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Scientific Reports Nov 2023Soft tissue sarcomas are aggressive mesenchymal-origin malignancies. Undifferentiated pleomorphic sarcoma (UPS) belongs to the aggressive, high-grade, and least...
Soft tissue sarcomas are aggressive mesenchymal-origin malignancies. Undifferentiated pleomorphic sarcoma (UPS) belongs to the aggressive, high-grade, and least characterized sarcoma subtype, affecting multiple tissues and metastasizing to many organs. The treatment of localized UPS includes surgery in combination with radiation therapy. Metastatic forms are treated with chemotherapy. Immunotherapy is a promising treatment modality for many cancers. However, the development of immunotherapy for UPS is limited due to its heterogeneity, antigenic landscape variation, lower infiltration with immune cells, and a limited number of established patient-derived UPS cell lines for preclinical research. In this study, we established and characterized a novel patient-derived UPS cell line, JBT19. The JBT19 cells express PD-L1 and collagen, a ligand of the immune checkpoint molecule LAIR-1. JBT19 cells can form spheroids in vitro and solid tumors in immunodeficient nude mice. We found JBT19 cells induce expansion of JBT19-reactive autologous and allogeneic NK, T, and NKT-like cells, and the reactivity of the expanded cells was associated with cytotoxic impact on JBT19 cells. The PD-1 and LAIR-1 ligand-expressing JBT19 cells show ex vivo immunogenicity and effective in vivo xenoengraftment properties that can offer a unique resource in the preclinical research developing novel immunotherapeutic interventions in the treatment of UPS.
Topics: Mice; Animals; Humans; B7-H1 Antigen; Mice, Nude; Ligands; Sarcoma; Histiocytoma, Malignant Fibrous; Immunotherapy; Cell Line
PubMed: 37925511
DOI: 10.1038/s41598-023-46305-7 -
Nature Communications Nov 2023Surface antigenic variation is crucial for major pathogens that infect humans. To escape the immune system, they exploit various mechanisms. Understanding these...
Surface antigenic variation is crucial for major pathogens that infect humans. To escape the immune system, they exploit various mechanisms. Understanding these mechanisms is important to better prevent and fight the deadly diseases caused. Those used by the fungus Pneumocystis jirovecii that causes life-threatening pneumonia in immunocompromised individuals remain poorly understood. Here, though this fungus is currently not cultivable, our detailed analysis of the subtelomeric sequence motifs and genes encoding surface proteins suggests that the system involves the reassortment of the repertoire of ca. 80 non-expressed genes present in each strain, from which single genes are retrieved for mutually exclusive expression. Dispersion of the new repertoires, supposedly by healthy carrier individuals, appears very efficient because identical alleles are observed in patients from different countries. Our observations reveal a unique strategy of antigenic variation. They also highlight the possible role in genome rearrangements of small imperfect mirror sequences forming DNA triplexes.
Topics: Humans; Mosaicism; Pneumocystis carinii; Antigenic Variation; DNA, Fungal
PubMed: 37919276
DOI: 10.1038/s41467-023-42685-6 -
Proceedings of the National Academy of... Nov 2023A hyperdiverse class of pathogens of humans and wildlife, including the malaria parasite , relies on multigene families to encode antigenic variation. As a result, high...
A hyperdiverse class of pathogens of humans and wildlife, including the malaria parasite , relies on multigene families to encode antigenic variation. As a result, high (asymptomatic) prevalence is observed despite high immunity in local populations under high-transmission settings. The vast diversity of "strains" and genes encoding this variation challenges the application of established models for the population dynamics of such infectious diseases. Agent-based models have been formulated to address theory on strain coexistence and structure, but their complexity can limit application to gain insights into population dynamics. Motivated by malaria, we develop an alternative formulation in the form of a structured susceptible-infected-susceptible population model in continuous time, where individuals are classified not only by age, as is standard, but also by the diversity of parasites they have been exposed to and retain in their specific immune memory. We analyze the population dynamics and bifurcation structure of this system of partial-differential equations, showing the existence of alternative steady states and an associated tipping point with transmission intensity. We attribute the critical transition to the positive feedback between parasite genetic diversity and force of infection. Basins of attraction show that intervention must drastically reduce diversity to prevent a rebound to high infection levels. Results emphasize the importance of explicitly considering pathogen diversity and associated specific immune memory in the population dynamics of hyperdiverse epidemiological systems. This statement is discussed in a more general context for ecological competition systems with hyperdiverse trait spaces.
Topics: Animals; Humans; Epidemiological Models; Immunologic Memory; Malaria, Falciparum; Plasmodium falciparum; Malaria; Parasites; Genetic Variation
PubMed: 37910552
DOI: 10.1073/pnas.2218499120 -
BioRxiv : the Preprint Server For... Oct 2023The genomes of and trypanosomes are organized into polycistronic transcription units flanked by a modified DNA base J involved in promoting RNA polymerase II (Pol II)...
The genomes of and trypanosomes are organized into polycistronic transcription units flanked by a modified DNA base J involved in promoting RNA polymerase II (Pol II) termination. We recently characterized a complex containing a J-binding protein, PP1 protein phosphatase 1, and PP1 regulatory protein (PNUTS) that controls transcription termination potentially via dephosphorylation of Pol II by PP1. While contains eight PP1 isoforms, none purified with the PNUTS complex, suggesting a unique PP1-independent mechanism of termination. We now demonstrate that the PP1-binding motif of TbPNUTS is required for function in termination and that TbPP1-1 modulates Pol II termination in involving dephosphorylation of the C-terminal domain of the large subunit of Pol II. PP1-1 knock-down results in increased cellular levels of phosphorylated large subunit of Pol II accompanied by readthrough transcription and pervasive transcription of the entire genome by Pol II, including Pol I transcribed loci that are typically silent, such as telomeric VSG expression sites involved in antigenic variation and production of TERRA RNA. These results provide important insights into the mechanism underlying Pol II transcription termination in primitive eukaryotes that rely on polycistronic transcription and maintain allelic exclusion of VSG genes.
PubMed: 37905150
DOI: 10.1101/2023.10.21.563358 -
Viruses Sep 2023Swine influenza is a respiratory disease that affects the pork industry and is a public health threat. It is caused by type A influenza virus (FLUAV), which continuously...
Swine influenza is a respiratory disease that affects the pork industry and is a public health threat. It is caused by type A influenza virus (FLUAV), which continuously undergoes genetic and antigenic variations. A large amount of information regarding FLUAV in pigs is available worldwide, but it is limited in Latin America. The HA sequences of H1 subtype FLUAV-positive samples obtained from pigs in Colombia between 2008-2021 were analyzed using sequence-based antigenic cartography and N-Glycosylation analyses. Of the 12 predicted global antigenic groups, Colombia contained five: four corresponding to pandemic strains and one to the classical swine H1N1 clade. Circulation of these clusters was observed in some regions during specific years. Ca2 was the immunodominant epitope among Colombian viruses. The counts of N-Glycosylation motifs were associated with the antigenic cluster ranging from three to five. The results show for the first time the existence of antigenic diversity of FLUAV in Colombia and highlight the impact of spatial and temporal factors on this diversity. This study provides information about FLUAV variability in pigs under natural conditions in the absence of vaccination and emphasizes the need for surveillance of its phylogenetic and antigenic characteristics.
Topics: Swine; Animals; Humans; Colombia; Influenza A Virus, H1N1 Subtype; Phylogeny; Hemagglutinin Glycoproteins, Influenza Virus; Orthomyxoviridae Infections; Influenza, Human; Antigenic Variation; Swine Diseases
PubMed: 37896808
DOI: 10.3390/v15102030 -
Viruses Sep 2023Respiratory syncytial virus (RSV) infections are a constant public health problem, especially in infants and older adults. Virtually all children will have been infected... (Review)
Review
Respiratory syncytial virus (RSV) infections are a constant public health problem, especially in infants and older adults. Virtually all children will have been infected with RSV by the age of two, and reinfections are common throughout life. Since antigenic variation, which is frequently observed among other respiratory viruses such as SARS-CoV-2 or influenza viruses, can only be observed for RSV to a limited extent, reinfections may result from short-term or incomplete immunity. After decades of research, two RSV vaccines were approved to prevent lower respiratory tract infections in older adults. Recently, the FDA approved a vaccine for active vaccination of pregnant women to prevent severe RSV disease in infants during their first RSV season. This review focuses on the host response to RSV infections mediated by epithelial cells as the first physical barrier, followed by responses of the innate and adaptive immune systems. We address possible RSV-mediated immunomodulatory and pathogenic mechanisms during infections and discuss the current vaccine candidates and alternative treatment options.
Topics: Infant; Child; Female; Pregnancy; Humans; Aged; Respiratory Syncytial Virus Infections; Reinfection; Respiratory Syncytial Viruses; Immunity; Vaccines; Respiratory Syncytial Virus Vaccines; Respiratory Syncytial Virus, Human
PubMed: 37896776
DOI: 10.3390/v15101999 -
Nature Microbiology Nov 2023Malaria-associated pathogenesis such as parasite invasion, egress, host cell remodelling and antigenic variation requires concerted action by many proteins, but the...
Malaria-associated pathogenesis such as parasite invasion, egress, host cell remodelling and antigenic variation requires concerted action by many proteins, but the molecular regulation is poorly understood. Here we have characterized an essential Plasmodium-specific Apicomplexan AP2 transcription factor in Plasmodium falciparum (PfAP2-P; pathogenesis) during the blood-stage development with two peaks of expression. An inducible knockout of gene function showed that PfAP2-P is essential for trophozoite development, and critical for var gene regulation, merozoite development and parasite egress. Chromatin immunoprecipitation sequencing data collected at timepoints matching the two peaks of pfap2-p expression demonstrate PfAP2-P binding to promoters of genes controlling trophozoite development, host cell remodelling, antigenic variation and pathogenicity. Single-cell RNA sequencing and fluorescence-activated cell sorting revealed de-repression of most var genes in Δpfap2-p parasites. Δpfap2-p parasites also overexpress early gametocyte marker genes, indicating a regulatory role in sexual stage conversion. We conclude that PfAP2-P is an essential upstream transcriptional regulator at two distinct stages of the intra-erythrocytic development cycle.
Topics: Animals; Parasites; Malaria; Gene Expression Regulation; Plasmodium falciparum; Plasmodium
PubMed: 37884813
DOI: 10.1038/s41564-023-01497-6 -
Cell Nov 2023The large-scale evolution of the SARS-CoV-2 virus has been marked by rapid turnover of genetic clades. New variants show intrinsic changes, notably increased...
The large-scale evolution of the SARS-CoV-2 virus has been marked by rapid turnover of genetic clades. New variants show intrinsic changes, notably increased transmissibility, and antigenic changes that reduce cross-immunity induced by previous infections or vaccinations. How this functional variation shapes global evolution has remained unclear. Here, we establish a predictive fitness model for SARS-CoV-2 that integrates antigenic and intrinsic selection. The model is informed by tracking of time-resolved sequence data, epidemiological records, and cross-neutralization data of viral variants. Our inference shows that immune pressure, including contributions of vaccinations and previous infections, has become the dominant force driving the recent evolution of SARS-CoV-2. The fitness model can serve continued surveillance in two ways. First, it successfully predicts the short-term evolution of circulating strains and flags emerging variants likely to displace the previously predominant variant. Second, it predicts likely antigenic profiles of successful escape variants prior to their emergence.
Topics: Humans; COVID-19; SARS-CoV-2; Vaccination; Models, Genetic; Epidemiological Monitoring
PubMed: 37875109
DOI: 10.1016/j.cell.2023.09.022 -
Proceedings of the National Academy of... Oct 2023Antigenic variation is the main immune escape mechanism for RNA viruses like influenza or SARS-CoV-2. While high mutation rates promote antigenic escape, they also...
Antigenic variation is the main immune escape mechanism for RNA viruses like influenza or SARS-CoV-2. While high mutation rates promote antigenic escape, they also induce large mutational loads and reduced fitness. It remains unclear how this cost-benefit trade-off selects the mutation rate of viruses. Using a traveling wave model for the coevolution of viruses and host immune systems in a finite population, we investigate how immunity affects the evolution of the mutation rate and other nonantigenic traits, such as virulence. We first show that the nature of the wave depends on how cross-reactive immune systems are, reconciling previous approaches. The immune-virus system behaves like a Fisher wave at low cross-reactivities, and like a fitness wave at high cross-reactivities. These regimes predict different outcomes for the evolution of nonantigenic traits. At low cross-reactivities, the evolutionarily stable strategy is to maximize the speed of the wave, implying a higher mutation rate and increased virulence. At large cross-reactivities, where our estimates place H3N2 influenza, the stable strategy is to increase the basic reproductive number, keeping the mutation rate to a minimum and virulence low.
Topics: Humans; Influenza, Human; Influenza A Virus, H3N2 Subtype; Antigenic Variation; RNA Viruses; Hemagglutinin Glycoproteins, Influenza Virus
PubMed: 37871216
DOI: 10.1073/pnas.2307712120 -
Emerging Microbes & Infections Dec 2023The emergence of SARS-CoV-2 recombinants is of particular concern as they can result in a sudden increase in immune evasion due to antigenic shift. Recent recombinants...
The emergence of SARS-CoV-2 recombinants is of particular concern as they can result in a sudden increase in immune evasion due to antigenic shift. Recent recombinants XBB and XBB.1.5 have higher transmissibility than previous recombinants such as "Deltacron." We hypothesized that immunity to a SARS-CoV-2 recombinant depends on prior exposure to its parental strains. To test this hypothesis, we examined whether Delta or Omicron (BA.1 or BA.2) immunity conferred through infection, vaccination, or breakthrough infection could neutralize Deltacron and XBB/XBB.1.5 recombinants. We found that Delta, BA.1, or BA.2 breakthrough infections provided better immune protection against Deltacron and its parental strains than did the vaccine booster. None of the sera were effective at neutralizing the XBB lineage or its parent BA.2.75.2, except for the sera from the BA.2 breakthrough group. These results support our hypothesis. In turn, our findings underscore the importance of multivalent vaccines that correspond to the antigenic profile of circulating variants of concern and of variant-specific diagnostics that may guide public health and individual decisions in response to emerging SARS-CoV-2 recombinants.
Topics: Humans; SARS-CoV-2; COVID-19; Vaccination; Antigenic Drift and Shift; Breakthrough Infections; Antibodies, Neutralizing; Antibodies, Viral
PubMed: 37869789
DOI: 10.1080/22221751.2023.2270071