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PubMed2025

Fe-S cluster deficiency drives small colony variant formation in persistent infections.

INTRODUCTION: Small colony variants (SCVs) of Staphylococcus aureus (S. aureus) are associated with persistent infections and poor clinical outcomes. The mechanisms driving stable SCV formation remain poorly understood, particularly concerning metabolic adaptations. This study explores the in-host evolutionary dynamics of S. aureus and identifies a novel genetic determinant linked to SCV formation. OBJECTIVES: To investigate the genetic mutations and phenotypic adaptations underlying SCV formation, with a focus on the role of a novel mutation in the sufB gene, which is critical for Fe-S cluster biosynthesis. METHODS: Sequential isolates from a patient with recurrent infections were analyzed using whole-genome sequencing, antimicrobial susceptibility testing, and functional assays. The phylogenetic relationship of the isolates was determined, and specific mutations were identified. Functional assays included aconitase and glutamate synthase activity measurements, ATP level quantification, reactive oxygen species (ROS) production, and biofilm formation assays. In vivo pathogenesis was assessed using a murine catheter infection model. RESULTS: A novel frameshift mutation in sufB was identified, disrupting Fe-S cluster biosynthesis and impairing the TCA cycle and electron transport chain, leading to reduced ATP and ROS production. This metabolic reprogramming promoted stable SCV formation, characterized by slow growth, enhanced tolerance to antibiotics and neutrophil-mediated killing, and persistent inflammation in vivo. Restoration of sufB reversed these phenotypes, confirming its pivotal role in SCV-associated persistence. CONCLUSION: sufB is a novel genetic determinant of stable SCV formation through Fe-S cluster deficiency, driving metabolic shifts that enhance immune evasion and chronic infection. Our findings highlight antibiotic stewardship and suggest potential therapeutic strategies for managing persistent SCV-associated infections.

Staphylococcus aureus↗
PubMed1997

Evolution of mouse hepatitis virus: detection and characterization of spike deletion variants during persistent infection.

High-frequency RNA recombination has been proposed as an important mechanism for generating viral deletion variants of murine coronavirus. Indeed, a number of variants with deletions in the spike glycoprotein have been isolated from persistently infected animals. However, the significance of generating and potentially accumulating deletion variants in the persisting viral RNA population is unclear. To study this issue, we evaluated the evolution of spike variants by examining the population of spike RNA sequences detected in the brains and spinal cords of mice inoculated with coronavirus and sacrificed at 4, 42, or 100 days postinoculation. We focused on the S1 hypervariable region since previous investigators had shown that this region is subject to recombination and deletion. RNA isolated from the brains or spinal cords of infected mice was rescued by reverse transcription-PCR, and the amplified products were cloned and used in differential colony hybridizations to identify individual isolates with deletions. We found that 11 of 20 persistently infected mice harbored spike deletion variants (SDVs), indicating that deletions are common but not required for persistent infection. To determine if a specific type of SDV accumulated during persistence, we sequenced 106 of the deletion isolates. We identified 23 distinct patterns of SDVs, including 5 double-deletion variants. Furthermore, we found that each mouse harbored distinct variants in its central nervous system (CNS), suggesting that SDVs are generated during viral replication in the CNS. Interestingly, mice with the most severe and persisting neurological disease harbored the most prevalent and diverse quasispecies of SDVs. Overall, these findings illustrate the complexity of the population of persisting viral RNAs which may contribute to chronic disease.

Animals↗
PubMed2006

Genetic variation of foot-and-mouth disease virus isolates recovered from persistently infected water buffalo (Bubalus bubalis).

Genetic variation of foot-and-mouth disease virus (FMDV) isolates, serotype O, recovered serially over a 1-year period from persistently infected buffalos was assessed. The persistent state was established experimentally with plaque-purified FMDV, strain O(1)Campos, in five buffalos (Bubalus bubalis). Viral isolates collected from esophageal-pharyngeal (EP) fluids for up to 71 weeks after infection were analyzed at different times by nucleotide sequencing and T(1) RNase oligonucleotide fingerprinting to assess variability in the VP1-coding region and in the complete genome, respectively. Genetic variation increased, although irregularly, with time after infection. The highest values observed for the VP1-coding region and for the whole genome were 2.5% and 1.8%, respectively. High rates of fixation of mutations were observed using both methodologies, reaching values of 0.65 substitutions per nucleotide per year (s/nt/y) and 0.44s/nt/y for nucleotide sequencing and oligonucleotide fingerprinting, respectively, when selected samples recovered at close time periods were analyzed. The data herein indicate that complex mixtures of genotypes may arise during FMDV type O persistent infection in water buffalos, which can act as viral reservoirs and also represent a potential source of viral variants. These results fit within the quasi-species dynamics described for FMDV, in which viral populations are constituted by related, non-identical genomes that evolve independently from each other, and may predominate at a given time.

Amino Acid Sequence↗
PubMed1996

Population dynamics of Theileria sergenti in persistently infected cattle and vector ticks analysed by a polymerase chain reaction.

Theileria sergenti Shintoku stock consists of 2 parasite populations bearing 2 allelic forms of p33/32, an immunodominant piroplasm surface protein. Parasite population changes during parasite passages among cattle and tick vectors, and during persistent infection in individual calves were analysed by using allele-specific polymerase chain reaction (PCR). The parasite DNAs were prepared from piroplasms from calves which had been infected with Shintoku stock by inoculation of sporozoite stabilates or parasitized erythrocytes, and from sporozoite stabilates which had been prepared from Shintoku stock-infected ticks. Changes in a dominant parasite population were demonstrated during transmission from calves to vector ticks and from infected ticks to calves. Parasite population changes were also apparent during persistent infection in cattle over several months, and this change is thought to occur under host immune pressure. The results of this study indicate that expression of diverse forms of p33/32 may play a role in parasite persistence within mammalian hosts and its transmission from tick vector.

Animals↗
PubMed1985

Characterization of virus obtained from MDBK cells persistently infected with a variant of herpes simplex virus type 1 strain MP [HSV-1(MP)].

Virus clones which express glycoprotein gC (gC+) were obtained from two persistently infected (p.i.) MDBK cell lines which had been independently established by infection with HSV-1(MP)10311, a gC- syncytial (syn) variant of herpes simplex virus type 1 strain MP [HSV-1(MP)]. The gC+ revertants were syn in MDBK, HEp-2, and Vero cell lines and in primary human fibroblasts; this offers further evidence that glycoprotein gC does not inhibit cell fusion. The gC+ revertants represented from 70 to 100 percent of the virions present in the virus populations examined, thus suggesting a possible selective advantage of the gC+ revertants in this system of persistent infection.

Animals↗
PubMed1997

The effects of measles virus persistent infection on AP-1 transcription factor binding in neuroblastoma cells.

Measles virus (MV) persistence in brain cells has broad effects on different cellular functions. We have previously shown that NS20Y clone, originally derived from C1300 neuroblastoma cells, persistently infected with MV (NS20Y/MS), displays constitutively elevated levels of c-fos and PKC mRNAs, implying MV-mediated effects on transcriptional regulation. Nonetheless, the mode by which virus affects the transcriptional machinery still remains obscure. In order to define this phenomenon, we studied the binding properties of major transcription factors (AP-1 and NFkappaB) in NS20Y/MS cells. Using electrophoretic mobility shift approach (EMSA) with the appropriate oligonucleotide probes, we have found that the persistent MV infection does not affect NFkappaB binding, while the AP-1 binding was significantly decreased. Similar inhibition was not observed in NS20Y cells acutely infected with MV. Anti-measles antibody-mediated restriction of viral gene expression restored AP-1 binding, thus suggesting that measles virus proteins may affect the components of the host transcriptional machinery.

Animals↗
PubMed2001

Chlamydia pneumoniae expresses genes required for DNA replication but not cytokinesis during persistent infection of HEp-2 cells.

Chlamydia pneumoniae causes community-acquired pneumonia and is associated with several chronic diseases, including asthma and atherosclerosis. The intracellular growth rate of C. pneumoniae slows dramatically during chronic infection, and such persistence leads to attenuated production of new elementary bodies, appearance of morphologically aberrant reticulate bodies, and altered expression of several chlamydial genes. We used an in vitro system to further characterize persistent C. pneumoniae infection, employing both ultrastructural and transcriptional activity measurements. HEp-2 cells were infected with C. pneumoniae (TW-183) at a multiplicity of infection of 3:1, and at 2 h postinfection gamma interferon (IFN-gamma) was added to the medium at 0.15 or 0.50 ng/ml. Treated and untreated cultures were harvested at several times postinfection. RNA was isolated and reverse transcribed, and reverse transcription (RT)-PCR analyses targeting primary transcripts from chlamydial rRNA operons as well as dnaA, polA, mutS, minD, ftsK, and ftsW mRNA were done. Some cultures were fixed and stained for electron microscopic analysis, and a real-time PCR assay was used to assess relative chlamydial chromosome accumulation under each culture condition. The latter assays showed that bacterial chromosome copies accumulated severalfold during IFN-gamma treatment of infected HEp-2 cells, although less accumulation was observed in cells treated with the higher dose. Electron microscopy demonstrated that high-dose IFN-gamma treatment elicited aberrant forms of the bacterium. RT-PCR showed that chlamydial primary rRNA transcripts were present in all IFN-gamma-treated and untreated cell cultures, indicating bacterial metabolic activity. Transcripts from dnaA, polA, mutS, and minD, all of which encode products for bacterial chromosome replication and partition, were expressed in IFN-gamma-treated and untreated cells. In contrast, ftsK and ftsW, encoding products for bacterial cell division, were expressed in untreated cells, but expression was attenuated in cells treated with low-dose IFN-gamma and absent in cells given the high dose of cytokine. Thus, the development of persistence included production of transcripts for DNA replication-related, but not cell division-related, genes. These results provide new insight regarding molecular activities that accompany persistence of C. pneumoniae, as well as suggesting requirements for reactivation from persistent to productive growth.

Bacterial Proteins↗
PubMed1977

Role of extracellular virus on the maintenance of the persistent infection induced in Aedes albopictus (mosquito) cells by Sindbis virus.

Sindbis virus infection of cultured mosquito cells was found to have no effect on the growth of these cells; instead, a persistent infection of the culture followed an initial acute phase of rapid virus synthesis. Nearly all of the cells in the acute stage of infection were found to actively release virus in an infectious-center assay and to contain significant amounts of virus antigen as determined by immunofluorescence. Cells in the persistent phase of infection released few virions into the media, and only a small percentage of the cultured cells could be demonstrated to contain detectable amounts of virus antigen by immunofluorescence assay. In spite of the fact that nearly 100% of the cells in the persistent phase of infection were found to be virus negative by the two assays described above, the culture as a whole totally excluded the expression of superinfecting virus, as did cells in the acute phase, suggesting that most of the persistently infected cells did, indeed, contain virus information. Prevention of reinfection of the cells in the persistent phase by eliminating extracellular virus resulted in a curing of the culture such that it responded to infection by added virus much as would an uninfected culture.

Aedes↗
PubMed1999

Genomic nucleotide sequence of a foot-and-mouth disease virus clone and its persistent derivatives. Implications for the evolution of viral quasispecies during a persistent infection.

The consensus nucleotide sequence of the entire genome of foot-and-mouth disease virus (FMDV) (biological clone C-S8c1) has been completed, and compared with that of two persistent derivatives R99 and R146, rescued after 99 and 146 passages of the carrier BHK-21 cells. Consensus sequences were determined directly from supernatants of persistently infected cells, without intervening cytolytic amplification of the viruses. These genomic sequences have also been compared with that of FMDV R100, a virus that was also rescued from persistently infected cells, but that was subjected to cytolytic amplification prior to sequencing. Mutation frequencies for R99 and R146 relative to C-S8c1 were in the range of 2.8x10(-3) to 7.7x10(-3) substitutions per nucleotide for the 5'-UTR and the L-, P1-, P2- and P3-coding regions. No mutations were fixed in the polymerase (3D)-coding region. Striking contrasts were noted regarding the distribution of mutation types along the persistent genomes, notably the complete absence of transversion mutations within the 5'-UTR, compared with 53% transversions in the L- and P1-coding regions. The sequencing results presented here, combined with previous sequences of FMDV C-S8c1 genomes at the onset of persistence, provide evidence of sequence fluctuations with a non-linear accumulation of mutations during prolonged persistence, a hallmark of quasispecies dynamics.

3' Untranslated Regions↗
PubMed2000

Pooled-sample testing as a herd-screening tool for detection of bovine viral diarrhea virus persistently infected cattle.

The study was conducted to develop methodology for least-cost strategies for using polymerase chain reaction (PCR)/probe testing of pooled blood samples to identify animals in a herd persistently infected with bovine viral diarrhea virus (BVDV). Cost was estimated for 5 protocols using Monte Carlo simulations for herd prevalences of BVDV persistent infection (BVDV-PI) ranging from 0.5% to 3%, assuming a cost for a PCR/probe test of $20. The protocol associated with the least cost per cow involved an initial testing of pools followed by repooling and testing of positive pools. For a herd prevalence of 1%, the least cost per cow was $2.64 (95% prediction interval = $1.72, $3.68), where pool sizes for the initial and repooled testing were 20 and 5 blood samples per pool, respectively. Optimization of the least cost for pooled-sample testing depended on how well a presumed prevalence of BVDV-PI approximated the true prevalence of BVDV infection in the herd. As prevalence increased beyond 3%, the least cost increased, thereby diminishing the competitive benefit of pooled testing. The protocols presented for sample pooling have general application to screening or surveillance using a sensitive diagnostic test to detect very low prevalence diseases or pathogens in flocks or herds.

Animals↗
PubMed1977

Infectivity of DNA recovered from cells persistently infected with SV5 paramyxovirus.

Infectivity of DNA isolated from L cells chronically infected with SV5 paramyxovirus was demonstrated by inoculation of continuous RH and HEp-2 cells. Infectivity of the DNA was completely abolished by treatment with deoxyribonuclease or by alkaline hydrolysis but did not change after treatment with ribonuclease and specific anti SV5 serum. The virus obtained as a result of transfection caused haemadsorption in susceptible cells and was neutralized by specific antiserum like the prototype SV5 strain.

Animals↗
PubMed1992

Oligo-2',5'-adenylate synthetase activity in cells persistently infected with human T-lymphotropic virus type I (HTLV-I).

Spontaneous production of interferon-gamma (IFN-gamma) was shown in several T-lymphoblastoid cell lines persistently infected with human T-lymphotropic virus (HTLV-1). However, the produced IFN-gamma was not always associated with the induction of the antivirus state. The induction of oligo-2',5'-adenylate synthetase (2-5AS) by IFN was studied in five human T-cell lines persistently infected with HTLV-I (MT-1, MT-2, SMT-1, HUT 102 and OKM-2). Four cell lines are able to produce IFN-gamma spontaneously, while the OKM-2 cell line is not. Poor induction of 2-5AS was recognized in three (MT-1, MT-2 and SMT-1) of the four cell lines producing IFN-gamma, though the poor induction was improved after long-term cultivation of cells with IFN-alpha. On the contrary, in the OKM-2 cell line, significant activity of the enzyme was induced by IFN-alpha. Induction of 2-5AS was not correlated with cell growth inhibition, but with the antivirus state. Furthermore, an inverse relationship between IFN-gamma production and 2-5AS induction was demonstrated in these cell lines with the exception of HUT 102 cells.

2',5'-Oligoadenylate Synthetase↗
PubMed1998

Human immunodeficiency virus induces a dual regulation of Bcl-2, resulting in persistent infection of CD4(+) T- or monocytic cell lines.

This work aims at characterizing the interplay between human immunodeficiency virus type 1 (HIV-1) and the antiapoptotic cellular protein Bcl-2 responsible for a persistent infection in lymphoblastoid T (J.Jhan) or monocytic (U937) cells. We report that the kinetics of Bcl-2 protein level during the establishment of a chronic infection is biphasic, characterized by a transient decrease followed by restoration to the initial level. The extent and duration of this transient decrease were inversely correlated with the basal level of Bcl-2 as shown by kinetics of Bcl-2 levels in J. Jhan or U937 clones exhibiting different levels of Bcl-2. Using these clones, we also showed that Bcl-2 downregulates HIV-1 replication. Therefore, the cells overexpressing Bcl-2 are characterized by a low viral burden which, in turn, has little effect on the level of this protein. The observed bipasic kinetics is the result of a dual regulation of Bcl-2 induced by HIV-1 infection itself: an upregulation at the transcriptional level of the bcl-2 gene concomitant with a downregulation at the protein level. Convergent data suggest that this downregulation is caused by the oxidative stress induced by the infection itself as shown by the associated modulations of glutathione and thioredoxin levels and by the prevention of these dysregulations by N-acetylcysteine. Altogether, these data indicate that infection first results in a decrease of Bcl-2, permitting an initial boost of replication. Then, as the synthesis at the transcriptional level proceeds, the replication is negatively controlled by Bcl-2 to reach a balance characterized by low virus production and a level of Bcl-2 compatible with cell survival. We suggest that the basal level of Bcl-2, together with infection-inducible transcription factors able to activate bcl-2 gene transcription, is a critical cellular determinant in the tendency toward an acute or a persistent infection.

Acetylcysteine↗
PubMed1997

Spontaneous occurrence of early region 1A reiteration mutants of type 5 adenovirus in persistently infected human T-lymphocytes.

Mutants of type 5 adenovirus (Ad5) with reiterated DNA sequences in the E1a region appeared in a human T-lymphocyte cell line, Molt-4, persistently infected with H5sub304, a deletion/substitution mutant that has a wild-type phenotype in viral replication. Endonuclease analyses and DNA sequencing revealed DNA reiteration in each mutant. In the four representative mutants investigated, the DNA reiterations all started within a six-base-pair consensus sequence, G(or C)CTGTG, located in the second exon of the E1a region (at nt 1333, 1367, or 1419). There was not any DNA homology between the breakpoints in the second exon and the inserting sequences (starting at nt 532, 710, or 792). Northern analyses suggested that the reiterated splicing sites of the representative mutants were all used in RNA splicing, and the closest donor and recipient joints were used most frequently. These observations imply that during persistent infection Ad5 underwent spontaneous mutations by sequence-specific breakage and nonhomologous end-end joining recombination events. These E1a reiteration mutants could be propagated in HeLa, A549, and KB cells; they were genetically stable; and they killed CREF cells at a strikingly high frequency. Preliminary observations tend to correlate this CREF cell killing with the accumulation of the early viral proteins and/or viral DNA in the infected cells. This degree of cell damage was not observed in Ad5wt or H5sub304 infection of CREF cells. The observed E1a reiterations provide a model to gain insight into understanding the evolutionary events of some, if not all, adenovirus types during many years of symbiotic, persistent relationship in human tonsils and adenoids and possibly other lymphoid organs.

Adenovirus E1A Proteins↗
PubMed1984

Antigenic variation during persistent infection by equine infectious anemia virus, a retrovirus.

The recurrent nature of equine infectious anemia has been attributed to relatively rapid antigenic variations in equine infectious anemia virus (EIAV) during persistent infection under selective immune pressures. This model was tested by serological and biochemical analysis of virus isolates recovered from separate febrile episodes in two experimentally infected ponies. Neutralization assays employing immune sera from the experimentally infected ponies demonstrated that distinct antigenic strains of virus predominate during sequential febrile episodes in a single pony. Analysis of the test strains of EIAV by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed varying electrophoretic mobilities for the respective virion glycoproteins gp90 and gp45. Furthermore, peptide mapping comparisons demonstrated structural variations between the gp90 components of the various strains. In contrast, the respective internal proteins of the virus strains displayed identical electrophoretic mobilities in sodium dodecyl sulfate-polyacrylamide gel electrophoresis and, in general, produced identical tryptic peptide maps. The observed differences in glycoprotein electrophoretic mobility and peptide maps were highly reproducible and did not vary with repeated passage of the virus strains in cell culture. Thus, these results demonstrate the occurrence of glycoprotein-specific structural variations during persistent infection by EIAV and support the concept of antigenic variation in this retrovirus. This capacity to alter envelope glycoprotein structure, previously reported for visna virus, may represent an important mechanism of retrovirus persistence in the presence of immune responses by the animal host.

Animals↗
PubMed1998

[Clinical-virologic course after superinfection of persistently infected cattle with cytopathogenic bovine viral diarrhea virus strains].

Vaccination with live cytopathogenic (cp) bovine viral diarrhoea virus (BVDV) is often used for control of this disease. In animals which are persistently infected with noncytopathogenic (ncp) BVDV this can lead to the outbreak of mucosal disease (MD). To simulate vaccination of such animals and to monitor the clinical-virological course after superinfection, nine clinically healthy calves which were persistently viremic were superinfected with different cp BVDV strains. One animal succumbed to early onset MD within three weeks after superinfection. During the observation period of 18 months four animals developed severe clinical signs. While two animals developed late onset MD, the other two had to be euthanized due to clinical signs which could not be related to the superinfecting BVDV. These results indicated that after superinfection or vaccination of persistently infected calves with cp BVDV the probability of developing early and/or late onset MD is significantly increased. The risks arising from uncritical vaccination of herds with unknown virological status in relation with the control of BVDV conforming to the actual official guidelines are discussed.

Animals↗
PubMed1983

Role of defective simian virus 40 genomes in establishment and maintenance of persistently infected primate cell lines.

Studies are reported of persistent simian virus 40 (SV40) infections of fully permissive monkey (TC-7 and BSC-1) and human (A172) cell lines, with emphasis on the role of viral defectives in establishment and maintenance of persistence. The presence of defectives prevented complete cell killing and allowed the establishment of persistently infected cultures. Hirt supernate DNAs from these cultures showed the continuing presence of defective genomes. Restriction enzyme analysis demonstrated that altered defective genomes evolved during passage of the carrier cultures, but that they always reflected structures of the genomes used to established the cultures. There was some host cell specificity in the effectiveness of establishment of persistence, e.g., TC-7-derived defectives were more effective in preventing killing of TC-7 than of BSC-1 or A172 cells. Persistent infections of TC-7 cells could also be established in the absence of defectives, but in the presence of neutralizing anti-SV40 antiserum. In fact, defectives were eliminated from carrier cultures established in the presence of antiserum. When antiserum was withdrawn, the wild-type SV40 grew and destroyed the cells. Antiserum maintains a low level of infection by neutralizing viruses outside the cells, so that many cells do not become infected. Defectives are eliminated because spread of infection is effectively at very low multiplicity. Carrier cultures that are established and maintained by defectives result from intracellular interference by the defectives with the normal development of wild-type virus.

Animals↗