For the RT-qPCR data, gene expression was assessed using 2 indepe

For the RT-qPCR data, gene expression was assessed using 2 independent samples from C57BL/6 mice and 3 independent samples from DBA/2 mice. RT-qPCR gene expression data (2-∆∆CT) was averaged within mouse strains and then used to calculate log2 fold change values between strains for direct comparison to microarray data. GS-9973 mouse A log2 fold change of

1 equates to an actual fold change of 2. A positive fold change indicates the gene was expressed to a greater extent in DBA/2 mice, and a negative fold change means higher expression in C57BL/6. An asterisk (*) indicates that the gene was significantly differentially expressed (p <0.05, t-test) between mice strains at day 14. Discussion Analysis of the gene expression differences between mice strains resistant (DBA/2) and sensitive (C57BL/6) to infection with C. immitis identified a large number of ISGs

associated with putative control of this fungal pathogen. Innate/adaptive immune responses as mediated by Type II interferon (IFN-γ) have previously been associated with resistance to infection with C. immitis[29, 30]. For example, Magee and Cox [29] found that IFN-γ protein levels as measured by ELISA were significantly this website elevated in DBA/2 mice compared to another susceptible strain (BALB/c) following infection with C. immitis. Furthermore, treatment of DBA/2 mice with an anti-IFN-γ monoclonal antibody resulted in a significant decrease in their ability to control this fungal pathogen after pulmonary challenge. This current study expands on their work by clearly demonstrating that downstream ISGs are expressed to a greater extent in resistant DBA/2 compared to sensitive C57BL/6 mice (selleck inhibitor Figures 2 and 7) and that these genes are modulated by the JAK/STAT pathway (Figures 4 and 6),

most likely activated by IFN-γ (Figure 7). These findings are highly relevant to human infection since patients with congenital deficiencies of IFN-γ and the interleukin 12 receptor beta 1 (IL-12rβ1) are susceptible to disseminated coccidioidomycosis [30, 31]. The upregulation of ISGs (i.e. CXCL9, IRGM1, PSMB9, STAT1 and UBD) in DBA/2 compared to C57BL/6 mice was confirmed by RT-qPCR at all days post-infection (Figure 7 and Additional file 1: Figure S3). STAT1 is integral to JAK/STAT signaling triggered by Type I and II IFN and upregulates a number of ISGs Elongation factor 2 kinase that are involved with the host defense against pathogen infection [32]. UBD was the ISG that exhibited the greatest upregulation in DBA/2 mice (Figures 2 and 7), and is induced to a greater extent by IFN-γ than IFN-α in human immune and non-immune cells [14]. Several roles have been ascribed to UBD including targeting proteins for proteosomal degradation [33], activation of the nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-κB) [34], which is a central mediator of innate immunity, as well as a functional involvement in the programmed cell death mediated by TNF-α in the murine B8 fibroblast cell line [35].

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