Studies of Pneumococcal Populations: from Genetic Loci to Coordination Pathways and Interkingdom Interactions

The human pathobiont Streptococcus pneumoniae (Spn) is a common colonizer of the nasopharynx but can cause invasive disease upon dissemination into other body sites. As such, Spn employs a wide range of molecular mechanisms to quickly respond to the diverse and ever-changing host environment and to interact with other resident microbes. This work outlines three aspects that contribute to the Spn bimodal lifestyle. 

To respond to environmental cues, Spn utilizes several cell-cell communication systems. Here, we addressed the question of how Spn may coordinate multiple communication systems from diverse protein families. We identified a transporter with a dual mode of action: it activates one communication system and delays another during infection. Ultimately, this shared molecular link coordinates bacterial communication and subsequent phenotypic responses in the host. 

Next, we explored Spn population level behaviors from the perspectives of genes, mechanisms, and regulation. We performed detailed comparative genomic analyses of the rtg locus that encodes a cell-cell communication system and a set of exported peptides. This characterization revealed extensive diversity and plasticity in this region and suggested that the peptides function in competition across strains and/or species. Overall, the genomic locus captured flexibility and modularity at the pangenome level and sets the stage to explore functional consequences of peptide secretion to bacterial communities. 

Secondary bacterial infection is a common and serious complication of Influenza A Virus (IAV) infection. We employed a ferret model to investigate growth and airborne transmission of Spn and IAV during coinfections. Our model captured the increased morbidity associated with coinfection relative to single infections. Moreover, Spn loads, and airborne transmission were increased by the virus, while, surprisingly, IAV titers in nasal fluids were significantly decreased during coinfection. Thus, our work revealed an asymmetric relationship between the two pathogens, rather than a synergistic one since secondary bacterial infection enhances Spn colonization and pathogenesis but decreases viral titers. 

In summary, this thesis is a lens into Spn genes, pathways, and host-associated phenotypes and their connection to and interactions with diverse host environments and resident microbes.