Host Stress Signals Stimulate Pneumococcal Transition from Colonization to Dissemination into the Lungs.

Streptococcus pneumoniae is an asymptomatic colonizer of the nasopharynx, but it is also one of the most important bacterial pathogens of humans, causing a wide range of mild to life-threatening diseases. The basis of the pneumococcal transition from a commensal to a parasitic lifestyle is not fully understood. We hypothesize that exposure to host catecholamine stress hormones is important for this transition. In this study, we demonstrated that pneumococci preexposed to a hormone released during stress, norepinephrine (NE), have an increased capacity to translocate from the nasopharynx into the lungs compared to untreated pneumococci. Examination of NE-treated pneumococci revealed major alterations in metabolic profiles, cell associations, capsule synthesis, and cell size. By systemically mutating all 12 two-component and 1 orphan regulatory systems, we also identified a unique genetic regulatory circuit involved in pneumococcal recognition and responsiveness to human stress hormones. IMPORTANCE Microbes acquire unique lifestyles under different environmental conditions. Although this is a widespread occurrence, our knowledge of the importance of various host signals and their impact on microbial behavior is not clear despite the therapeutic value of this knowledge. We discovered that catecholamine stress hormones are the host signals that trigger the passage of Streptococcus pneumoniae from a commensal to a parasitic state. We identify that stress hormone treatment of this microbe leads to reductions in cell size and capsule synthesis and renders it more able to migrate from the nasopharynx into the lungs in a mouse model of infection. The microbe requires the TCS09 protein for the recognition and processing of stress hormone signals. Our work has particular clinical significance as catecholamines are abundant in upper respiratory fluids as well as being administered therapeutically to reduce inflammation in ventilated patients, which may explain why intubation in the critically ill is a recognized risk factor for the development of pneumococcal pneumonia.

Glutamate Dehydrogenase (GdhA) of Streptococcus pneumoniae Is Required for High Temperature Adaptation.

During its progression from the nasopharynx to other sterile and nonsterile niches of its human host, Streptococcus pneumoniae must cope with changes in temperature. We hypothesized that the temperature adaptation is an important facet of pneumococcal survival in the host. Here, we evaluated the effect of temperature on pneumococcus and studied the role of glutamate dehydrogenase (GdhA) in thermal adaptation associated with virulence and survival. Microarray analysis revealed a significant transcriptional response to changes in temperature, affecting the expression of 252 genes in total at 34°C and 40°C relative to at 37°C. One of the differentially regulated genes was gdhA, which is upregulated at 40°C and downregulated at 34°C relative to 37°C. Deletion of gdhA attenuated the growth, cell size, biofilm formation, pH survival, and biosynthesis of proteins associated with virulence in a temperature-dependent manner. Moreover, deletion of gdhA stimulated formate production irrespective of temperature fluctuation. Finally, ΔgdhA grown at 40°C was less virulent than other temperatures or the wild type at the same temperature in a Galleria mellonella infection model, suggesting that GdhA is required for pneumococcal virulence at elevated temperature.