| Summary: | <i>Pneumocystis jirovecii</i> is a fungal pathogen that can cause life-threatening infections in individuals who are immunocompromised. Acquired via inhalation, upon entering the respiratory tract, the fungi first encounter innate immune cells such as alveolar macrophages (AMs). Relatively little is known about the AM cellular responses to the organism, and particularly transcription factor (TF) profiles leading to early host responses during infection. Utilizing the Mouse Transcription Factors RT<sup>2</sup> Profiler™ PCR Array, we report an initial TF survey of these macrophage and <i>Pneumocystis</i> interactions. Expression levels of a panel of mouse TFs were compared between unstimulated and <i>Pneumocystis murina</i>-stimulated AMs. Interestingly, a number of TFs previously implicated in pathogen–host cell interactions were highly up- or downregulated, including <i>hif1a</i> and <i>Pparg</i>. qPCR experiments were further conducted to verify the results of these surveyed transcripts. Furthermore, with immunoblotting, we show that HIF-1A and PPAR-γ are indeed significantly upregulated and downregulated, respectively. Lastly, and importantly, we report that in the mouse model of <i>Pneumocystis</i> pneumonia (PCP), which mimics human <i>Pneumocystis jirovecii</i> pneumonia (PJP), qPCR analysis of <i>Pneumocystis murina</i> lungs also mimic the initial TF profile analysis, suggesting an importance for these TFs in immunocompromised hosts with <i>Pneumocystis</i> pneumonia. These data demonstrate the use of TF profiling in host AMs and <i>Pneumocystis</i> organism interactions that may lead to a better understanding of the specific inflammatory responses of the host to <i>Pneumocystis</i> pneumonia and may inform novel strategies for potential therapeutics.
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