A gene expression map of host immune response in human brucellosis

Abstract

ABSTRACTBrucellosis is a common zoonotic disease caused by intracellular pathogens of the genus Brucella. Brucella infects macrophages and evades clearance mechanisms, which results in chronic parasitism. Herein, we studied the molecular changes that take place in human brucellosis bothin vitroandin vivo. RNA sequencing was performed in primary human macrophages (Μφ) and polymorphonuclear neutrophils (PMNs) infected with clinical strains ofB. melitensis. We observed a downregulation in the expression of genes involved in host response, such as TNF signaling, IL-1β production and phagosome formation in Μφ, and phosphatidylinositol signaling and TNF signaling in PMNs, being in line with the ability of the pathogen to survive within phagocytes. Further transcriptomic analysis of isolated peripheral blood mononuclear cells (PBMCs) and PMNs from patients with acute brucellosis before treatment initiation and after successful treatment revealed a positive correlation of the molecular signature of active disease with pathways associated with response to interferons (IFN). We identified 24 common genes that were significantly altered in both PMNs and PBMCs, including genes involved in IFN signaling that were downregulated after treatment in both cell populations, andIL1R1that was upregulated. The levels of several inflammatory mediators were evaluated in the serum of these patients, and we observed increased levels of IFN-γ, IL-1β and IL-6 before the treatment of acute brucellosis. An independent cohort of patients with chronic brucellosis also revealed the increased levels of IFN-γ during relapse compared to remissions. Taken together, this study provides for the first time an in-depth analysis of the molecular alterations that take place in human phagocytes upon infection, and in peripheral blood immune populations during active disease.