The high rate of aerobic glycolysis of transformed 3T3 cells persists after cell homogenization.
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Aerobiosis↗
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Evidence for the in vivo production and release into the serum of a T-cell lymphokine, persisting-cell stimulating factor (PSF), during graft-versus-host reactions.
The T-cell lymphokine, persisting-cell stimulating factor (PSF or interleukin-3), was detected in the serum of mice undergoing graft-versus-host reactions (GVHR). Gel filtration under non-dissociating conditions indicated that the PSF in the serum had an apparent molecular weight of 34,000, a figure identical with that of PSF generated from activated T cells in vitro, indicating that PSF was not bound by serum proteins. The GVHR was accompanied by increases in the numbers in the bone marrow and spleen of precursors of PSF-dependent mast cells, and increases in the numbers of mast cells, megakaryocytes and immature and mature neutrophils in the spleen. These effects of GVHR on haemopoietic cells paralleled those seen when haemopoietic tissues were stimulated with pure PSF in vitro and closely resembled those induced in previous studies by the presence of a tumour that secreted PSF alone. These studies are the first to show that PSF can enter the circulation during immune reactions in vivo and suggest that much of the stimulation of haemopoietic cells seen in GVHR, can be accounted for by the release of PSF from activated T cells.
Animals↗
Effect of interferon on Vero cells persistently infected with Sendai virus compared to Vero cells persistently infected with SSPE virus.
Persistent infections with Sendai and SSPE virus were established in Vero cells. Sequential passages of these cells were monitored by immunofluorescence and for their sensitivity to the antiviral and antiproliferative effects of interferon (IFN). The cells rapidly developed resistance to the antiviral effect of IFN as judged by the inability of IFN to inhibit the replication of exogenous Sindbis virus. This decrease was accompanied by a reduction in the induction of the 2'-5' oligo A synthetase. Both cell lines were resistant to the antiproliferative effect of IFN. A decrease or absence of IFN receptors on the surface of the cells was not found to be the cause of their resistance to IFN.
2',5'-Oligoadenylate Synthetase↗
Epigenetic Repression of TP53 Transcription Underlies Cancer Cell Persistence for Carboplatin Resistance in Non-Small Cell Lung Cancer.
While chemoresistance in non-small cell lung cancer (NSCLC) cells has historically been attributed to permanent genetic mutations, emerging evidence highlights the role of nongenetic transcriptional plasticity and 'drug-tolerant persister' cells. To systematically map these epigenetic vulnerabilities, we utilized a genome-wide CRISPR interference library to screen wild-type TP53 NSCLC (A549) cells under carboplatin selection. Using the DrugZ algorithm and subsequent pathway enrichment analyses, this screen revealed that transcriptional suppression of interstrand crosslink DNA repair networks, including the Fanconi anemia pathway, markedly sensitized cells to carboplatin. Unexpectedly, transcriptional silencing of TP53 and its downstream target CDKN1A emerged as the strongest drivers of resistance, enabling cells to bypass therapy-induced senescence and maintain their proliferative potential later. To validate these findings in a clinically relevant context, we established a chronic carboplatin-resistant cell model (A549CarboR cells). A549CarboR exhibited a reduction in TP53 transcripts, along with decreased H3K27 acetylation and increased DNA hypermethylation on its promoter. Epigenetic remodeling using the DNA methyltransferase inhibitor (DNMTi) was associated with unblocking TP53 transcription, restored p53 signaling, and resensitization of resistant cells to carboplatin. Conversely, histone deacetylase inhibitors induced CDKN1A transcription to bypass TP53, indicating distinct epigenetic circuits. Collectively, the results demonstrate for the first time that TP53 expression is dynamically regulated at the transcriptional level through promoter methylation related to the drug tolerance. These insights emphasize that epigenetic silencing, rather than exclusive genetic loss-of-function, contribute to platinum resistance and underscore the therapeutic potential of pairing platinum regimens with DNMTi to target the transcriptomic plasticity of persistent cancer cell populations.
CRISPR interference screening↗
Phage vB_KpnM_NB cocktail synergizing with amikacin in inhibiting persister cells of Klebsiella pneumoniae.
UNLABELLED: The emergence of multidrug-resistant Klebsiella pneumoniae (KPN) and antibiotic-tolerant persister cells poses a significant challenge to existing anti-infection therapies. Given the urgent need for sustainable alternatives to antibiotics, phage cocktails are emerging as a promising alternative to control K. pneumoniae infections. We isolated three lytic phages vB_KpnM_NB (1-3) from Ningbo environmental samples, classified them into the Drexlerviridae family, and determined the biological characteristics of two representative phages. Genomic analysis confirmed that these phages are closely related and lack resistance and virulence genes, ensuring biosafety. Subsequently, a stable KPN persister model was established using amikacin, with a biphasic killing pattern observed during treatment. At a multiplicity of infection of 10, the phage cocktail eliminated 99.00% of persister cells, while individual phages were less effective. The phage cocktail also inhibited persister-derived biofilm formation, showing improved results when combined with amikacin. This combination significantly reduced capsule polysaccharide production in persisters, weakening the outer membrane barrier. These findings demonstrate that the phage cocktail-amikacin combination effectively targets planktonic cells, persister cells, and biofilms, providing a promising strategy against persisters and recurrent K. pneumoniae infections. IMPORTANCE: This study fills the critical gap in understanding how phage cocktails synergize with amikacin against K. pneumoniae persister cells. By constructing a highly specific phage vB_KpnM_NB cocktail, establishing a stable persister model, and performing in vitro bactericidal and biofilm assays, we demonstrate that the cocktail effectively eliminates planktonic cells, persisters, and biofilms. We clarify the core synergistic mechanism: inhibiting capsular polysaccharide synthesis, improving phage adsorption, and disrupting the bacterial outer membrane barrier. These findings provide experimental evidence for the prevention and control of multidrug-resistant and carbapenem-resistant K. pneumoniae persister infections, establishing a safe and effective phage-antibiotic combination therapy. The results are crucial for addressing antibiotic tolerance and controlling chronic, recurrent infections. They hold significant theoretical and translational value for the treatment of refractory infections in clinical settings and offer new insights into the development of novel antimicrobial strategies.
Klebsiella pneumoniae↗
Detection of anti-rabies virus cytotoxic T lymphocytes in mice of four distinct H-2 haplotypes using target cells persistently infected with ERA rabies virus.
Cells persistently infected with Evelyn-Rokitnicki-Abelseth (ERA) rabies virus were established. The cells were used as stimulator and target cells to compare H-2 restricted cytotoxic T lymphocyte (CTL) responses specific for rabies virus in A/WySnJ (H-2a), C57BL/6J (H-2b), BALB/cByJ (H-2d), A.SW/SnJ (H-2s) and SJL/J (H-2s) mice. Using a 51chromium release assay, it was determined that an effector/target (E/T) ratio of 5:1 was necessary to demonstrate specific lysis of ERA virus persistently infected mouse neuroblastoma (MNB) (H-2a), EL-4 (H-2b) and P815 (H-2d) cells. Effectors at an E:T ratio of only 0.05:1 specifically lysed an SV-40 transformed SJL/J mouse fibroblast (SSSV) (H-2s) target monolayer. The CTL destruction of the SSSV monolayer was observed visually following Giemsa staining. This is the first instance in which a detailed method for detection of murine anti-rabies virus CTLs has been reported. Furthermore, it is the first time target cells persistently infected with rabies virus were used as stimulator cells to amplify CTLs in vitro and as target cells in the CTL assay. It also is the initial report in which rabies specific CTLs were characterized in H-2d and H-2s rabies virus infected mice.
Animals↗
Expression of constitutive and inducible HSP70 and HSP47 is enhanced in cells persistently spread on OPN1 or collagen.
Cells persistently spread on OPN or collagen survive heat shock better than cells transiently spread on fibronectin or tissue culture plates. Thus, a central question is whether constitutively or inducible stress proteins are enhanced in cells grown on adhesive proteins that maintain a persistent spread cell shape. Levels of Hsp 72,73, and colligin/Hsp47 were determined by Western blot analyses. The inducible Hsp 72 was prominently expressed following heat shock in cells grown on OPN or collagen, but not in cells plated on fibronectin coated substratum or on tissue culture plates. Colligin/Hsp 47 and Hsp 73 manifested a similar pattern of expression indicating that these adhesive attachment proteins accommodate cell function through organization of cell architecture.
Cell Adhesion↗
Teicoplanin associated gene tcaA inactivation increases persister cell formation in Staphylococcus aureus.
Staphylococcus aureus is part of normal human flora and is widely associated with hospital-acquired bacteremia. S. aureus has shown a diverse array of resistance to environmental stresses and antibiotics. Methicillin-resistant S. aureus (MRSA) is on the high priority list of new antibiotics discovery and glycopeptides are considered the last drug of choice against MRSA. S. aureus has developed resistance against glycopeptides and the emergence of vancomycin-intermediate-resistant, vancomycin-resistant, and teicoplanin-resistant strains is globally reported. Teicoplanin-associated genes tcaR-tcaA-tcaB (tcaRAB) is known as the S. aureus glycopeptide resistance operon that is associated with glycopeptide resistance. Here, for the first time, the role of tcaRAB in S. aureus persister cells formation, and ΔtcaA dependent persisters' ability to resuscitate the bacterial population was explored. We recovered a clinical strain of MRSA from a COVID-19 patient which showed a high level of resistance to teicoplanin, vancomycin, and methicillin. Whole genome RNA sequencing revealed that the tcaRAB operon expression was altered followed by high expression of glyS and sgtB. The RNA-seq data revealed a significant decrease in tcaA (p = 0.008) and tcaB (p = 0.04) expression while tcaR was not significantly altered. We knocked down tcaA, tcaB, and tcaR using CRISPR-dCas9 and the results showed that when tcaA was suppressed by dCas9, a significant increase was witnessed in persister cells while tcaB suppression did not induce persistence. The results were further evaluated by creating a tcaA mutant that showed ΔtcaA formed a significant increase in persisters in comparison to the wild type. Based on our findings, we concluded that tcaA is the gene that increases persister cells and glycopeptide resistance and could be a potential therapeutic target in S. aureus.
MRSA↗
Studies of L cells persistently infected with VSV: factors involved in the regulation of persistent infection.
Infection of interferon-treated L cells with VSV led frequently to the establishment of L cells persistently infected with VSV (LVSV cells). These cells were characterized by the following properties; (I) no supplement of antiviral factors such as anti-VSV antiserum, interferon, was required for their maintenance; (2) virus antigens were detected in about 5 to 30% of the cells by immunofluorescence staining; (3) the cells were not only resistant to superinfection by homologous virus, but also resistant to challenge by heterologous viruses such as Mengo virus; (4) the cells were destroyed by co-cultivation with heterologous cells susceptible to VSV infection; (5) the cells could be cured by serial cultivation in medium containing antiviral antibody, and the cured cells were as susceptible to VSV as normal L cells. It was shown that at least three factors (interferon, defective interfering [DI] particles and a selection of small-plaque temperature-sensitive [ts] mutants) took part in the maintenance of LVSV cells although it was difficult to evaluate exactly the relative importance of these factors. The effect of antiviral antibody, interferon and incubation temperature upon the maintenance of LVSV cells are discussed further.
Animals↗
Temperature-sensitive virus derived from BHK cells persistently infected with HVJ (Sendai virus).
BHK-HVJ cells, a cell line of baby hamster kidney cells persistantly infected with HVJ (Sendai virus), started to produce infectious virus by shifting down the incubation temperature from 38 to 32 C. The virus derived from BHK-HVJ cells, designated as HJV-pB, was effectively neutralized with antibody against wild-type virus (HVJ-W) which was used for the establishment of BHK-HVJ cells. HVJ-pB replicated in eggs at 32 C, but not at 38 C, while HVJ-W grew equally well at both temperatures. When BHK cells infected with HVJ-PB were incubated at 38 C, production of infectious virus, hemagglutinin, and neuraminidase was markedly restrained, whereas a considerable amount of viral nucleocapisid and envelope antigens was detected in the cells by complement fixation tests. These viral activities became detectable immediately after temperature shift-down from 38 to 32 C even at the later stage of infection. HVJ-pB was indistinguishable from HJV-W with respect to particle size, density, and morphological characteristics, but appeared to possess a higher neuraminidase activity and was inactivated more rapidly at 50 C than HVJ-W. HVJ-pB was less cytocidal and could easily cause latent infection in BHK and mouse L cells.
Animals↗
Decrease of oligo-2',5'-adenylate synthetase activity in BALB3T3 cell persistently infected with Moloney murine leukemia virus.
The induction of oligo-2',5'-adenylate synthetase (2-5AS) activity by interferon (IFN) was decreased in BALB3T3 cells persistently infected with Moloney murine leukemia virus (Mo-MLV) as compared with uninfected cells. Furthermore, the correlation between increased susceptibility to vesicular stomatitis virus (VSV) infection and reduced 2-5AS activity was recognized in the Mo-MLV persistently infected cells. The decrease of enzyme activity was confirmed by a solid phase reaction and an analysis of reaction products by Fast Polynucleotide Liquid Chromatography (FPLC) in addition to a liquid phase reaction. In a solid-phase reaction, the enzyme protein binds to polyinosinate-cytidylate (Poly I:C) agarose beads and other cellular proteins can be washed out from the reaction mixtures. Therefore, these results indicate that the decrease of IFN-induced enzyme activity is due to the suppression of transcription and/or translation of 2-5AS mRNA. A decreased amount of 2-5AS mRNA in persistently infected cells was observed by Northern blot and dot-blot hybridization. On the other hand, cell lysate of Mo-MLV infected cells inhibited the 2-5AS activity in liquid phase reaction. The inhibition may also be partly due to the degradation of oligo-2',5'-adenylate (2-5A) formed by 2-5AS.
2',5'-Oligoadenylate Synthetase↗
An electron microscopic study of MDBK cells persistently infected with Newcastle disease virus.
Ultrastructural examination of a line of MDBK cells persistently infected with Newcastle disease virus (MDBKpi cells) revealed the presence of cytoplasmic aggregates of both smooth and granular nucleocapsids. Only granular nucleocapsids aligned under modified areas of plasma membrane and were incorporated into virus particles. On the grounds of morphogenesis, there was no apparent explanation for the persistent, not-cytocidal nature of the infection. Both nuclear and cytoplasmic aggregates of smooth nucleocapsids were present in MDBKpi cells which had been held without subculture for between 40 and 130 days (aged MDBKpi cells). Modified areas of plasma membrane with associated alignment of nucleocapsids were not present in aged MDBKpi cells, and neither budding nor released virus particles were observed, indicating a block in virus maturation. It is suggested that the granular material coating granular nucleocapsids allows them to interact with modified areas of plasma membrane, thereby inducing virus budding. A deficiency of this material, as apparently occurs in aged MDBKpi cells, would therefore cause a block in virus maturation. The nature of this granular material is discussed, and we suggest that it consists of M protein.
Animals↗
Fusion properties of cells persistently infected with human parainfluenza virus type 3: participation of hemagglutinin-neuraminidase in membrane fusion.
Cells persistently infected with human parainfluenza virus type 3 (HPF3) exhibit a novel phenotype. They are completely resistant to fusion with each other but readily fuse with uninfected cells. We demonstrate that the inability of these cells to fuse with each other is due to a lack of cell surface neuraminic acid. Neuraminic acid is the receptor for the HPF3 hemagglutinin-neuraminidase (HN) glycoprotein, the molecule responsible for binding of the virus to cell surfaces. Uninfected CV-1 cells were treated with neuraminidase and then tested for their ability to fuse with the persistently infected (pi) cells. Neuraminidase treatment totally abolished cell fusion. To extend this result, we used a cell line deficient in sialic acid and demonstrated that these cells, like the neuraminidase-treated CV-1 cells, were unable to fuse with pi cells. We then tested whether mimicking the agglutinating function of the HN molecule with lectins would result in cell fusion. We added a panel of five lectins to the neuraminic acid-deficient cells and showed that binding of these cells to the pi cells did not result in fusion; the lectins could not substitute for interaction of neuraminic acid with the HN molecule in promoting membrane fusion. These results provide compelling evidence that the HN molecule of HPF3 and its interaction with neuraminic acid participate in membrane fusion and that cell fusion is mediated by an interaction more complex than mere juxtaposition of the cell membranes.
Animals↗
Evidence for phenotypic mixing between newcastle disease virus (NDV) and a latent virus of BHK 21/WI-2 cells in the early passaged BHK21/WI-2 cells persistently infected with NDV.
NDV variants released from the early passaged BHK21/WI-2 cells persistently infected with NDV carry the structural antigen of a latent virus of BHK21/WI-2 cells as a result of phenotypic mixing between NDV and the latent virus.
Antigens, Viral↗
Iterferon induction in mice by BHK cells persistently infected with HVJ.
Intraperitoneal injection into mice of BHK-HVJ cells (BHK cells persistently infected with HVJ) induced considerable amounts of circulating interferon. Sonication of BHK-HVJ cells almost totally abolished their interferon inducing capacities. This result suggests that a certain native organized structure of virus infected cells might be essential for production of interferon in this system, as is suggested in the in vitro sytem.
Animals↗
Immune enhancement of the tumorigenicity of hamster brain tumor cells persistently infected with measles virus.
Studies were conducted on the tumorigenicity of a hamster brain tumor (HBT) cell line persistently infected with measles virus (MV). This cell population, termed HBT-M, exhibited decreased tumorigenicity in weanling hamsters when implanted intracutaneously. The lowered tumorigenicity of the HBT-M cells could be counteracted by concurrent hydrocortisone treatment restoring the tumor-producing capacity to levels comparable to those of the highly tumorigenic HBT cells. It was also determined that prior immunization of hamsters with MV resulted in enhancement of tumor formation from usually subtumorigenic doses of HBT-M cells. This increase in tumorigenicity appeared to correlate with high titers of MV antibody. Treatment of hamsters with cyclophosphamide resulted in a reduction of MV antibody titers and effected a decrease of HBT-M cell tumorigenicity to control levels. Preliminary studies with passive immunizations indicated that the enhancing factor could be transferred in the sera from hamsters hyperimmunized with MV. These data suggested that MV antibody may potentiate the development of neoplasia of cells persistently infected with MV in a manner similar to the enhancement of tumor growth by blocking antibody.
Animals↗
Interferon-alpha treatment leads to accumulation of virus particles on the surface of cells persistently infected with the human immunodeficiency virus type 1.
The effect of interferon-alpha (IFN-alpha) on virus replication in cells acutely infected with human immunodeficiency virus type 1 (HIV-1) and virus production from cells persistently infected with HIV-1 was studied. In both cell systems, significant suppression was observed. However, this suppression was not due to protein synthesis of the major viral proteins. Electron microscopy revealed the accumulation of intact virus particles on the cell surface of the cells treated with IFN-alpha. Thus, IFN-alpha might suppress the release stage of the particle from infected cells.
Cell Line↗
Defective RNAs in mosquito cells persistently infected with Bunyamwera virus.
Viral protein and RNA synthesis were compared in BHK and Aedes albopictus C6/36 (mosquito) cells infected with Bunyamwera virus. In BHK cells host protein synthesis was inhibited and viral proteins were detected until the cells died; in C6/36 cells there was little inhibition of host proteins and viral proteins could not be detected after 36 h post-infection. Relatively more S segment RNA than L or M segment RNA was produced in infected C6/36 cells compared to BHK cells. A persistent infection of C6/36 cells was established and the cells were passaged at weekly intervals for over a year. The titre of virus released from the cells and the level of viral RNA in the cells at different passages fluctuated markedly, but there was no simple relationship between virus titre and the amount of viral RNA. Northern blot analysis of viral RNA extracted from persistently infected cells revealed the presence of subgenomic RNAs derived from the L RNA segment. These defective RNAs were not packaged into nucleocapsids. The presence of the defective RNAs did not correlate with resistance of cells cloned from the persistently infected population to superinfection with homologous virus. Hence the role of these defective RNAs in the maintenance of the persistent state remains to be elucidated.
Animals↗