Abstract
Understanding how immune challenges elicit different responses is critical for diagnosing and deciphering immune regulation. Using a modular strategy to interpret the complex transcriptional host response in mouse models of infection and inflammation, we show a breadth of immune responses in the lung. Lung immune signatures are dominated by either IFN-γ and IFN-inducible, IL-17-induced neutrophil- or allergy-associated gene expression. Type I IFN and IFN-γ-inducible, but not IL-17- or allergy-associated signatures, are preserved in the blood. While IL-17-associated genes identified in lung are detected in blood, the allergy signature is only detectable in blood CD4+ effector cells. Type I IFN-inducible genes are abrogated in the absence of IFN-γ signaling and decrease in the absence of IFNAR signaling, both independently contributing to the regulation of granulocyte responses and pathology during Toxoplasma gondii infection. Our framework provides an ideal tool for comparative analyses of transcriptional signatures contributing to protection or pathogenesis in disease.
Highlights
To determine the global changes in the host response to infection and allergens, we performed RNA-based next-generation sequencing (RNA-Seq) on RNA isolated from both lung and blood, at the predetermined peak of the response of mice infected with T. gondii; influenza A virus; respiratory syncytial virus (RSV); acute Burkholderia pseudomallei (B. pseudomallei); Candida albicans (C. albicans); or challenged with the allergen house dust mite (HDM), to capture the breadth of TH1, to type I IFN, to TH17, to TH2 responses (Fig. 1a; Supplementary Fig. 1a; Supplementary Data 1a)
The blood transcriptional signatures were investigated in a distinct set of mice infected with Plasmodium chabaudi chabaudi (P. chabaudi, malaria), murine cytomegalovirus (MCMV), Listeria monocytogenes (Listeria) and chronic B. pseudomallei (Supplementary Fig. 1a), and shown to cluster away from the controls, with each disease clustering independently of each other, transcriptional signatures of P. chabaudi and MCMV clustered closely to each other (Supplementary Fig. 1b)
Additional to the observed increase of neutrophilassociated genes (Figs. 5c and 8a, b), we show an increase in the proportion of granulocytes/neutrophils in the lungs and blood of all Ifnar−/−, Ifngr−/− and Ifnar−/− × Ifngr−/− mice as compared to Wild type infected with T. gondii, using cellular deconvolution analyses of our RNA-Seq data (Fig. 8c)
Summary
Rnf[213] Oasl[2] Slfn[8] Irf[7] Dhx[58] Lgals3bp Isg[15] Ifi[44] Zbp[1] Phf11b Fcgr[1] Apol9b Apol9a Xaf[1] Cmpk[2] Phf11d Ifit[3] Ifit[1] Irf[9] Rtp[4] Mx1 Gm4955 Bst[2] Rsad[2] Oas[2] Oas[3] Oasl[1] Oas1a Oas1g Ifi27l2b Saa[4]. The absence of type I IFN signaling in the Ifnar−/− mice showed a robust but not absolute decrease in the induction of the hub genes in the Type I IFN/Ifit/Oas module (L5), across all tissues, with the greatest decrease observed in the liver and spleen upon T. gondii infection (Fig. 7). An increase in certain neutrophil-associated genes from the IL-17 pathway/granulocytes module (L11), was observed in all IFNreceptor-deficient mice upon infection (Cluster i and ii, Fig. 8a, b), ll17a itself was not detectable in T. gondii infected tissues, except in the absence of IFN-γ signaling (Supplementary Data 14). 5c and 8a, b), we show an increase in the proportion of granulocytes/neutrophils in the lungs and blood of all Ifnar−/−, Ifngr−/− and Ifnar−/− × Ifngr−/− mice as compared to Wild type infected with T. gondii, using cellular deconvolution analyses of our RNA-Seq data (Fig. 8c). For example inhibition of type I IFN by IL-1 as has been reported during Mycobacterium tuberculosis infection[51]
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