Nada Alshaer

Introduction. Streptococcus pneumoniae is a Gram-positive, extracellular, opportunistic pathogen and is a leading cause of a wide range of infections, including otitis media, community-acquired pneumonia, sepsis and meningitis.¹ Colonization occurs in the mucosal surfaces of the upper respiratory tract and its spread into the lower airways, other organs and tissues cause pathogenesis.¹ The microbiota has a significant influence on health, and individuals in a state of dysbiosis or weakened immunity are susceptible to infection by S. pneumoniae.^{1, 2} The balance between resident flora and invaders can help to clear S. pneumoniae before it becomes pathogenic.² The aim was to identify members of the microbiota that drive protection against respiratory infection, and to define the mechanistic basis for their effect.³ This creates an avenue for microbiota-based treatments that alleviate symptoms in infected patients, reduce the risk of developing pneumococcal-associated illnesses and secondary infections due to the pathogen.² Preventing and treating pneumococcal diseases are of major concern for the clinical field due to the high death rates and antibiotic resistance.² Methods. Testing occurred via methods of microbiota depletion, gnotobiotic approaches with cultured commensal bacteria, and models of respiratory infection.³ Bacterial loads were collected from antibiotic and non-antibiotic treated mice.³ Antibiotic therapy was stopped 3 days prior to infection.³ PRR ligands were prepared and administered by oral gavage.³ Anti-GM-CSF, anti-CXCL2, anti-CXCL1, and isotype control, rGM-CSF or rIL-17A, were administered intranasally concomitant with S. pneumoniae inoculation.³ Alveolar macrophages were isolated and bacterial killing assays were performed.³ Results. The microbiota was found to enhance respiratory defenses via granulocyte–macrophage colony-stimulating factor (GM-CSF) signaling, which stimulates pathogen killing and clearance by alveolar macrophages through extracellular signal-regulated kinase signaling.³ Increased pulmonary GM-CSF production in response to infection is primed by the microbiota through interleukin-17A.³  Potent Nod-like receptor-stimulating bacteria in the upper airway promote resistance to lung infection through Nod2 and GM-CSF.³ Conclusion. Microbiota-mediated stimulation of GM-CSF production was found to require IL-17A during the innate response to pulmonary bacterial infection.^{1, 3} GM-CSF programs alveolar macrophage function via an ERK-specific signaling pathway leading to increased pathogen killing via ROS.^{1, 3} Identifying bacteria in the microbiota that protect against respiratory infection and the mechanistic basis for their effect, provides potential of these resident bacteria to combat respiratory infection which remains a major cause of human mortality.^{1, 3}

1. Weiser JN, Ferreira DM, Paton JC. Streptococcus pneumoniae: transmission, colonization and invasion. Nat Rev Microbiol. 2018;16(6):355-367. doi:10.1038/s41579-018-0001-8
2. Brooks LRK, Mias GI. Streptococcus pneumoniae’s Virulence and Host Immunity: Aging, Diagnostics, and Prevention. Front Immunol. 2018;9:1366. Published 2018 Jun 22. doi:10.3389/fimmu.2018.01366
3. Brown RL, Sequeira RP, Clarke TB. The microbiota protects against respiratory infection via GM-CSF signaling. Nat Commun. 2017;8(1):1512. Published 2017 Nov 15. doi:10.1038/s41467-017-01803-x