Innate Immune Response to Streptococcus pyogenes Depends on the Combined Activation of TLR13 and TLR2

International audienceInnate immune recognition of the major human-specific Gram-positive pathogen Strepto-coccus pyogenes is not understood. Here we show that mice employ Toll-like receptor (TLR) 2-and TLR13-mediated recognition of S. pyogenes. These TLR pathways are non-redundant in the in vivo context of animal infection, but are largely redundant in vitro, as only inactivation of both of them abolishes inflammatory cytokine production by macrophages and dendritic cells infected with S. pyogenes. Mechanistically, S. pyogenes is initially recognized in a phagocytosis-independent manner by TLR2 and subsequently by TLR13 upon in-ternalization. We show that the TLR13 response is specifically triggered by S. pyogenes rRNA and that Tlr13 −/− cells respond to S. pyogenes infection solely by engagement of TLR2. TLR13 is absent from humans and, remarkably, we find no equivalent route for S. pyogenes RNA recognition in human macrophages. Phylogenetic analysis reveals that TLR13 occurs in all kingdoms but only in few mammals, including mice and rats, which are naturally resistant against S. pyogenes. Our study establishes that the dissimilar expression of TLR13 in mice and humans has functional consequences for recognition of S. pyogenes in these organisms

Case Report HPV Type 6 and 18 Coinfection in a Case of Adult-Onset Laryngeal Papillomatosis: Immunization with Gardasil

Laryngeal papillomatosis (LP) is a rare human papillomavirus (HPV) related disease that often requires multiple surgical interventions and residual impairment of voice is almost inevitable. We report the case of a patient with adult onset recurrent LP, showing moderate dysplasia and coinfection with HPV types 6 and 18. The tetravalent HPV vaccine Gardasil was prescribed off label, with the aim of triggering an immunogenic response and consequently reducing the probability of further recurrences. The patient was followed for 9 months with no sign of relapse of his LP. The postexposure use of the anti-HPV vaccine could represent a promising therapeutic agent in established LP. Unfortunately, the potential efficacy of this new therapeutic option in this situation has been suggested only by isolated case reports. Further controlled studies, with a longer follow-up and a larger sample size, are needed to assess efficacy of Gardasil in LP

Crucial Role of Nucleic Acid Sensing via Endosomal Toll-Like Receptors for the Defense of Streptococcus pyogenes in vitro and in vivo

Streptococcus pyogenes is a major human pathogen causing a variety of diseases ranging from common pharyngitis to life-threatening soft tissue infections and sepsis. Microbial nucleic acids, especially bacterial RNA, have recently been recognized as a major group of pathogen-associated molecular patterns (PAMPs) involved in the detection of Streptococcus pyogenes via endosomal Toll-like receptors (TLRs) in vitro. However, the individual contribution and cooperation between TLRs as well as cell-type and strain specific differences in dependency on nucleic acid detection during S. pyogenes infection in vitro have not been clarified in detail. Moreover, the role of particularly bacterial RNA for the defense of S. pyogenes infection in vivo remains poorly defined. In this study, we report that in all investigated innate immune cells involved in the resolution of bacterial infections, including murine macrophages, dendritic cells and neutrophils, recognition of S. pyogenes strain ATCC12344 is almost completely dependent on nucleic acid sensing via endosomal TLRs at lower MOIs, whereas at higher MOIs, detection via TLR2 plays an additional, yet redundant role. We further demonstrate that different S. pyogenes strains display a considerable inter-strain variability with respect to their nucleic acid dependent recognition. Moreover, TLR13-dependent recognition of S. pyogenes RNA is largely non-redundant in bone marrow-derived macrophages (BMDMs), but less relevant in neutrophils and bone marrow-derived myeloid dendritic cells (BMDCs) for the induction of an innate immune response in vitro. In vivo, we show that a loss of nucleic acid sensing blunts early recognition of S. pyogenes, leading to a reduced local containment of the bacterial infection with subsequent pronounced systemic inflammation at later time points. Thus, our results argue for a crucial role of nucleic acid sensing via endosomal TLRs in defense of S. pyogenes infection both in vitro and in vivo

Caffeine Prevents Transcription Inhibition and P-TEFb/7SK Dissociation Following UV-Induced DNA Damage

Background: The mechanisms by which DNA damage triggers suppression of transcription of a large number of genes are poorly understood. DNA damage rapidly induces a release of the positive transcription elongation factor b (P-TEFb) from the large inactive multisubunit 7SK snRNP complex. P-TEFb is required for transcription of most class II genes through stimulation of RNA polymerase II elongation and cotranscriptional pre-mRNA processing. Methodology/Principal Findings: We show here that caffeine prevents UV-induced dissociation of P-TEFb as well as transcription inhibition. The caffeine-effect does not involve PI3-kinase-related protein kinases, because inhibition of phosphatidylinositol 3-kinase family members (ATM, ATR and DNA-PK) neither prevents P-TEFb dissociation nor transcription inhibition. Finally, caffeine prevention of transcription inhibition is independent from DNA damage. Conclusion/Significance: Pharmacological prevention of P-TEFb/7SK snRNP dissociation and transcription inhibitio

La gestión académica en pandemia : adecuaciones, innovaciones y desafíos de la Universidad Nacional de Cuyo

Este libro remite a un contexto especial e inédito que surge a partir de la pandemia de covid-19. Se trata de un contexto de alcance global signado por efectos intensos y perdurables sobre diferentes aspectos de la realidad social, económica y ambiental. En general, estos efectos provocaron, por un lado, situaciones problemáticas nuevas y, por otro lado, agravaron situaciones problemáticas preexistentes que adquirieron mayor visibilidad. En el caso argentino, las restricciones derivadas de la pandemia agudizaron la brecha socioeducativa existente y, al mismo tiempo, exigieron una gestión ágil, dinámica, resolutiva, propositiva y resiliente, especialmente a las instituciones educativas con el objeto de asegurar el derecho a la educación y su calidad. Lógicamente, la provincia de Mendoza y, por tanto, la Universidad Nacional de Cuyo (UNCUYO) no quedaron exentas de los efectos mencionados. Aunque aún no resulta posible identificar con rigor el impacto concreto que ha tenido la pandemia sobre el funcionamiento del sistema educativo provincial, se pueden entrever algunos indicadores que vale la pena atender. Por ejemplo, el egreso en la oferta de educación superior de la uncuyo registró, en 2020, una caída interanual cercana al -18 % 1. Esta oscilación se torna más relevante si se considera que este indicador se mostraba estable a lo largo de los últimos años.Fil: Castañeda, Linda. Universidad de Murcia.Fil: Viñoles Cosentino, Virginia. Universidad de Murcia.Fil: Falcón, Paulo.Fil: Martínez, Ana María.Fil: Meljin Lombard, Mariela Beatriz. Universidad Nacional de Cuyo. Facultad de Artes y Diseño.Fil: Van Den Bosch, Silvia. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias.Fil: Castro, María Eugenia. Universidad Nacional de Cuyo. Facultad de Ciencias Aplicadas a la Industria.Fil: Puebla, Patricia. Universidad Nacional de Cuyo. Facultad de Ciencias Económicas.Fil: Sánchez, Esther Lucía. Universidad Nacional de Cuyo. Facultad de Ciencias Económicas.Fil: González Gaviola, Miguel. Universidad Nacional de Cuyo. Facultad de Ciencias Económicas.Fil: Tarabelli, María Florencia. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales.Fil: Rüttler, María Elena. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas.Fil: Nalda, Gonzalo. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas.Fil: Castiglia, Mariana. Universidad Nacional de Cuyo. Facultad de Ciencias Políticas y Sociales.Fil: Mussuto, Matías M.. Universidad Nacional de Cuyo. Facultad de Derecho.Fil: Griffouliere, María Gabriela. Universidad Nacional de Cuyo. Facultad de Educación.Fil: Verstraete, María Ana. Universidad Nacional de Cuyo. Facultad de Filosofía y Letras.Fil: Echagaray, Patricia. Universidad Nacional de Cuyo. Facultad de Odontología.Fil: Mirasso, Aníbal. Universidad Nacional de Cuyo. Facultad de Ingeniería.Fil: Molina, Fabiana. Universidad Nacional de Cuyo. Instituto Tecnológico Universitario.Fil: Corral, Patricia. Universidad Nacional de Cuyo. Instituto Universitario de Seguridad Pública.Fil: Chrabalowski, Marina. Universidad Nacional de Cuyo.Fil: Barrozo, María Ana. Universidad Nacional de Cuyo.Fil: Zabala, Cecilia. Universidad Nacional de Cuyo. Escuela de Comercio Martín Zapata.Fil: Sauer, Marcelo. Universidad Nacional de Cuyo.Fil: Romero Day, Marcela. Universidad Nacional de Cuyo. Liceo Agrícola y Enológico Domingo F. Sarmiento.Fil: Marlia, Nora. Universidad Nacional de Cuyo. Facultad de Filosofía y Letras. Departamento de Aplicación Docente.Fil: Zamorano, Cristina. Universidad Nacional de Cuyo. Colegio Universitario Central.Fil: Yapura, Susana. Universidad Nacional de Cuyo. Escuela del Magisterio.Fil: Navarro, María Fernanda. Universidad Nacional de Cuyo.Fil: Bosio, Iris Viviana. Universidad Nacional de Cuyo. EDIUNC.Fil: Degiorgi, Horacio. Universidad Nacional de Cuyo. Sistema Integrado de Documentación.Fil: Bocco, María Susana. Universidad Nacional de Cuyo.Fil: Guayco, Mariana. Universidad Nacional de Cuyo.Fil: Pizzi, Daniel. Universidad Nacional de Cuyo.Fil: Lettelier, Dolores. Universidad Nacional de Cuyo. Secretaría Académica

Rhinoscleroma pathogenesis: The type K3 capsule of Klebsiella rhinoscleromatis is a virulence factor not involved in Mikulicz cells formation.

Rhinoscleroma is a human specific chronic granulomatous infection of the nose and upper airways caused by the Gram-negative bacterium Klebsiella pneumoniae subsp. rhinoscleromatis. Although considered a rare disease, it is endemic in low-income countries where hygienic conditions are poor. A hallmark of this pathology is the appearance of atypical foamy monocytes called Mikulicz cells. However, the pathogenesis of rhinoscleroma remains poorly investigated. Capsule polysaccharide (CPS) is a prominent virulence factor in bacteria. All K. rhinoscleromatis strains are of K3 serotype, suggesting that CPS can be an important driver of rhinoscleroma disease. In this study, we describe the creation of the first mutant of K. rhinoscleromatis, inactivated in its capsule export machinery. Using a murine model recapitulating the formation of Mikulicz cells in lungs, we observed that a K. rhinoscleromatis CPS mutant (KR cps-) is strongly attenuated and that mice infected with a high dose of KR cps- are still able to induce Mikulicz cells formation, unlike a K. pneumoniae capsule mutant, and to partially recapitulate the characteristic strong production of IL-10. Altogether, the results of this study show that CPS is a virulence factor of K. rhinoscleromatis not involved in the specific appearance of Mikulicz cells

HPV Type 6 and 18 coinfection in a case of adult-onset laryngeal papillomatosis: Immunization with Gardasil

Laryngeal papillomatosis (LP) is a rare human papillomavirus (HPV) related disease that often requires multiple surgical interventions and residual impairment of voice is almost inevitable. We report the case of a patient with adult onset recurrent LP, showing moderate dysplasia and coinfection with HPV types 6 and 18. The tetravalent HPV vaccine Gardasil was prescribed off label, with the aim of triggering an immunogenic response and consequently reducing the probability of further recurrences. The patient was followed for 9 months with no sign of relapse of his LP. The postexposure use of the anti-HPV vaccine could represent a promising therapeutic agent in established LP. Unfortunately, the potential efficacy of this new therapeutic option in this situation has been suggested only by isolated case reports. Further controlled studies, with a longer follow-up and a larger sample size, are needed to assess efficacy of Gardasil in LP.</p