Evasion of host defense by Brucella

Abstract

Brucella, an adept intracellular pathogen, causes brucellosis, a zoonotic disease leading to significant global impacts on animal welfare and the economy. Regrettably, there is currently no approved and effective vaccine for human use. The ability of Brucella to evade host defenses is essential for establishing chronic infection and ensuring stable intracellular growth. Brucella employs various mechanisms to evade and undermine the innate and adaptive immune responses of the host through modulating the activation of pattern recognition receptors (PRRs), inflammatory responses, or the activation of immune cells like dendritic cells (DCs) to inhibit antigen presentation. Moreover, it regulates multiple cellular processes such as apoptosis, pyroptosis, and autophagy to establish persistent infection within host cells. This review summarizes the recently discovered mechanisms employed by Brucella to subvert host immune responses and research progress on vaccines, with the aim of advancing our understanding of brucellosis and facilitating the development of more effective vaccines and therapeutic approaches against Brucella.

Fig. 1

The replication cycle of Brucella and potential mechanisms to evade innate immunity.Brucella binds to the host cell membrane using lipid rafts and utilizes intracellular vesicles for transportation. Once inside the host cell, it forms a vesicle called the Brucella-containing vacuole (BCV). The BCV then acquires certain host marker molecules (EEA1 and Rab5), which transforms it into an early BCV (eBCV). The eBCV interacts with lysosomes, acquiring additional host marker proteins (Rab7 and LAMP-1) to facilitate the fusion between the eBCV and lysosomes, allowing Brucella to evade the damaging effects of lysosomes. Through T4SS, an effector protein interacts with the exit site of the ER, enabling the eBCV transition to the ER, where it acquires marker molecules (Rab2 and Sar1), resulting in the formation of rBCV. The ER provides an optimal environment for Brucella replication. Ultimately, Brucella establishes colonization within the ER, undergoes proliferation, and is eventually released, initiating a new round of pathogenic infection. Several effector proteins secreted by Brucella's T4SS are crucial for suppressing the host immune response. BtpA competitively binds to TIRAP/MAL, which prevents TIRAP/MAL from interacting with MyD88 and inhibits the NF-κB signaling pathway activated by TLR4, enabling Brucella to evade the innate immune response. Brucella VceC is involved in endoplasmic reticulum stress. The arrowhead represents the directional translocation of vesicles and signal transduction.

Fig. 2

Brucella modulates adaptive immune responses. Recognition of Brucella antigens by antigen-presenting cells (APCs) leads to the production of IL-12 cytokines. These cytokines activate CD4⁺ T cells and Th2 helper T cells, which secrete cytokines like IL-4 and IL-10. These cytokines further stimulate B lymphocytes, enhancing their involvement in humoral immunity and facilitating the rapid elimination of pathogens from the host. Additionally, APCs can activate Th1 helper T cells, promote the maturation of CD8⁺ T cells, and participate in cytotoxic T cell (CTL) activity. This CTL activity specifically targets and destroys Brucella-infected cells, while also releasing various cytokines such as TNF-α, IL-2, and IFN-γ. These cytokines play a role in promoting the immune clearance of Brucella by macrophages.