FUNCTIONAL CHARACTERIZATION OF THE LINK BETWEEN CARBOHYDRATE METABOLISM AND THE PATHOGENESIS OF THE INVASIVE M1T1 GROUP A STREPTOCOCCUS

The Group A Streptococcus (GAS), or Streptococcus pyogenes, is a strict human pathogen that colonizes a variety of sites within the host. Infections can vary from minor and easily treatable, to life-threatening, invasive forms of disease. In order to adapt to niches, GAS utilizes environmental cues, such as carbohydrates, to coordinate the expression of virulence factors. Research efforts to date have focused on identifying how either components of the phosphoenolpyruvate-phosphotransferase system (PTS) or global transcriptional networks affect the regulation of virulence factors, but not the synergistic relationship between the two. The present study investigates the role of a putative PTS-fructose operon encoded by fruRBA and its role in virulence in the M1T1 strain 5448. Growth in fructose resulted in induction of fruRBA. RT-PCR showed that fruRBA formed an operon, which was repressed by FruR in the absence of fructose. Growth and carbon utilization profiles revealed that although the entire fruRBA operon was required for growth in fructose, FruA was the main fructose transporter. The ability of both ΔfruR and ΔfruB mutants to survive in whole human blood or neutrophils was impaired. However, the phenotypes were not reproduced in murine whole blood or in a mouse intraperitoneal infection, indicating a human-specific mechanism. While it is known that the PTS can affect activity of the Mga virulence regulator, further characterization of the mechanism by which sugars and its protein domains affect activity have not been studied. Transcriptional studies revealed that the core Mga regulon is activated more in a glucose-rich than a glucose-poor environment. This activation correlates with the differential phosphorylation of Mga at its PTS regulatory domains (PRDs). Using a 5448 mga mutant, transcriptome studies in THY or C media established that the Mga regulon reflects the media used. Interestingly, Mga regulates phage-encoded DNases in a low glucose environment. We also show that Mga activity is dependent on C-terminal amino acid interactions that aid in the formation of homodimers. Overall, the studies presented sought to define how external environmental cues, specifically carbohydrates, control complex regulatory networks used by GAS, contribute to pathogenesis, and aid in adaptation to various nutrient conditions encountered.

Functional Neuroimaging of the Social Regulation of Emotion in Schizophrenia

Negative symptoms in schizophrenia are characterized by deficits in normative experiences and expression of emotion. Social anhedonia (diminished pleasure from social experiences) is one negative symptom that may impact patients’ motivation to engage in meaningful social relationships. Past research has begun to examine the mechanisms that underlie social anhedonia, but it is unclear how this lack of social interest may impact the typically positive effects of social buffering and social baseline theory whereby social support attenuates stress. The present pilot study examines how social affiliation through hand holding is related to subjective and neural threat processing, negative symptoms, and social functioning. Twenty-one participants (14 controls; 7 schizophrenia) developed social affiliation with a member of the research staff who served as the supportive partner during the threat task. Participants displayed greater subjective benefit to holding the hand of their partner during times of stress relative to being alone or with an anonymous experimenter, as indicated by self-reported increased positive valence and decreased arousal ratings. When examining the effects of group, hand holding, and their interaction on the neurological experience of threat during the fMRI task, the results were not significant. However, exploratory analyses identified preliminary data suggesting that controls experienced small relative increases in BOLD signal to threat when alone compared to being with the anonymous experimenter or their partner, whereas the schizophrenia group results indicated subtle relative decreases in BOLD signal to threat when alone compared to either of the hand holding conditions. Additionally, within the schizophrenia group, more positive valence in the partner condition was associated with less severe negative symptoms, better social functioning, and more social affiliation, whereas less arousal was correlated with more social affiliation. Our pilot study offers initial insights about the difficulties of building and using social affiliation and support through hand holding with individuals with schizophrenia during times of stress. Further research is necessary to clarify which types of support may be more or less beneficial to individuals with schizophrenia who may experience social anhedonia or paranoia with others that may challenge the otherwise positive effects of social buffering and maintaining a social baseline.