80 passages after infection. The morphology, cell count and viability of virus- and mock-infected cells were similar. Approximately 1% of the cells scored as infectious centers, and the cultures could be cured by specific antiserum. Virus produced during persistent infections initiated with a virus that readily forms plaques at 40 degrees, Mahoney virus, showed an increase in temperature sensitivity and a decrease in plaque size.

Cell Division↗
PubMed2001

High numbers of viral RNA copies in the central nervous system of mice during persistent infection with Theiler's virus.

The low-neurovirulence Theiler's murine encephalomyelitis viruses (TMEV), such as BeAn virus, cause a persistent infection of the central nervous system (CNS) in susceptible mouse strains that results in inflammatory demyelination. The ability of TMEV to persist in the mouse CNS has traditionally been demonstrated by recovering infectious virus from the spinal cord. Results of infectivity assays led to the notion that TMEV persists at low levels. In the present study, we analyzed the copy number of TMEV genomes, plus- to minus-strand ratios, and full-length species in the spinal cords of infected mice and infected tissue culture cells by using Northern hybridization. Considering the low levels of infectious virus in the spinal cord, a surprisingly large number of viral genomes (mean of 3.0 x 10(9)) was detected in persistently infected mice. In the transition from the acute (approximately postinfection [p.i.] day 7) to the persistent (beginning on p.i. day 28) phase of infection, viral RNA copy numbers steadily increased, indicating that TMEV persistence involves active viral RNA replication. Further, BeAn viral genomes were full-length in size; i.e., no subgenomic species were detected and the ratio of BeAn virus plus- to minus-strand RNA indicated that viral RNA replication is unperturbed in the mouse spinal cord. Analysis of cultured macrophages and oligodendrocytes suggests that either of these cell types can potentially synthesize high numbers of viral RNA copies if infected in the spinal cord and therefore account for the heavy viral load. A scheme is presented for the direct isolation of both cell types directly from infected spinal cords for further viral analyses.

Animals↗
PubMed1995

Measles virus antisense sequences specifically cure cells persistently infected with measles virus.

Vectors expressing antisense mRNAs complementary to the measles virus (MV) nucleoprotein N or hemagglutinin H genes were used to transfect MV-permissive Vero cells, MV-nonpermissive C6 rat glioma cells, and C6 cells persistently infected with measles/SSPE virus (C6/SSPE cells). Transfected Vero cells infected with MV showed a drastically reduced yield of infectious virus (90-99.99%). In plaque assays, plaque numbers and plaque size were significantly reduced compared with untransfected Vero cells. With an unrelated control virus, VSV, no effects were seen in the transfected Vero cells, underlining the specificity for MV. Following stable transfection with MV antisense vectors, C6 rat glioma cells, which are normally suitable to establish persistently MV-infected lines, can no longer be infected with the virus. In this case also, VSV infection was not influenced. Furthermore, antisense transfection of already persistently infected C6/SSPE cells leads to a loss of MV-specific immunofluorescence, concomitant with a disappearance of viral RNA. Single cell clones from the antisense-transfected C6/SSPE cells appear to be totally free of virus in cocultivation with Vero cells, suggesting that they are really cured. The effectiveness of even low amounts of antisense sequences suggests that they are good candidates for antisense oligonucleotide therapy in tissue culture and might eventually also be useful for in vivo application.

Animals↗
PubMed1996

Fine mapping of outer membrane protein P2 antigenic sites which vary during persistent infection by Haemophilus influenzae.

Antigenic drift of the major outer membrane protein (MOMP) P2 of nonencapsulated Haemophilus influenzae as observed during persistent infections in patients with chronic bronchitis was mimicked in a rabbit model in which H. influenzae persisted in subcutaneous cages. The antigenic drift resulted from amino acid substitutions in potentially surface-exposed loops of MOMP P2. Since in a rabbit model the appearance of antigenic variants was associated with the presence of strain-specific bactericidal antibodies (L. Vogel, B. Duim, F. Geluk, P. Eijk, H. Jansen, J. Dankert, and L. van Alphen, Infect. Immun. 64:980-986, 1996), we determined the epitope specificities of these bactericidal antibodies. The eight loops of MOMP P2 of H. influenzae d1 were separately expressed as fusion proteins with glutathione S-transferase. Sera of rabbits persistently infected with H. influenzae reacted with the loop 5 and loop 6 fusion proteins in immunoblotting and enzyme-linked immunosorbent assay. For fine mapping of the epitopes with pepscan analysis, overlapping synthetic peptides consisting of 12 amino acids were made. Rabbit sera contained antibodies reacting with peptides derived from loop 5 and peptides containing amino acids of the side of loop 6. In addition, MOMP P2 variant-specific reactions with the amino acids located at the tip of loop 6 were detected. The rabbit sera showed variant-specific complement-dependent bactericidal activities, which were eliminated by affinity chromatography with fusion proteins of loop 6 but not of loop 5. We conclude that, during persistence of H. influenzae in rabbits, variant-specific bactericidal antibodies are elicited to the variable tip of MOMP P2 loop 6.

Animals↗
PubMed1974

Role of interferon in six cell lines persistently infected with rubella virus.

Presistent infections with rubella virus were established in baby hamster kidney, BSC-1, HeLa, RK-13, rabbit embryo chondrocyte, and Vero cell lines. All of the cultures except Vero continually produced rubella virus and interferon to which the virus was sensitive. Concurrently, only the Vero cells did not display interference against superinfection with Newcastle disease and vesicular stomatitis viruses. The addition of 1,000 U of exogenous interferon to the cultures cured only the rabbit embryo and Vero cells of the persistent infection. That the interferon is not required for the initiation and maintenance of rubella viral persistence in vitro is implied by the following. (1) Vero cells were persistently infected in the absence of interferon; (2) actinomycin D or cortisone inhibited interferon synthesis but not the rubella viral infection; and (3) cells continuously cultured in the presence of cortisone maintained a viral persistence without interferon synthesis. On the other hand, interferon seems to be responsible for the viral interference; Vero cells infected with rubella virus and cultures inoculated with rubella virus in the presence of actinomycin D or cortisone did not display interference against Newcastle disease or vesicular stomatitis viruses.

Amnion↗
PubMed1999

Persistent infection promotes cross-species transmissibility of mouse hepatitis virus.

Persistent infection with mouse hepatitis virus (MHV) strain A59 in murine DBT (delayed brain tumor) cells resulted in the emergence of host range variants, designated V51A and V51B, at 210 days postinfection. These host range mutants replicated efficiently in normally nonpermissive Chinese hamster ovary (CHO), in human hepatocarcinoma (HepG2), and to a lesser extent in human breast carcinoma (MCF7) cell lines. Little if any replication was noted in baby hamster kidney (BHK), green African monkey kidney (COS-7), feline kidney (CRFK), and swine testicular (ST) cell lines. By fluorescent antibody (FA) staining, persistent viruses V10B and V30B, isolated at days 38 and 119 days postinfection, also demonstrated very low levels of replication in human HepG2 cells. These data suggest that persistence may rapidly select for host range expansion of animal viruses. Pretreatment of HepG2 cells with a polyclonal antibody directed against human carcinoembryonic antigens (CEA) or with some monoclonal antibodies (Col-1, Col-4, Col-12, and Col-14) that bind human CEA significantly inhibited V51B infection. Under identical conditions, little or no blockade was evident with other monoclonal antibodies (kat4c or Col-6) which also bind the human CEA glycoproteins. In addition, an antibody (EDDA) directed against irrelevant antigens did not block V51B replication. Pretreatment with the Col-4 and Col-14 antibodies did not block Sindbis virus replication in HepG2 cells or MHV infection in DBT cells, suggesting that one or more CEA glycoproteins likely functioned as receptors for V51B entry into human cell lines. To test this hypothesis, the human biliary glycoprotein (Bgp) and CEA genes were cloned and expressed in normally nonpermissive BHK cell lines by using noncytopathic Sindbis virus replicons (pSinRep19). By growth curves and FA staining, human CEA and to a much lesser extent human Bgp functioned as receptors for V51B entry. Furthermore, V51B replication was blocked with polyclonal antiserum directed against human CEA and Bgp. Under identical conditions, the parental MHV strain A59 failed to replicate in BHK cells expressing human Bgp or CEA. These data suggest that MHV persistence may promote virus cross-species transmissibility by selecting for virus variants that recognize phylogenetic homologues of the normal receptor.

Animals↗
PubMed1982

Persistent infection with infectious pancreatic necrosis virus mediated by defective-interfering (DI) virus particles in a cell line showing strong interference but little DI replication.

The characteristics of chinook salmon embryo cells persistently infected with infectious pancreatic necrosis virus were consistent with defective-interfering (DI) particle-mediated persistence. All the cells were infected and were slowly releasing virus, but they could be cured of virus in the presence of antiserum. Immunofluorescence showed that the amount of virus antigen in persistently infected cells was low. This fact, coupled with the observation that few DI particles were released by these cells, indicated that DI particles were not replicated to excess in this cell line.

Animals↗
PubMed1992

Persistent infection with Chlamydia pneumoniae following acute respiratory illness.

Chlamydia pneumoniae is emerging as a significant cause of respiratory disease, including pneumonia and bronchitis, in humans. In this recently completed study of infection due to C. pneumoniae in patients presenting with pneumonia to SUNY Health Science Center at Brooklyn, we identified two individuals for whom cultures were positive on multiple occasions over a 1-year period. To determine the frequency of persistent respiratory infection with C. pneumoniae, follow-up specimens were obtained from nine individuals with culture-documented C. pneumoniae infection. Five of these individuals had persistent infection: four had a flulike illness characterized by pharyngitis, and one had bronchitis with prominent bronchospasm. All five individuals appeared to have acute C. pneumoniae infection as determined by results of serologic tests (titers of IgM antibody for all individuals were greater than or equal to 1:16). For three patients, cultures remained positive for 11 months despite therapy with 10- to 21-day courses of tetracycline or doxycycline. These observations suggest that persistent infection with C. pneumoniae may follow acute infection and may persist for many months. Infection with C. pneumoniae may be very difficult to eradicate with use of currently available antibiotics even if there is a clinical response to therapy.

Acute Disease↗
PubMedDate not supplied

[Model of coxsackievirus B3 persistent infection in orally-inoculated BALB/c mouse].

Many mouse models of human enterovirus disease have been pro- posed, concerning both acute and persistent infection. However, rather paradoxically since the usual way of contamination is fecal-oral, most of them used a systemic route of infection. The aim of the present work was to follow the development of an experimental enterovirus infection and to study the viral persistence at the organ level. Twenty-eight female 3-week old BALB/c mice were infected with 5 x 10(4) TCID(50) of coxsackievirus B3 (CV-B3), Nancy strain, by oral route using a rigid cannula introduced into the stomach. The kinetics of infection was studied by sacrificing 2 animals at different times post infection (from 1 hour to 90 days). The presence of the virus in various organs (small intestine, heart, pancreas, lung, spleen, kidney, liver) was studied by cell culture and RT-PCR. As soon as one hour post infection, the virus was detected in the small intestine. In the heart, the virus was present at 24 and 48 hours post infection by RT-PCR and culture, respectively. At 5 days post infection, all the organs but the liver were found infected. The virus was detected up to 15 days in kidney, 21 days in pancreas, 30 days in lung and spleen, and 45 days in intestine, by both culture and PCR. The heart was still found infected 90 days post infection by both techniques. These results show the dramatic cardiotropism of CV-B3 inoculated by oral route, with a detection of the virus very soon in the course of infection (24 hours) and a persistence of the virus for more than 3 months. The intestine, the initial target of enterovirus infection, can also be considered as a site of viral persistence.

Animals↗
PubMed1994

FVB mice transgenic for the H-2Db gene become resistant to persistent infection by Theiler's virus.

The DA strain of Theiler's virus causes a persistent infection of the white matter of the spinal cord with chronic inflammation and primary demyelination. Inbred strains of mice differ greatly in their susceptibility to this disease. It has been shown that both viral persistence and demyelination are controlled mainly by a gene located in the H-2D region. This raised the possibility that the H-2D gene itself controls viral persistence, which in turn determines demyelination. In the present work we introduced the H-2Db gene of resistant C57BL/6 mice into the genome of susceptible H-2q FVB mice and showed that the FVB mice become resistant to persistence of the infection and did not develop inflammatory lesions.

Animals↗
PubMed2001

Strain composition of the ehrlichia Anaplasma marginale within persistently infected cattle, a mammalian reservoir for tick transmission.

Tick-borne ehrlichial pathogens of animals and humans require a mammalian reservoir of infection from which ticks acquire the organism for subsequent transmission. In the present study, we examined the strain structure of Anaplasma marginale, a genogroup II ehrlichial pathogen, in both an acute outbreak and in persistently infected cattle that serve as a reservoir for tick transmission. Using the msp1alpha genotype as a stable strain marker, only a single genotype was detected in a disease outbreak in a previously uninfected herd. In contrast, a diverse set of genotypes was detected in a persistently infected reservoir herd within a region where A. marginale is endemic. Genotypic diversity did not appear to be rapidly generated within an individual animal, because only a single genotype, identical to that of the inoculating strain, was detected at time points up to 2 years after experimental infection, and only a single identical genotype was found in repeat sampling of individual naturally infected cattle. Similarly, only a single genotype, identical to that of the experimentally inoculated St. Maries or South Idaho strain, was identified in the bloodmeal taken by Dermacentor andersoni ticks, in the midgut and salivary glands of the infected ticks, and in the blood of acutely infected cattle following tick transmission. The results show that mammalian reservoirs harbor genetically heterogeneous A. marginale and suggest that different genotypes are maintained by transmission within the reservoir population.

Amino Acid Sequence↗
PubMed1995

Tyrosine phosphorylation of measles virus nucleocapsid protein in persistently infected neuroblastoma cells.

Subacute sclerosing panencephalitis is a slowly progressing fatal human disease of the central nervous system which is a delayed sequel of measles virus (MV) infection. A typical pathological feature of this disease is the presence of viral ribonucleocapsid structures in the form of inclusion bodies and the absence of infectious virus or budding viral particles. The mechanisms governing the establishment and maintenance of a persistent MV infection in brain cells are still largely unknown. To understand the mechanisms underlying MV persistence in neuronal cells, a tissue culture model was studied. Clone NS20Y/MS of the murine neuroblastoma C1300 persistently infected with the wild-type Edmonston strain of MV secretes relatively high levels of alpha/beta interferon (IFN). As shown previously, treatment of the persistently infected cultures with anti-IFN serum converted the persistent state into a productive infection indicated by the appearance of multinucleated giant cells. In this study, we have investigated whether alpha/beta IFN produced by NS20Y/MS cells activates cellular protein tyrosine kinases which will induce tyrosine phosphorylating activity specific to virus-infected cells. We present data to show augmented protein tyrosine kinase activity in the persistently infected cells. We demonstrate that the MV N protein is phosphorylated on tyrosine in addition to serine and threonine in the persistent state but not in NS20Y cells acutely infected with MV.

2',5'-Oligoadenylate Synthetase↗
PubMed1995

Mycoplasmas and oncogenesis: persistent infection and multistage malignant transformation.

Oncogenic potential of human mycoplasmas was studied using cultured mouse embryo cells, C3H/10T1/2 (C3H). Mycoplasma fermentans and Mycoplasma penetrans, mycoplasmas found in unusually high frequencies among patients with AIDS, were examined. Instead of acute transformation, a multistage process in promotion and progression of malignant cell transformation with long latency was noted; after 6 passages (1 wk per passage) of persistent infection with M. fermentans, C3H cells exhibited phenotypic changes with malignant characteristics that became progressively more prominent with further prolonged infection. Up to at least the 11th passage, all malignant changes were reversible if mycoplasmas were eradicated by antibiotic treatment. Further persistent infection with the mycoplasmas until 18 passages resulted in an irreversible form of transformation that included the ability to form tumors in animals and high soft agar cloning efficiency. Whereas chromosomal loss and translocational changes in C3H cells infected by either mycoplasma during the reversible stage were not prominent, the onset of the irreversible phase of transformation coincided with such karyotypic alteration. Genetic instability--i.e., prominent chromosomal alteration of permanently transformed cells--was most likely caused by mutation of a gene(s) responsible for fidelity of DNA replication or repair. Once induced, chromosomal alterations continued to accumulate both in cultured cells and in animals without the continued presence of the transforming microbes. Mycoplasma-mediated multistage oncogenesis exhibited here shares many characteristics found in the development of human cancer.

AIDS-Related Opportunistic Infections↗
PubMed1992

The expression of major histocompatibility complex (MHC) class I antigens in the brain differs markedly in acute and persistent infections with lymphocytic choriomeningitis virus (LCMV).

Intracranial inoculation of immunocompetent mice with lymphocytic choriomeningitis virus (LCMV) induces a fatal neurologic illness. In this disease a marked increase in MHC class I expression was found, closely associated with viral antigens and inflammatory infiltrates, in meninges, choroid plexus and ventricular ependyma but not within the brain parenchyma. Immunosuppression prevented MHC induction. Mice inoculated at birth had persistent infections, with LCMV antigens found primarily in neurons, but no inflammatory cells or focal increase in MHC class I. Failure of infected neurons to express MHC class I allows them to escape destruction by cytotoxic T cells (CTL) but may increase their susceptibility to be persistently infected by non-lytic viruses.

Acute Disease↗