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Frontiers in Molecular Biosciences 2023Telomere maintenance is essential for genome integrity and chromosome stability in eukaryotic cells harboring linear chromosomes, as telomere forms a specialized... (Review)
Review
Telomere maintenance is essential for genome integrity and chromosome stability in eukaryotic cells harboring linear chromosomes, as telomere forms a specialized structure to mask the natural chromosome ends from DNA damage repair machineries and to prevent nucleolytic degradation of the telomeric DNA. In and several other microbial pathogens, virulence genes involved in antigenic variation, a key pathogenesis mechanism essential for host immune evasion and long-term infections, are located at subtelomeres, and expression and switching of these major surface antigens are regulated by telomere proteins and the telomere structure. Therefore, understanding telomere maintenance mechanisms and how these pathogens achieve a balance between stability and plasticity at telomere/subtelomere will help develop better means to eradicate human diseases caused by these pathogens. Telomere replication faces several challenges, and the "end replication problem" is a key obstacle that can cause progressive telomere shortening in proliferating cells. To overcome this challenge, most eukaryotes use telomerase to extend the G-rich telomere strand. In addition, a number of telomere proteins use sophisticated mechanisms to coordinate the telomerase-mediated telomere G-strand synthesis and the telomere C-strand fill-in, which has been extensively studied in mammalian cells. However, we recently discovered that trypanosomes lack many telomere proteins identified in its mammalian host that are critical for telomere end processing. Rather, uses a unique DNA polymerase, PolIE that belongs to the DNA polymerase A family ( DNA PolI family), to coordinate the telomere G- and C-strand syntheses. In this review, I will first briefly summarize current understanding of telomere end processing in mammals. Subsequently, I will describe PolIE-mediated coordination of telomere G- and C-strand synthesis in and implication of this recent discovery.
PubMed: 38074093
DOI: 10.3389/fmolb.2023.1302557 -
International Journal of Molecular... Nov 2023Lyme disease (LD) spirochetes are well known to be able to disseminate into the tissues of infected hosts, including humans. The diverse strategies used by spirochetes...
Lyme disease (LD) spirochetes are well known to be able to disseminate into the tissues of infected hosts, including humans. The diverse strategies used by spirochetes to avoid the host immune system and persist in the host include active immune suppression, induction of immune tolerance, phase and antigenic variation, intracellular seclusion, changing of morphological and physiological state in varying environments, formation of biofilms and persistent forms, and, importantly, incursion into immune-privileged sites such as the brain. Invasion of immune-privileged sites allows the spirochetes to not only escape from the host immune system but can also reduce the efficacy of antibiotic therapy. Here we present a case of the detection of spirochetal DNA in multiple loci in a LD patient's post-mortem brain. The presence of co-infection with sensu stricto and in this LD patient's brain was confirmed by PCR. Even though both spirochete species were simultaneously present in human brain tissue, the brain regions where the two species were detected were different and non-overlapping. The presence of atypical spirochete morphology was noted by immunohistochemistry of the brain samples. Atypical morphology was also found in the tissues of experimentally infected mice, which were used as a control.
Topics: Humans; Borrelia; Borrelia burgdorferi; Borrelia burgdorferi Group; Brain; Lyme Disease
PubMed: 38069228
DOI: 10.3390/ijms242316906 -
Nature Communications Dec 2023
PubMed: 38040716
DOI: 10.1038/s41467-023-43993-7 -
PloS One 2023The human malaria parasite Plasmodium falciparum is responsible for the majority of mortality and morbidity caused by malaria infection and differs from other human...
The human malaria parasite Plasmodium falciparum is responsible for the majority of mortality and morbidity caused by malaria infection and differs from other human malaria species in the degree of accumulation of parasite-infected red blood cells in the microvasculature, known as cytoadherence or sequestration. In P. falciparum, cytoadherence is mediated by a protein called PfEMP1 which, due to its exposure to the host immune system, undergoes antigenic variation resulting in the expression of different PfEMP1 variants on the infected erythrocyte membrane. These PfEMP1s contain various combinations of adhesive domains, which allow for the differential engagement of a repertoire of endothelial receptors on the host microvasculature, with specific receptor usage associated with severe disease. We used a co-culture model of cytoadherence incubating human brain microvascular endothelial cells with erythrocytes infected with two parasite lines expressing different PfEMP1s that demonstrate different binding profiles to vascular endothelium. We determined the transcriptional profile of human brain microvascular endothelial cells (HBMEC) following different incubation periods with infected erythrocytes, identifying different transcriptional profiles of pathways previously found to be involved in the pathology of severe malaria, such as inflammation, apoptosis and barrier integrity, induced by the two PfEMP1 variants.
Topics: Humans; Plasmodium falciparum; Endothelial Cells; Coculture Techniques; Protozoan Proteins; Malaria, Falciparum; Erythrocytes; Endothelium, Vascular; Cell Adhesion
PubMed: 38033133
DOI: 10.1371/journal.pone.0295053 -
Journal of Family Medicine and Primary... Sep 2023The COVID-19 pandemic is considered one of the most devastating situations globally, the worst affected were the senior citizens. A number of initiatives were carried...
Assessment of lung involvement using HRCT among vaccinated and non-vaccinated elderly COVID-19 patients admitted in a designated hospital, Tamil Nadu - A retrospective study.
INTRODUCTION
The COVID-19 pandemic is considered one of the most devastating situations globally, the worst affected were the senior citizens. A number of initiatives were carried out to control the COVID-19 pandemic; one such important measure is the development of COVID-19 vaccines to prevent the disease. But the continuous emergence of new SARS-COV2 variants (antigenic drift) and its demographic variation in virulence makes the vaccine's efficacy questionable. This study is intended to evaluate the association between the degree of lung involvement and the effectiveness of vaccination against the disease in cases admitted to a designated hospital in Tamil Nadu.
MATERIALS AND METHODS
A hospital records-based-retrospective research was conducted among COVID-19 patients admitted from the 1 of April 2021 to the 31 of May 2021, and information was gathered regarding their vaccination status, comorbid conditions, and CT severity score (CTSS) in the HRCT lung report. A consecutive sampling technique was used to choose the study participants; about 120 participants were included in the study. The Chi-square test and Fisher's extract test were used to evaluate the hypothesis. The relationship between a dependent variable and independent factors was estimated using multiple linear regression.
RESULTS
Among 120 participants, about 60.2% were males and 39.8% were females. Vaccination status and comorbid conditions had a significant association with severe lung involvement in COVID-19 patients.
CONCLUSION
Non-vaccinated patients had severe lung involvement based on the HRCT lung scan findings than the vaccinated patients. To reduce mortality, it is essential to ensure universal coverage of COVID-19 vaccination.
PubMed: 38024934
DOI: 10.4103/jfmpc.jfmpc_2491_22 -
ELife Nov 2023African trypanosomes evade host immune clearance by antigenic variation, causing persistent infections in humans and animals. These parasites express a homogeneous...
African trypanosomes evade host immune clearance by antigenic variation, causing persistent infections in humans and animals. These parasites express a homogeneous surface coat of variant surface glycoproteins (VSGs). They transcribe one out of hundreds of VSG genes at a time from telomeric expression sites (ESs) and periodically change the VSG expressed by transcriptional switching or recombination. The mechanisms underlying the control of VSG switching and its developmental silencing remain elusive. We report that telomeric ES activation and silencing entail an on/off genetic switch controlled by a nuclear phosphoinositide signaling system. This system includes a nuclear phosphatidylinositol 5-phosphatase (PIP5Pase), its substrate PI(3,4,5)P3, and the repressor-activator protein 1 (RAP1). RAP1 binds to ES sequences flanking VSG genes via its DNA binding domains and represses VSG transcription. In contrast, PI(3,4,5)P3 binds to the N-terminus of RAP1 and controls its DNA binding activity. Transient inactivation of PIP5Pase results in the accumulation of nuclear PI(3,4,5)P3, which binds RAP1 and displaces it from ESs, activating transcription of silent ESs and VSG switching. The system is also required for the developmental silencing of VSG genes. The data provides a mechanism controlling reversible telomere silencing essential for the periodic switching in VSG expression and its developmental regulation.
Topics: Animals; Humans; Allosteric Regulation; Transcription Factor AP-1; Trypanosoma; Antigenic Variation; DNA
PubMed: 38019264
DOI: 10.7554/eLife.89331 -
Proceedings of the National Academy of... Nov 2023RNA-DNA hybrids are epigenetic features of all genomes that intersect with many processes, including transcription, telomere homeostasis, and centromere function....
RNA-DNA hybrids are epigenetic features of all genomes that intersect with many processes, including transcription, telomere homeostasis, and centromere function. Increasing evidence suggests that RNA-DNA hybrids can provide two conflicting roles in the maintenance and transmission of genomes: They can be the triggers of DNA damage, leading to genome change, or can aid the DNA repair processes needed to respond to DNA lesions. Evasion of host immunity by African trypanosomes, such as , relies on targeted recombination of silent Variant Surface Glycoprotein () genes into a specialized telomeric locus that directs transcription of just one from thousands. How such recombination is targeted and initiated is unclear. Here, we show that a key enzyme of homologous recombination, RAD51, interacts with RNA-DNA hybrids. In addition, we show that RNA-DNA hybrids display a genome-wide colocalization with DNA breaks and that this relationship is impaired by mutation of RAD51. Finally, we show that RAD51 acts to repair highly abundant, localised DNA breaks at the single transcribed and that mutation of RAD51 alters RNA-DNA hybrid abundance at 70 bp repeats both around the transcribed and across the silent archive. This work reveals a widespread, generalised role for RNA-DNA hybrids in directing RAD51 activity during recombination and uncovers a specialised application of this interplay during targeted DNA break repair needed for the critical immune evasion reaction of antigenic variation.
Topics: Trypanosoma brucei brucei; R-Loop Structures; Antigenic Variation; DNA Breaks; DNA; RNA; Variant Surface Glycoproteins, Trypanosoma
PubMed: 37988471
DOI: 10.1073/pnas.2309306120 -
PLoS Pathogens Nov 2023Foot-and-mouth disease virus (FMDV) serotype A is antigenically most variable within serotypes. The structures of conserved and variable antigenic sites were not well...
Foot-and-mouth disease virus (FMDV) serotype A is antigenically most variable within serotypes. The structures of conserved and variable antigenic sites were not well resolved. Here, a historical A/AF72 strain from A22 lineage and a latest A/GDMM/2013 strain from G2 genotype of Sea97 lineage were respectively used as bait antigen to screen single B cell antibodies from bovine sequentially vaccinated with A/WH/CHA/09 (G1 genotype of Sea97 lineage), A/GDMM/2013 and A/AF72 antigens. Total of 39 strain-specific and 5 broad neutralizing antibodies (bnAbs) were isolated and characterized. Two conserved antigenic sites were revealed by the Cryo-EM structures of FMDV serotype A with two bnAbs W2 and W125. The contact sites with both VH and VL of W125 were closely around icosahedral threefold axis and covered the B-C, E-F, and H-I loops on VP2 and the B-B knob and H-I loop on VP3; while contact sites with only VH of W2 concentrated on B-B knob, B-C and E-F loops on VP3 scattering around the three-fold axis of viral particle. Additional highly conserved epitopes also involved key residues of VP158, VP1147 and both VP272 / VP1147 as determined respectively by bnAb W153, W145 and W151-resistant mutants. Furthermore, the epitopes recognized by 20 strain-specific neutralization antibodies involved the key residues located on VP3 68 for A/AF72 (11/20) and VP3 175 position for A/GDMM/2013 (9/19), respectively, which revealed antigenic variation between different strains of serotype A. Analysis of antibody-driven variations on capsid of two virus strains showed a relatively stable VP2 and more variable VP3 and VP1. This study provided important information on conserve and variable antigen structures to design broad-spectrum molecular vaccine against FMDV serotype A.
Topics: Animals; Cattle; Antibodies, Neutralizing; Foot-and-Mouth Disease Virus; Serogroup; Antibodies, Viral; Broadly Neutralizing Antibodies; Epitopes; Capsid Proteins; Antibodies, Monoclonal; Foot-and-Mouth Disease
PubMed: 37983290
DOI: 10.1371/journal.ppat.1011811 -
Frontiers in Microbiology 2023African trypanosomiasis, a neglected tropical disease, is caused by diverse species of the protozoan parasite belonging to the genus . Although anti-trypanosomal...
African trypanosomiasis, a neglected tropical disease, is caused by diverse species of the protozoan parasite belonging to the genus . Although anti-trypanosomal medications exist, the increase in drug resistance and persistent antigenic variation has necessitated the development of newer and more efficacious therapeutic agents which are selectively toxic to the parasite. In this study, we assessed the trypanocidal efficacy of leaf extract (-extract) . Following treatment of parasites with -extract, we observed a significant decrease in parasite number and an elevation in the expression of the apoptotic markers, Annexin V and 7-Aminoactinomycin D (7AAD). Interestingly, at the same concentration (50 μg/mL), -extract was not cytotoxic to murine whole splenocytes. We also observed a significant increase in pro-inflammatory cytokines and nitric oxide secretion by bone marrow derived macrophages following treatment with (10 μg/mL and 50 μg/mL) compared to PBS treated controls, suggesting that the extract possesses an immune regulatory effect. Treatment of infected mice with -extract led to significant decrease in parasite numbers and a modest increase in mouse survival compared to PBS treated controls. In addition, there was a significant increase in CD4IFN-γ T cells and a decrease in CD4IL-10 T cells in the spleens of infected mice treated with -extract. Interestingly, -extract treatment decreased the activity of superoxide dismutase (an enzyme that protects unicellular organisms from oxidative stress) in parasites but not in splenocytes. Collectively, our study has identified C.f/L-extract as a potential anti-trypanosomal agent that warrant further investigation and possibly explored as a treatment option for infection.
PubMed: 37954253
DOI: 10.3389/fmicb.2023.1275365 -
MBio Nov 2023Influenza virus hemagglutinin mediates infection by binding sialic acids, whereas neuraminidase cleaves sialic acids to release progeny virions. Both are targets of...
Influenza virus hemagglutinin mediates infection by binding sialic acids, whereas neuraminidase cleaves sialic acids to release progeny virions. Both are targets of protective antibodies, but influenza vaccine strain selection and antigen dose are based on hemagglutinin alone. Virus characterization using first infection ferret sera indicates that escape from hemagglutination inhibiting (HI) antibodies occurs more frequently and is not coordinated with escape from neuraminidase inhibiting (NI) antibodies. A key question addressed by Daulagala et al. (P. Daulagala, B. R. Mann, K. Leung, E. H. Y. Lau, et al., mBio 14:e00084-23, 2023, https://doi.org/10.1128/mbio.00084-23) is how this translates to humans who encounter multiple influenza viruses throughout life. Their cross-sectional study, using sera from a wide age range of participants and H1N1 viruses spanning 1977-2015, indicates that NI antibodies are more broadly cross-reactive than HI antibodies. Both HI and NI titers were highest against strains encountered in childhood indicating that both are shaped by priming exposures. The study further supports the development of NA-optimized vaccines.
PubMed: 37933976
DOI: 10.1128/mbio.01654-23