Immunosuppressive Mechanisms in Brucellosis in Light of Chronic Bacterial Diseases

Abstract

Brucellosis is considered one of the major zoonoses worldwide, constituting a critical livestock and human health concern with a huge socio-economic burden. Brucella genus, its etiologic agent, is composed of intracellular bacteria that have evolved a prodigious ability to elude and shape host immunity to establish chronic infection. Brucella's intracellular lifestyle and pathogen-associated molecular patterns, such as its specific lipopolysaccharide (LPS), are key factors for hiding and hampering recognition by the immune system. Here, we will review the current knowledge of evading and immunosuppressive mechanisms elicited by Brucella species to persist stealthily in their hosts, such as those triggered by their LPS and cyclic β-1,2-d-glucan or involved in neutrophil and monocyte avoidance, antigen presentation impairment, the modulation of T cell responses and immunometabolism. Attractive strategies exploited by other successful chronic pathogenic bacteria, including Mycobacteria, Salmonella, and Chlamydia, will be also discussed, with a special emphasis on the mechanisms operating in brucellosis, such as granuloma formation, pyroptosis, and manipulation of type I and III IFNs, B cells, innate lymphoid cells, and host lipids. A better understanding of these stratagems is essential to fighting bacterial chronic infections and designing innovative treatments and vaccines.

Keywords: Brucella; chronic infection; immunosuppression; intracellular bacteria; persistence.

Figure 1

Mechanisms of Brucella’s antigen presentation impairment. Brucella has evolved multiple ways to dampen antigen presentation by (A) macrophages and (B) dendritic cells, preventing proficient development of an adaptive immunity. (A) Recognition of Brucella lipoproteins by TLR2 leads to IL-6-dependent inhibition of the transcription factor CIITA, resulting in diminished transcription and expression of IFN-γ-induced MHC-II. Moreover, Brucella abortus LPS (Ba LPS) reaches the cell surface, forming macrodomains with MHC-II molecules and interfering with the presentation of peptides to CD4⁺ T cells. This impairment also influences cytotoxic CD8⁺ T cells, since recognition of Brucella abortus RNA (Ba RNA) induces retention of MHCI molecules within the Golgi apparatus via TLR8 and the EGFR pathway. (B) The Omp25-SLAMF1 interaction limits NF-κB translocation to the nucleus, decreasing pro-inflammatory cytokine secretion and costimulatory molecules expression in dendritic cells. The Brucella effectors BtpA and BtpB, translocated to the cytoplasm during infection, interfere with TLR2 and TLR4 signalling and control dendritic cell maturation. In both cell types, the peculiar structure of the Ba LPS, specially its core, makes it poorly recognised by the TLR4-MD2 complex preventing full activation, NF-κB translocation and impairing dendritic cell maturation and T cell activation. Nuclear phosphorylated active NF-κB dimers are represented in green.

Figure 2

Shared strategies by intracellular pathogenic bacteria during chronic infections. Granulomas are focal aggregates of heterogeneous macrophages together with other immune cells at the infection site that form a physical barrier for escaping immune surveillance, but also offer a beneficial microenvironment for the bacteria (red rod), including Brucella, to remain viable for decades. The enriched anti-inflammatory milieu and the limitation of the positioning of effector immune cells provide a safe niche, and the constant movement of cells gives the opportunity for secondary infections. Interaction and use of host lipids by pathogenic bacteria play a central role for internalization, dissemination, intracellular growth and immunomodulation during chronic infection. The relative balance of eicosanoids modulates key processes, shown in blue boxes, and is essential for determining the pathogenesis and development of a proper anti-bacterial immunity. The role of type I interferons during bacterial infections is highly context-dependent with both beneficial and detrimental outcomes for the host. In infected macrophages, IRF3-mediated type I IFN production is promoted by c-GAS-STING recognition of Brucella DNA. IFNAR-deficient murine models of chronic infection have shown reduced bacterial burden and pathology, correlating with enhanced IFN-γ and nitric oxide production and diminished splenocyte apoptosis. Type I IFNs have been related to inhibit IL-17⁺γδ T cells and neutrophil expansion in Francisella tularensis-infected mice. The outcome of caspase-1/inflammasome-induced pyroptotic cell death is also highly dependent on timing and cell type. Pyroptotic intestinal epithelial cells are expelled into the lumen restricting Salmonella dissemination and replication. In contrast, efferocytosis of Salmonella or Brucella entrapped in pyroptotic macrophages shields the bacteria from the neutrophil respiratory burst, contributing to their persistence.