ABSTRACT
Emerging multidrug-resistant bacteria are a challenge for modern medicine, but how these pathogens are so successful is not fully understood. Robust antibacterial vaccines have prevented and reduced resistance suggesting a pivotal role for immunity in deterring antibiotic resistance. Here, we show the increased prevalence of Klebsiella pneumoniae lipopolysaccharide O2 serotype strains in all major drug resistance groups correlating with a paucity of anti-O2 antibodies in human B cell repertoires. We identify human monoclonal antibodies to O-antigens that are highly protective in mouse models of infection, even against heavily encapsulated strains. These antibodies, including a rare anti-O2 specific antibody, synergistically protect against drug-resistant strains in adjunctive therapy with meropenem, a standard-of-care antibiotic, confirming the importance of immune assistance in antibiotic therapy. These findings support an antibody-based immunotherapeutic strategy even for highly resistant K. pneumoniae infections, and underscore the effect humoral immunity has on evolving drug resistance.
Subject(s)
Antibodies, Bacterial/therapeutic use , Antibodies, Monoclonal/therapeutic use , Klebsiella Infections/therapy , Klebsiella pneumoniae/physiology , O Antigens/immunology , Animals , Anti-Bacterial Agents/therapeutic use , Antibodies, Bacterial/immunology , Antibodies, Monoclonal/immunology , Cell Line , Disease Models, Animal , Drug Resistance, Multiple, Bacterial/genetics , Drug Resistance, Multiple, Bacterial/immunology , Humans , Immunity, Humoral , Immunologic Factors/therapeutic use , Immunotherapy/methods , Klebsiella Infections/immunology , Klebsiella Infections/microbiology , Klebsiella Infections/mortality , Klebsiella pneumoniae/drug effects , Meropenem , Mice , Mice, Inbred C57BL , Microbial Sensitivity Tests , Serogroup , Survival Rate , Thienamycins/therapeutic useABSTRACT
The mammalian TOR pathway ("Target Of Rapamycin") is a regulatory protein network involved in a wide range of processes including cell growth and differentiation, providing a functional switch between anabolic and catabolic cell metabolism. Trypanosoma cruzi, the etiologic agent of Chagas disease, has a complex life cycle with different morphological stages in various hosts. This life cycle implies that parasites have to deal with fluctuations in the extracellular medium that should be detected and counteracted adapting their metabolism. A candidate to be the mediator between the receptors / sensors of the environment and cellular adaptive response is the TOR pathway. In this paper we integrate the bibliographic data of the TOR pathway in trypanosomatids by in silico analysis (computer simulation of biological structures and processes) of the parasite's genome. Possible effectors and processes regulated by this metabolic pathway are also proposed. Given that the information on the mechanisms of signal transduction in trypanosomatids is scarce, we consider the model presented in this work may be a reference for future experimental work.
Subject(s)
Chagas Disease/parasitology , TOR Serine-Threonine Kinases/genetics , Trypanosoma cruzi/genetics , Animals , Computer Simulation , Life Cycle Stages , Mammals/genetics , Metabolic Networks and Pathways , Signal Transduction , TOR Serine-Threonine Kinases/metabolismABSTRACT
La vía TOR ("Target Of Rapamycin") de mamíferos es una red proteica de regulación para una amplia gama de procesos involucrados en el crecimiento y la diferenciación celular, constituyendo un interruptor funcional entre el metabolismo anabólico y catabólico de la célula. El Trypanosoma cruzi, agente etiológico de la enfermedad de Chagas, tiene un ciclo de vida muy complejo con diferentes estadios morfológicos en varios hospedadores. Este ciclo de vida implica que los parásitos enfrentan grandes fluctuaciones en el medio extracelular que deben ser detectadas y a las cuales deben responder adaptando su metabolismo. Un candidato a ser el mediador entre los receptores/sensores del medio y la respuesta adaptativa celular es la vía TOR. En este trabajo integramos los datos bibliográficos de la vía TOR de organismos tripanosomátidos con un análisis in silico (simulación computacional de procesos o estructuras biológicas) del genoma del parásito. Se proponen además posibles efectores y procesos regulados por esta ruta metabólica. Teniendo en cuenta que existe muy poca información sobre los mecanismos de transducción de señales en tripanosomátidos, consideramos que el mapa presentado en este trabajo puede ser una referencia para futuros trabajos experimentales.(AU)
The mammalian TOR pathway ("Target Of Rapamycin") is a regulatory protein network involved in a wide range of processes including cell growth and differentiation, providing a functional switch between anabolic and catabolic cell metabolism. Trypanosoma cruzi, the etiologic agent of Chagas disease, has a complex life cycle with different morphological stages in various hosts. This life cycle implies that parasites have to deal with fluctuations in the extracellular medium that should be detected and counteracted adapting their metabolism. A candidate to be the mediator between the receptors / sensors of the environment and cellular adaptive response is the TOR pathway. In this paper we integrate the bibliographic data of the TOR pathway in trypanosomatids by in silico analysis (computer simulation of biological structures and processes) of the parasites genome. Possible effectors and processes regulated by this metabolic pathway are also proposed. Given that the information on the mechanisms of signal transduction in trypanosomatids is scarce, we consider the model presented in this work may be a reference for future experimental work.(AU)
Subject(s)
Animals , Chagas Disease/parasitology , TOR Serine-Threonine Kinases/genetics , Trypanosoma cruzi/genetics , Computer Simulation , Life Cycle Stages , Mammals/genetics , Metabolic Networks and Pathways , Signal Transduction , TOR Serine-Threonine Kinases/metabolismABSTRACT
La vía TOR ("Target Of Rapamycin") de mamíferos es una red proteica de regulación para una amplia gama de procesos involucrados en el crecimiento y la diferenciación celular, constituyendo un interruptor funcional entre el metabolismo anabólico y catabólico de la célula. El Trypanosoma cruzi, agente etiológico de la enfermedad de Chagas, tiene un ciclo de vida muy complejo con diferentes estadios morfológicos en varios hospedadores. Este ciclo de vida implica que los parásitos enfrentan grandes fluctuaciones en el medio extracelular que deben ser detectadas y a las cuales deben responder adaptando su metabolismo. Un candidato a ser el mediador entre los receptores/sensores del medio y la respuesta adaptativa celular es la vía TOR. En este trabajo integramos los datos bibliográficos de la vía TOR de organismos tripanosomátidos con un análisis in silico (simulación computacional de procesos o estructuras biológicas) del genoma del parásito. Se proponen además posibles efectores y procesos regulados por esta ruta metabólica. Teniendo en cuenta que existe muy poca información sobre los mecanismos de transducción de señales en tripanosomátidos, consideramos que el mapa presentado en este trabajo puede ser una referencia para futuros trabajos experimentales.
The mammalian TOR pathway ("Target Of Rapamycin") is a regulatory protein network involved in a wide range of processes including cell growth and differentiation, providing a functional switch between anabolic and catabolic cell metabolism. Trypanosoma cruzi, the etiologic agent of Chagas disease, has a complex life cycle with different morphological stages in various hosts. This life cycle implies that parasites have to deal with fluctuations in the extracellular medium that should be detected and counteracted adapting their metabolism. A candidate to be the mediator between the receptors / sensors of the environment and cellular adaptive response is the TOR pathway. In this paper we integrate the bibliographic data of the TOR pathway in trypanosomatids by in silico analysis (computer simulation of biological structures and processes) of the parasite's genome. Possible effectors and processes regulated by this metabolic pathway are also proposed. Given that the information on the mechanisms of signal transduction in trypanosomatids is scarce, we consider the model presented in this work may be a reference for future experimental work.
Subject(s)
Animals , Chagas Disease/parasitology , TOR Serine-Threonine Kinases/genetics , Trypanosoma cruzi/genetics , Computer Simulation , Life Cycle Stages , Metabolic Networks and Pathways , Mammals/genetics , Signal Transduction , TOR Serine-Threonine Kinases/metabolismABSTRACT
BACKGROUND AND OBJECTIVE: HIV protease inhibitors (PI) were licensed without a direct evidence of their relative efficacy. PATIENTS AND METHOD: 137 patients attending our clinics between November 1997 and March 1998, to whom treatment with a PI was recommended, were randomized to receive indinavir (IDV), saquinavir (SQV) or ritonavir (RTV). Main outcome variables were one-year mean changes in HIV-RNA plasma concentrations and CD4 cells counts and proportion of patients with HIV viral load below level of detection. RESULTS: Mean HIV viral load reductions were 0.95 for SQV, 0.72 for IDV and 0.65 for RTV (p = 0.44), equaling losses and changes to failures. In a standard intent-to-treat analysis, mean changes in viral load were 1.16, 1.01 and 1.50 (p = 0.21), respectively. The proportion of patients with undetectable viral load was 50%, with no differences between treatment arms. CONCLUSIONS: No differences were observed in the effectiveness of SQV, IDV and RTV.
Subject(s)
HIV Infections/drug therapy , HIV Protease Inhibitors/therapeutic use , Indinavir/therapeutic use , Ritonavir/therapeutic use , Saquinavir/therapeutic use , Adult , Aged , Antiretroviral Therapy, Highly Active , CD4 Lymphocyte Count , Female , HIV Infections/blood , Humans , Male , Middle Aged , Viral LoadABSTRACT
FUNDAMENTO Y OBJETIVO: Los inhibidores de la proteinasa del virus de la inmunodeficiencia humana (VIH) fueron introducidos en la clínica sin datos directos de sus eficacias relativas. PACIENTES Y MÉTODO: Ciento treinta y siete pacientes atendidos entre noviembre de 1997 y marzo de 1998 en quienes se indicó tratamiento con un inhibidor de la proteinasa fueron asignados aleatoriamente a recibir indinavir, ritonavir o saquinavir. Las variables principales fueron los cambios medios respectivos en las concentraciones plasmáticas de VIH-ARN y en los recuentos de linfocitos CD4 y la proporción de pacientes con carga viral indetectable después de 12 meses. RESULTADOS: Los cambios respectivos del log10 de la carga viral fueron: saquinavir, 0,97; indinavir, 0,72 y ritonavir 0,65 (p = 0,44), equiparando pérdidas y cambios a fracaso. En un análisis estándar por intención de tratar, los cambios fueron 1,16, 1,01 y 1,50, respectivamente (p = 0,21). La proporción de pacientes con carga viral indetectable fue del 50 por ciento, sin diferencias entre los 3 grupos. CONCLUSIONES: No se observaron diferencias en la efectividad de saquinavir, indinavir y ritonavir para reducir la carga viral del VIH (AU)
