Browsing by MeSH term "Immune Evasion"
Now showing 1 - 7 of 7
Results Per Page
Sort Options
Publication Biofilm formation avoids complement immunity and phagocytosis of Streptococcus pneumoniae(American Society for Microbiology (ASM), 2013-07) Domenech, Mirian; Ramos-Sevillano, Elisa; García, Ernesto; Moscoso, Miriam; Yuste, Jose Enrique; Ministerio de Economía y Competitividad (España); Centro de Investigación Biomedica en Red - CIBERStreptococcus pneumoniae is a frequent member of the microbiota of the human nasopharynx. Colonization of the nasopharyngeal tract is a first and necessary step in the infectious process and often involves the formation of sessile microbial communities by this human pathogen. The ability to grow and persist as biofilms is an advantage for many microorganisms, because biofilm-grown bacteria show reduced susceptibility to antimicrobial agents and hinder recognition by the immune system. The extent of host protection against biofilm-related pneumococcal disease has not been determined yet. Using pneumococcal strains growing as planktonic cultures or as biofilms, we have investigated the recognition of S. pneumoniae by the complement system and its interactions with human neutrophils. Deposition of C3b, the key complement component, was impaired on S. pneumoniae biofilms. In addition, binding of C-reactive protein and the complement component C1q to the pneumococcal surface was reduced in biofilm bacteria, demonstrating that pneumococcal biofilms avoid the activation of the classical complement pathway. In addition, recruitment of factor H, the downregulator of the alternative pathway, was enhanced by S. pneumoniae growing as biofilms. Our results also show that biofilm formation diverts the alternative complement pathway activation by a PspC-mediated mechanism. Furthermore, phagocytosis of pneumococcal biofilms was also impaired. The present study confirms that biofilm formation in S. pneumoniae is an efficient means of evading both the classical and the PspC-dependent alternative complement pathways the host immune system.Publication Emergence of Amoxicillin-Resistant Variants of Spain9V-ST156 Pneumococci Expressing Serotype 11A Correlates with Their Ability to Evade the Host Immune Response(Public Library of Science (PLOS), 2015) Aguinagalde, Leire; Corsini, Bruno; Domenech, Arnau; Domenech Lucas, Mirian; Cámara, Jordi; Ardanuy, Carmen; García, Ernesto; Liñares, Josefina; Fenoll, Asuncion; Yuste, Jose EnriqueCapsular switching allows pre-existing clones of Streptococcus pneumoniae expressing vaccine serotypes to escape the vaccine-induced immunity by acquisition of capsular genes from pneumococci of a non-vaccine serotype. Here, we have analysed the clonal composition of 492 clinical isolates of serotype 11A causing invasive disease in Spain (2000-2012), and their ability to evade the host immune response. Antibiograms, serotyping and molecular typing were performed. The restriction profiles of pbp2x, pbp1a and pbp2b genes were also analysed. Interaction with the complement components C1q, C3b, C4BP, and factor H was explored whereas opsonophagocytosis assays were performed using a human cell line differentiated to neutrophils. Biofilm formation and the polymorphisms of the major autolysin LytA were evaluated. The main genotypes of the 11A pneumococci were: ST62 (447 isolates, 90.6%), followed by ST6521 (35 isolates, 7.3%) and ST838 (10 isolates, 2.1%). Beta lactam resistant serotype 11A variants of genotypes ST838 and ST6521 closely related to the Spain9V-ST156 clone were first detected in 2005. A different pattern of evasion of complement immunity and phagocytosis was observed between genotypes. The emergence of one vaccine escape variant of Spain9V-ST156 (ST652111A), showing a high potential to avoid the host immune response, was observed. In addition, isolates of ST652111A showed higher ability to produce biofilms than ST83811A or ST6211A, which may have contributed to the emergence of this PEN-resistant ST652111A genotype in the last few years. The emergence of penicillin-resistant 11A invasive variants of the highly successful ST156 clonal complex merits close monitoring.Publication Functional Genomic Screen Identifies Klebsiella pneumoniae Factors Implicated in Blocking Nuclear Factor kappa B (NF-kappa B) Signaling(Amer Soc Biochemistry Molecular Biology Inc, 2015-07-03) Tomas, Anna; Lery, Leticia; Regueiro, Veronica; Perez-Gutierrez, Camino; Martinez, Veronica; Moranta, David; Llobet, Enrique; González-Nicolau, María Del Mar; Insua, Jose L; Tomas, Juan M; Sansonetti, Philippe J; Tournebize, Regis; Bengoechea, Jose AntonioKlebsiella pneumoniae is an etiologic agent of community-acquired and nosocomial pneumonia. It has been shown that K. pneumoniae infections are characterized by reduced early inflammatory response. Recently our group has shown that K. pneumoniae dampens the activation of inflammatory responses by antagonizing the activation of the NF-kappa B canonical pathway. Our results revealed that K. pneumoniae capsule polysaccharide (CPS) was necessary but not sufficient to attenuate inflammation. To identify additional Klebsiella factors required to dampen inflammation, we standardized and applied a high-throughput gain-of-function screen to examine a Klebsiella transposon mutant library. We identified 114 mutants that triggered the activation of NF-kappa B. Two gene ontology categories accounted for half of the loci identified in the screening: metabolism and transport genes (32% of the mutants) and envelope-related genes (17%). Characterization of the mutants revealed that the lack of the enterobactin siderophore was linked to a reduced CPS expression, which in turn underlined the NF-kappa B activation induced by the mutant. The lipopolysaccharide (LPS) O-polysaccharide and the pullulanase (PulA) type 2 secretion system (T2SS) are required for full effectiveness of the immune evasion. Importantly, these factors do not play a redundant role. The fact that LPS O-polysaccharide and T2SS mutant-induced responses were dependent on TLR2-TLR4-MyD88 activation suggested that LPS O-polysaccharide and PulA perturbed Toll-like receptor (TLR)-dependent recognition of K. pneumoniae. Finally, we demonstrate that LPS O-polysaccharide and pulA mutants are attenuated in the pneumonia mouse model. We propose that LPS O-polysaccharide and PulA T2SS could be new targets for the design of new antimicrobials. Increasing TLR-governed defense responses might provide also selective alternatives for the management of K. pneumoniae pneumonia.Publication Genetic and Epigenetic Biomarkers of Immune Checkpoint Blockade Response(Multidisciplinary Digital Publishing Institute (MDPI), 2020-01-20) Xiao, Qingyang; Nobre, André; Piñeiro, Pilar; Berciano-Guerrero, Miguel-Ángel; Alba, Emilio; Cobo, Manuel; Lauschke, Volker M.; Barragán, Isabel; [Xiao,Q; Nobre,A; Berciano-Guerrero,MA; Barragán,I] Group of Pharmacoepigenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. [Xiao,Q; Piñeiro,P; Berciano-Guerrero,MA; Alba,E; Cobo,M; Barragán,I] Section of Immuno-Oncology, Medical Oncology Service, University Hospitals Regional and Virgen de la Victoria, Biomedical Research Institute of Malaga (IBIMA), Málaga, Spain. [Lauschke,VM] Group of Personalized Medicine and Drug Development, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.Checkpoint inhibitor therapy constitutes a promising cancer treatment strategy that targets the immune checkpoints to re-activate silenced T cell cytotoxicity. In recent pivotal trials, immune checkpoint blockade (ICB) demonstrated durable responses and acceptable toxicity, resulting in the regulatory approval of 8 checkpoint inhibitors to date for 15 cancer indications. However, up to ~85% of patients present with innate or acquired resistance to ICB, limiting its clinical utility. Current response biomarker candidates, including DNA mutation and neoantigen load, immune profiles, as well as programmed death-ligand 1 (PD-L1) expression, are only weak predictors of ICB response. Thus, identification of novel, more predictive biomarkers that could identify patients who would benefit from ICB constitutes one of the most important areas of immunotherapy research. Aberrant DNA methylation (5mC) and hydroxymethylation (5hmC) were discovered in multiple cancers, and dynamic changes of the epigenomic landscape have been identified during T cell differentiation and activation. While their role in cancer immunosuppression remains to be elucidated, recent evidence suggests that 5mC and 5hmC may serve as prognostic and predictive biomarkers of ICB-sensitive cancers. In this review, we describe the role of epigenetic phenomena in tumor immunoediting and other immune evasion related processes, provide a comprehensive update of the current status of ICB-response biomarkers, and highlight promising epigenomic biomarker candidates.Publication Hookworms Evade Host Immunity by Secreting a Deoxyribonuclease to Degrade Neutrophil Extracellular Traps.(Cell Press, 2020) Bouchery, Tiffany; Moyat, Mati; Sotillo, Javier; Silverstein, Solomon; Volpe, Beatrice; Coakley, Gillian; Tsourouktsoglou, Theodora-Dorita; Becker, Luke; Shah, Kathleen; Kulagin, Manuel; Guiet, Romain; Camberis, Mali; Schmidt, Alfonso; Seitz, Arne; Giacomin, Paul; Le Gros, Graham; Papayannopoulos, Venizelos; Loukas, Alex; Harris, Nicola L; Swiss National Science Foundation; National Health and Medical Research Council (Australia)Hookworms cause a major neglected tropical disease, occurring after larvae penetrate the host skin. Neutrophils are phagocytes that kill large pathogens by releasing neutrophil extracellular traps (NETs), but whether they target hookworms during skin infection is unknown. Using a murine hookworm, Nippostrongylus brasiliensis, we observed neutrophils being rapidly recruited and deploying NETs around skin-penetrating larvae. Neutrophils depletion or NET inhibition altered larvae behavior and enhanced the number of adult worms following murine infection. Nevertheless, larvae were able to mitigate the effect of NETs by secreting a deoxyribonuclease (Nb-DNase II) to degrade the DNA backbone. Critically, neutrophils were able to kill larvae in vitro, which was enhanced by neutralizing Nb-DNase II. Homologs of Nb-DNase II are present in other nematodes, including the human hookworm, Necator americanus, which also evaded NETs in vitro. These findings highlight the importance of neutrophils in hookworm infection and a potential conserved mechanism of immune evasion.Publication Immune activation promotes evolutionary conservation of T-cell epitopes in HIV-1(Public Library of Science (PLOS), 2013-04-02) Sanjuán, Rafael; Nebot, Miguel R; Peris, Joan B; Alcamí, José; Ministerio de Ciencia e Innovación (España); Unión Europea. Comisión Europea. European Research Council (ERC); Instituto de Salud Carlos III; Red de Investigación Cooperativa en Investigación en Sida (España)The immune system should constitute a strong selective pressure promoting viral genetic diversity and evolution. However, HIV shows lower sequence variability at T-cell epitopes than elsewhere in the genome, in contrast with other human RNA viruses. Here, we propose that epitope conservation is a consequence of the particular interactions established between HIV and the immune system. On one hand, epitope recognition triggers an anti-HIV response mediated by cytotoxic T-lymphocytes (CTLs), but on the other hand, activation of CD4(+) helper T lymphocytes (TH cells) promotes HIV replication. Mathematical modeling of these opposite selective forces revealed that selection at the intrapatient level can promote either T-cell epitope conservation or escape. We predict greater conservation for epitopes contributing significantly to total immune activation levels (immunodominance), and when TH cell infection is concomitant to epitope recognition (trans-infection). We suggest that HIV-driven immune activation in the lymph nodes during the chronic stage of the disease may offer a favorable scenario for epitope conservation. Our results also support the view that some pathogens draw benefits from the immune response and suggest that vaccination strategies based on conserved TH epitopes may be counterproductive.Publication The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells.(BMJ Publishing Group, 2024-08-08) López-Gil, Juan Carlos; García-Silva, Susana; Ruiz-Cañas, Laura; Navarro, Diego; Palencia-Campos, Adrián; Giráldez-Trujillo, Antonio; Earl, Julie; Dorado, Jorge; Gómez-López, Gonzalo; Monfort-Vengut, Ana; Alcalá, Sonia; Gaida, Matthias M; García-Mulero, Sandra; Cabezas-Sáinz, Pablo; Batres-Ramos, Sandra; Barreto, Emma; Sánchez-Tomero, Patricia; Vallespinós, Mireia; Ambler, Leah; Lin, Meng-Lay; Aicher, Alexandra; García García de Paredes, Ana; de la Pinta, Carolina; Sanjuanbenito, Alfonso; Ruz-Caracuel, Ignacio; Rodríguez-Garrote, Mercedes; Guerra, Carmen; Carrato, Alfredo; de Cárcer, Guillermo; Sánchez, Laura; Nombela-Arrieta, César; Espinet, Elisa; Sanchez-Arevalo Lobo, Víctor Javier; Heeschen, Christopher; Sainz, Bruno; Fundación La Caixa; EMBO Scientific Exchange Fellowship; Juan de la Cierva Formacion; Fero Foundation Grant; Ministerio de Economía y Competitividad (España); Asociación Española Contra el Cáncer; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Centro de Investigación Biomédica en Red - CIBERONC (Cáncer); Xunta de Galicia (España); University of Zurich; German Research Foundation (DFG); Unión Europea. Comisión Europea. European Research Council (ERC); Fondazione AIRC per la ricerca sul cancro; Shanghai Municipal Education Commission (SHMEC); National Natural Science Foundation of China (NSFC)OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant 'stem-like' cells, known as cancer stem cells (CSCs), are implicated in PDAC aggressiveness. Thus, comprehending how this subset of cells evades the immune system is crucial for advancing novel therapies. DESIGN: We used the KPC mouse model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) and primary tumour cell lines to investigate putative CSC populations. Transcriptomic analyses were conducted to pinpoint new genes involved in immune evasion. Overexpressing and knockout cell lines were established with lentiviral vectors. Subsequent in vitro coculture assays, in vivo mouse and zebrafish tumorigenesis studies, and in silico database approaches were performed. RESULTS: Using the KPC mouse model, we functionally confirmed a population of cells marked by EpCAM, Sca-1 and CD133 as authentic CSCs and investigated their transcriptional profile. Immune evasion signatures/genes, notably the gene peptidoglycan recognition protein 1 (PGLYRP1), were significantly overexpressed in these CSCs. Modulating PGLYRP1 impacted CSC immune evasion, affecting their resistance to macrophage-mediated and T-cell-mediated killing and their tumourigenesis in immunocompetent mice. Mechanistically, tumour necrosis factor alpha (TNF?)-regulated PGLYRP1 expression interferes with the immune tumour microenvironment (TME) landscape, promoting myeloid cell-derived immunosuppression and activated T-cell death. Importantly, these findings were not only replicated in human models, but clinically, secreted PGLYRP1 levels were significantly elevated in patients with PDAC. CONCLUSIONS: This study establishes PGLYRP1 as a novel CSC-associated marker crucial for immune evasion, particularly against macrophage phagocytosis and T-cell killing, presenting it as a promising target for PDAC immunotherapy.