RESUMEN
Baculovirus inhibitor of apoptosis repeat-containing 1 (Birc1) proteins have homology to several germline-encoded receptors of the innate immune system. However, their function in immune surveillance is not clear. Here we describe a Birc1e-dependent signaling pathway that restricted replication of the intracellular pathogen Legionella pneumophila in mouse macrophages. Translocation of bacterial products into host-cell cytosol was essential for Birc1e-mediated control of bacterial replication. Caspase-1 was required for Birc1e-dependent antibacterial responses ex vivo in macrophages and in a mouse model of Legionnaires' disease. The interleukin 1beta converting enzyme-protease-activating factor was necessary for L. pneumophila growth restriction, but interleukin 1beta was not required. These results establish Birc1e as a nucleotide-binding oligomerization-leucine-rich repeat protein involved in the detection and control of intracellular L. pneumophila.
Asunto(s)
Enfermedad de los Legionarios/inmunología , Proteína Inhibidora de la Apoptosis Neuronal/inmunología , Transducción de Señal/inmunología , Animales , Traslocación Bacteriana , Caspasa 1/inmunología , Caspasa 1/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Immunoblotting , Legionella pneumophila/fisiología , Macrófagos/inmunología , Macrófagos/microbiología , Ratones , Proteína Inhibidora de la Apoptosis Neuronal/metabolismo , TransfecciónRESUMEN
African women frequently acquire several genetically distinct human immunodeficiency virus type 1 (HIV-1) variants from a heterosexual partner, whereas the acquisition of multiple variants appears to be rare in men. To determine whether newly infected individuals in other risk groups acquire genetically diverse viruses, we examined the viral envelope sequences in plasma samples from 13 women and 4 men from the United States infected with subtype B viruses and 10 men from Kenya infected with non-subtype B viruses. HIV-1 envelope sequences differed by more than 2% in three U.S. women, one U.S. man, and one Kenyan man near the time of seroconversion. These findings suggest that early HIV-1 genetic diversity is not exclusive to women from Africa or to infection with any particular HIV-1 subtype.
Asunto(s)
Variación Genética , Infecciones por VIH/virología , VIH-1/clasificación , VIH-1/patogenicidad , Femenino , Productos del Gen env/genética , VIH-1/genética , Análisis Heterodúplex , Humanos , Kenia , Masculino , Datos de Secuencia Molecular , Factores de Riesgo , Análisis de Secuencia de ADN , Estados UnidosRESUMEN
BACKGROUND: Legionella pneumophila is a gram-negative bacterial pathogen that is the cause of Legionnaires' Disease. Legionella produces disease because it can replicate inside a specialized compartment of host macrophages. Macrophages isolated from various inbred mice exhibit large differences in permissiveness for intracellular replication of Legionella. A locus affecting this host-resistance phenotype, Lgn1, has been mapped to chromosome 13, but the responsible gene has not been identified. RESULTS: Here, we report that Naip5 (also known as Birc1e) influences susceptibility to Legionella. Naip5 encodes a protein that is homologous to plant innate immunity (so-called "resistance") proteins and has been implicated in signaling pathways related to apoptosis regulation. Detailed recombination mapping and analysis of expression implicates Naip5 in the Legionella permissiveness differences among mouse strains. A bacterial artificial chromosome (BAC) transgenic line expressing a nonpermissive allele of Naip5 exhibits a reduction in macrophage Legionella permissiveness. In addition, morpholino-based antisense inhibition of Naip5 causes an increase in the Legionella permissiveness of macrophages. CONCLUSIONS: We conclude that polymorphisms in Naip5 are involved in the permissiveness differences of mouse macrophages for intracellular Legionella replication. We speculate that Naip5 is a functional mammalian homolog of plant "resistance" proteins that monitor for, and initiate host response to, the presence of secreted bacterial virulence proteins.
Asunto(s)
Predisposición Genética a la Enfermedad , Legionella pneumophila/patogenicidad , Enfermedad de los Legionarios/genética , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Animales , Elementos sin Sentido (Genética)/farmacología , Células Cultivadas , Mapeo Cromosómico , Cromosomas Artificiales Bacterianos , Regulación de la Expresión Génica , Enfermedad de los Legionarios/microbiología , Macrófagos/efectos de los fármacos , Macrófagos/microbiología , Ratones , Ratones Endogámicos , Ratones Transgénicos , Proteína Inhibidora de la Apoptosis Neuronal , Polimorfismo Genético , TransgenesRESUMEN
Although nearly half of the HIV-1-infected adults in the world are women, little is known about the virologic determinants of transmission to women. Studies suggest that women are frequently infected with multiple HIV-1 genotypes, whereas men are infected with a single genotype. In the current study, we assessed whether the diverse HIV-1 genomes present at the time of infection in women encode viruses that have diverse coreceptor specificities. For this purpose, we defined the coreceptor requirements of viruses found in recently infected Kenyan women, three of whom had multiple viral genotypes and the remaining two of whom had a single genotype. Full-length envelope clones were amplified directly from blood and the dominant genotypes were identified. Envelope clones derived from all five women were able to pseudotype infectious particles competent to infect cells expressing CCR5, but not cells expressing only CXCR4. Thus, regardless of viral complexity at the time of infection, the viruses present at early stages of HIV-1 infection in women use CCR5, suggesting that cells expressing CCR5 are important targets for heterosexual HIV-1 transmission to women.