Functional alterations of immune gene expression in ICU and non-ICU patients with Legionnaires’ disease, a prospective observational study

Abstract Legionnaires’ disease (LD), a pneumonia caused by Legionella pneumophila intracellular bacterium, leads to intensive care unit (ICU) admission in 20-40% of cases. While these ICU-LD patients display severe lung injury or septic shock, their functional immune response remains poorly understood. The present study aimed, through a large immune gene expression assessment, to improve the understanding of immune cell functionality after whole blood LPS ex vivo stimulation in ICU-LD patients compared with non-ICU. Both ICU and non-ICU-LD displayed altered gene expression indicating that both patients’ immune cells are less able to respond to the LPS ex vivo stimulus than a healthy population. ICU-LD patients had 1.6-fold greater number of less-expressed genes (35/93 vs 22/93, p=0.039), and lower Log2(FC) of these genes (median [IQR]: -1.9 [-2.6;-1.5] vs -1.2 [-1.7;-0.9], p=0.0011) than non-ICU-LD. Seven genes were significantly less expressed by ICU-LD patients ( IRF7 , MX1 , NFKBI2 , NFKBIA , RELB , SRC , TIM3 ; p-value range: 0.029-0.0080). Top five gene ontology biological processes, subcellular localisations, and reactome pathways (STRING database) uniquely enriched in ICU-LD-patients and related less-expressed genes were cellular response to LPS ( CCL2 , NFKBIA , IRAK2 , TIM3, SRC , NFKB1 ), regulation of IFN-β production ( IRF7 , RIG1 , OAS2 , RELB ), I-κB/NF-κB complex ( NFKBIA , NFKB1 , NFKB2 ), IFN regulatory factor complex ( RIG1 , IRF7 ), and TRAF6-mediated NF-κB activation pathway ( NFKBIA , NFKB1 , NFKB2 , RIG1 ). Immune gene expression alterations in LD after LPS stimulation were found herein, with more pronounced alterations in ICU-LD patients. A reduced expression of key genes and pathways involved in controlling Legionella proliferation in ICU-LD patients may contribute to increased disease severity.