Defining Host Responses during Systemic Bacterial Infection through Construction of a Murine Organ Proteome Atlas

• Published in: Cell systems Vol. 6; no. 5; pp. 579 - 592.e4
• Main Authors: Lapek, John D., Mills, Robert H., Wozniak, Jacob M., Campeau, Anaamika, Fang, Ronnie H., Wei, Xiaoli, van de Groep, Kirsten, Perez-Lopez, Araceli, van Sorge, Nina M., Raffatellu, Manuela, Knight, Rob, Zhang, Liangfang, Gonzalez, David J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.05.2018
• Subjects: Animals; Bacterial Proteins - metabolism; group A Streptococcus; Host-Pathogen Interactions - immunology; Mice; Mice, Inbred C57BL; multiplexed proteomics; Orbitrap; Organ Specificity; Pharyngitis - microbiology; Protein Interaction Maps - immunology; Proteome - metabolism; Proteomics - methods; S. pyogenes; Sepsis - microbiology; Streptococcal Infections - immunology; Streptococcal Infections - microbiology; Streptococcus - genetics; Streptococcus - immunology; Streptococcus - pathogenicity; Streptococcus pyogenes - metabolism; systemic infection; Tandem Mass Spectrometry; Tandem Mass Tag; systemic infection; Orbitrap; Tandem Mass Tag; S. pyogenes; multiplexed proteomics; group A Streptococcus
• ISSN: 2405-4712; 2405-4720
• DOI: 10.1016/j.cels.2018.04.010

Group A Streptococcus (GAS) remains one of the top 10 deadliest human pathogens worldwide despite its sensitivity to penicillin. Although the most common GAS infection is pharyngitis (strep throat), it also causes life-threatening systemic infections. A series of complex networks between host and pathogen drive invasive infections, which have not been comprehensively mapped. Attempting to map these interactions, we examined organ-level protein dynamics using a mouse model of systemic GAS infection. We quantified over 11,000 proteins, defining organ-specific markers for all analyzed tissues. From this analysis, an atlas of dynamically regulated proteins and pathways was constructed. Through statistical methods, we narrowed organ-specific markers of infection to 34 from the defined atlas. We show these markers are trackable in blood of infected mice, and a subset has been observed in plasma samples from GAS-infected clinical patients. This proteomics-based strategy provides insight into host defense responses, establishes potentially useful targets for therapeutic intervention, and presents biomarkers for determining affected organs during bacterial infection. [Display omitted] •Group A Streptococcus-infected mouse organs have consistent proteomic responses•Combining statistical methods reveals organ-specific responses to infection•Protein networks shift during infection in an organ-specific and systemic fashion•Selected blood biomarkers for site of infection are present in clinical patients Group A Streptococcus (GAS) pathogenesis has largely been studied from a bacteria-centric perspective. Utilizing multiplexing proteomics, we characterize organ-specific and systemic responses to infection from a host-centric perspective. Analysis of clinical blood samples suggests a potential application for the identified biomarkers to diagnose the site of GAS infection.