Establishment of Chronic Infection: Brucella's Stealth Strategy

Abstract

Brucella is a facultative intracellular pathogen that causes zoonotic infection known as brucellosis which results in abortion and infertility in natural host. Humans, especially in low income countries, can acquire infection by direct contact with infected animal or by consumption of animal products and show high morbidity, severe economic losses and public health problems. However for survival, host cells develop complex immune mechanisms to defeat and battle against attacking pathogens and maintain a balance between host resistance and Brucella virulence. On the other hand as a successful intracellular pathogen, Brucella has evolved multiple strategies to evade immune response mechanisms to establish persistent infection and replication within host. In this review, we mainly summarize the "Stealth" strategies employed by Brucella to modulate innate and the adaptive immune systems, autophagy, apoptosis and possible role of small noncoding RNA in the establishment of chronic infection. The purpose of this review is to give an overview for recent understanding how this pathogen evades immune response mechanisms of host, which will facilitate to understanding the pathogenesis of brucellosis and the development of novel, more effective therapeutic approaches to treat brucellosis.

Keywords: Brucella; adaptive immunity; apoptosis; autophagy; chronic infection; innate immunity; small noncoding RNA; “Stealth” strategy.

Figure 1

Model of Brucella invasion and intracellular trafficking within macrophage cells. Smooth Brucella and lipid rafts interact on the plasma membrane. Brucella derived β-1,2-glucans help in the conversion of external vacuole lipid rich domains that leads to fusion with lysosomes for replication of bacteria. This interaction ultimately activates the T4SS proteins. T4SS proteins in the cytosol of host cell facilitate the interaction with the endoplasmic reticulum that converted into the replicative vacuole. Conversion of the eBCV into rBCV is facilitated by Yip1A dependent activation of IRE1α and results in formation of large vacuoles that depend upon ATG9 and WIPI. The aBCVs formation is dependent on the autophagy initiation proteins, ULK1, ATG14L and BECLIN1, that complete the intracellular cycle and finally through lytic and non-lytic mechanisms the pathogen is released from the cell. While the role of the rough Brucella outer membrane protein has been verified, their internalization and intracellular trafficking is unclear but involved in lysosomal degradation.

Figure 2

Strategies of Brucella to evade the innate and adaptive immunity. Brucella Btp1/TcpB is proposed to act in host cytosol where it interferes with TLR signaling pathway and facilitates ubiquitination and degradation of Mal which in turn inhibits TLR2 and TLR4 pathway, resulting in inhibition of NF-κB secretion and lymphocyte activation. On the other hand, the antigen loading compartment, comprised of Br-LPS and MHC class II molecules, is capable of interacting with functional microdomain which result in lymphocyte activation and inhibition of OVA presentation to CD4+ T cells. Straight arrows indicate the innate immunity pathways while dashed arrows are related to adaptive immunity pathways.

Figure 3

Overview of stealth strategies of Brucella. TLR signaling pathway is involved in the recognition of Brucella which mediates the secretion of TNF-α and IL-12 by DCs and Møs during the initial stages of infection that favor intracellular survival and replication. Brucella produces Btp1/TcpB protein that inhibits TLR2/4 signaling pathway while flagellin inhibits TLR5. Brucella LPS O-antigen binds with C3 preventing activation of complement cascade. Brucella inhibits activation of NK cells and neutrophil degranulation to interfere with innate immune response of host. Btp1/TcpB produced by this bacteria inhibit dendritic cells maturation, and Brucella LPS inhibits of antigen presentation, coupled together ultimately interfere with innate and adaptive immunity of host facilitating chronic infection. Brucella lipoprotein increases apoptosis of T cells which is dependent upon TNF-α secretion that directly inhibits the T cell response. Furthermore, Brucella inhibits macrophage apoptosis and autophagolysosomal fusion which are among the key stealth strategies of this pathogen. The final consequence of interfering with these mechanism results in the clinical manifestations of human brucellosis and in the natural hosts.