RESUMEN
Candida albicans and Staphylococcus aureus are two commonly associated pathogens that cause nosocomial infections with high morbidity and mortality. Our prior and current work using a murine model of polymicrobial intra-abdominal infection (IAI) demonstrates that synergistic lethality is driven by Candida-induced upregulation of functional S. aureus α-toxin leading to polymicrobial sepsis and organ damage. In order to determine the candidal effector(s) mediating enhanced virulence, an unbiased screen of C. albicans transcription factor mutants was undertaken revealing that zcf13Δ/Δ fails to drive augmented α-toxin or lethal synergism during co-infection. A combination of transcriptional and phenotypic profiling approaches shows that ZCF13 regulates genes involved in pentose metabolism, including RBK1 and HGT7 that contribute to fungal ribose catabolism and uptake, respectively. Subsequent experiments reveal that ribose inhibits the staphylococcal agr quorum sensing system and concomitantly represses toxicity. Unlike wild-type C. albicans, zcf13Δ/Δ did not effectively utilize ribose during co-culture or co-infection leading to exogenous ribose accumulation and agr repression. Forced expression of RBK1 and HGT7 in the zcf13Δ/Δ mutant fully restores pathogenicity during co-infection. Collectively, our results detail the interwoven complexities of cross-kingdom interactions and highlight how intermicrobial metabolism impacts polymicrobial disease pathogenesis with devastating consequences for the host.
Asunto(s)
Candida albicans , Candidiasis , Coinfección , Proteínas Fúngicas , Infecciones Estafilocócicas , Staphylococcus aureus , Candida albicans/metabolismo , Candida albicans/patogenicidad , Candida albicans/genética , Animales , Coinfección/microbiología , Staphylococcus aureus/patogenicidad , Staphylococcus aureus/metabolismo , Staphylococcus aureus/genética , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/metabolismo , Candidiasis/microbiología , Ratones , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Infecciones Intraabdominales/microbiología , Femenino , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Percepción de Quorum/genética , Virulencia , Regulación Fúngica de la Expresión Génica , Modelos Animales de Enfermedad , Transactivadores/metabolismo , Transactivadores/genéticaRESUMEN
Candida tropicalis is a human pathogen and one of the most prevalent non-Candida albicans Candida (NCAC) species causing invasive infections. Azole antifungal resistance in C. tropicalis is also gradually increasing with the increasing incidence of infections. The pathogenic success of C. tropicalis depends on its effective response in the host microenvironment. To become a successful pathogen, cellular metabolism, and physiological status determine the ability of the pathogen to counter diverse stresses inside the host. However, to date, limited knowledge is available on the impact of carbon substrate metabolism on stress adaptation and azole resistance in C. tropicalis. In this study, we determined the impact of glucose, fructose, and sucrose as the sole carbon source on the fluconazole resistance and osmotic (NaCl), oxidative (H2O2) stress adaptation in C. tropicalis clinical isolates. We confirmed that the abundance of carbon substrates influences or increases drug resistance and osmotic and oxidative stress tolerance in C. tropicalis. Additionally, both azole-resistant and susceptible isolates showed similar stress adaptation phenotypes, confirming the equal efficiency of becoming successful pathogens irrespective of drug susceptibility profile. To the best of our knowledge, our study is the first on C. tropicalis to demonstrate the direct relation between carbon substrate metabolism and stress tolerance or drug resistance.
Asunto(s)
Antifúngicos , Candida tropicalis , Carbono , Farmacorresistencia Fúngica , Fluconazol , Pruebas de Sensibilidad Microbiana , Estrés Oxidativo , Candida tropicalis/efectos de los fármacos , Candida tropicalis/fisiología , Antifúngicos/farmacología , Humanos , Fluconazol/farmacología , Carbono/metabolismo , Candidiasis/microbiología , Presión Osmótica , Glucosa/metabolismo , Sacarosa/metabolismo , Sacarosa/farmacología , Peróxido de Hidrógeno/farmacología , Peróxido de Hidrógeno/metabolismo , Fructosa/metabolismo , Fructosa/farmacología , Estrés FisiológicoRESUMEN
Messenger RNAs (mRNAs) are the templates for protein translation but can also act as non-cell-autonomous signaling molecules. Plants input endogenous and exogenous cues to mobile mRNAs and output them to local or systemic target cells and organs to support specific plant responses. Mobile mRNAs form ribonucleoprotein (RNP) complexes with proteins during transport. Components of these RNP complexes could interact with plasmodesmata (PDs), a major mediator of mRNA transport, to ensure mRNA mobility and transport selectivity. Based on advances in the last two to three years, this review summarizes mRNA transport mechanisms in local and systemic signaling from the perspective of RNP complex formation and PD transport. We also discuss the physiological roles of endogenous mRNA transport and the recently revealed roles of non-cell-autonomous mRNAs in inter-organism communication.
Asunto(s)
Plasmodesmos , ARN Mensajero , ARN Mensajero/metabolismo , ARN Mensajero/genética , Plasmodesmos/metabolismo , Ribonucleoproteínas/metabolismo , Ribonucleoproteínas/genética , ARN de Planta/metabolismo , ARN de Planta/genética , Transporte de ARN , Plantas/metabolismo , Plantas/genética , Transducción de Señal , Comunicación CelularRESUMEN
Candida albicans and Staphylococcus aureus are two commonly associated pathogens that cause nosocomial infections with high morbidity and mortality. Our prior and current work using a murine model of polymicrobial intra-abdominal infection (IAI) uncovered synergistic lethality that was driven by Candida -induced upregulation of functional S. aureus âº-toxin leading to polymicrobial sepsis and organ damage. In order to determine the candidal effector(s) mediating enhanced virulence, an unbiased screen of C. albicans transcription factor mutants was undertaken and revealed that zcf13 Δ/Δ failed to drive augmented âº-toxin or lethal synergism during co-infection. Using a combination of transcriptional and phenotypic profiling approaches, ZCF13 was shown to regulate genes involved in pentose metabolism, including RBK1 and HGT7 that contribute to fungal ribose catabolism and uptake, respectively. Subsequent experiments revealed that ribose inhibited the staphylococcal agr quorum sensing system and concomitantly repressed toxicity. Unlike wild-type C. albicans , zcf13 Δ/Δ was unable to effectively utilize ribose during co-culture or co-infection leading to exogenous ribose accumulation and agr repression. Forced expression of RBK1 and HGT7 in the zcf13 Δ/Δ mutant fully restored pathogenicity during co-infection. Collectively, our results detail the interwoven complexities of cross-kingdom interactions and highlight how intermicrobial metabolism impacts polymicrobial disease pathogenesis with devastating consequences for the host.