Abstract
Brucella spp. are facultative intracellular parasitic pathogens that can survive and multiply in professional and nonprofessional phagocytes. These pathogens are responsible for brucellosis, which can cause abortion in domestic animals and undulant fever in humans. Brucella spp. can survive in a variety of cells and their virulence and chronic infections are thought to be due to their ability to evade the killing mechanisms within host cells, one of which is the inhibition of phagosome-lysosome fusion. Lipid raft-associated molecules, such as GPI-anchored proteins, GM1 ganglioside, and cholesterol, are selectively integrated into Brucella-containing macropinosomes following the internalization of Brucella into macrophages, continuously sustaining a dynamic state of the phagosomal membrane. Toll-like receptors (TLRs) are important systems that detect microbial invasion via recognition of microbial components that triggers signaling pathways to promote the expression of genes and regulate innate immune responses. Recent several studies have revealed the importance between TLRs-Brucella interactions to control Brucella infection. Here, we reviewed selected aspects of lipid raft-associated molecules and TLRs-Brucella interaction, which may help to understand the mechanism of Brucella pathogenesis.
Keywords
- Brucella
- phagocytes
- lipid-rafts associated molecules
- TLRs
- intracellular survival
1. Introduction
Brucellosis is a major zoonotic disease worldwide that causes a serious debilitating disorder in humans known as undulant fever, and abortion and sterility in domestic animals.
The most common points of entry of
A tenth of the total
Phagocytosis is a critical step for a successful immune reaction against microbial pathogens that provokes both degradation of pathogens and the subsequent presentation of pathogen peptide antigens. Ligation of various phagocytic receptors, including Fc gamma receptors and complement receptor 3, activates a series of intracellular signal transductions that induce dynamic and rapid rearrangement of the actin cytoskeleton essential for phagocytic uptake [27]. Several host cells such as M cells, macrophages, and neutrophils ingest
Toll-like receptors (TLRs) are the best characterized pattern recognition receptors (PRRs) of host cells. Receptor-ligand interaction via TLRs leads to the production of antimicrobial peptides and proinflammatory cytokines through NF-κB, mitogen-activated protein kinase (MAPK), and other various signaling pathways [32]. As a result, TLR signaling is crucial to develop host innate immune response, including recruitment of DCs and T effector cells, upregulation of MHC I and II on antigen presenting cells (APCs), and extension of adaptive immunity against infection. In Brucellosis, many studies have reported that TLRs play important roles in controlling
In this section, we will discuss the key roles of several receptors for
2. The roles of lipid rafts on Brucella infection
2.1. Roles of lipid rafts-associated molecules in Brucella infection
Time-lapse videomicroscopy has been used to follow the internalization of
2.2. Roles of cellular prion protein in Brucella infection
In addition to membrane sorting for brucella infection, key roles have been made in describing bacterial entry where it has been shown that these bacteria penetrate into the macrophage through a particular structure found in eukaryotic cells, lipid rafts, or lipid microdomains [48]. In order to interact with lipid rafts,
2.3. Roles of clathrin in Brucella infection
Lipid raft-associated clathrin is essential for host-pathogen interactions in infectious processes. The focus of a recent study was to elucidate the clathrin-mediated phagocytic mechanisms of
3. General aspects of toll-like receptors
Toll-like receptors (TLRs) are single-pass type I transmembrane-spanning proteins with a single intracellular Toll/interleukin-1 (IL-1) receptor (TIR) domain and multiple extracellular leucine-rich repeats (LRRs) responsible for binding to ligands that recognize and are activated by a small collection of microbe-derived molecules [51]. Through studies of targeted mutants among 13 paralogous TLRs, 10 in humans and 12 in mice, the diverse mode of ligands recognition of individual TLRs were determined, except for TLR8, TLR10 (only present in humans), and TLR11–13 (only present in mice). TLR2 is activated by lipopeptides and other gram-positive bacterial components in conjunction with either TLR1 or TLR6; TLR4 detects LPS, which requires accessory protein MD-2; TLR5 detects flagellin; TLR3 detects poly I:C, a double-stranded RNA (dsRNA) analog; TLR9 detects unmethylated DNA and CpG-oligodeoxynucleotides (CpG-DNA) proposed to be delivered by Granulin and high mobility group (HMG) B proteins through an ability to bind simultaneously to both CpG-DNA and TLR9; and TLR7 is activated by single-stranded RNA and its synthetic analogs such as resiquimod, imiquimod, and loxoribine. All known TLR dimer structures display the same arrangement with the two carboxy-terminal tails closely juxtaposed and the amino termini at opposite ends but each varies in modes of ligand recognition [51–54]. This conformation may be required to bring the intracellular TIR domains into close proximity to initiate signaling. TLR activation can induce cell-intrinsic antimicrobial activity such as activation of TLR2 and TLR4 can recruit NADPH oxidase assembly and mitochondria to bacteria-containing phagosome, which lead to a burst of reactive oxygen and nitrogen species within this compartment [55–57]. Evidence suggests that possibly through recruitment of vacuolar-ATPase subunits to the phagosomal membrane, TLR signaling can cause a rapid acidification of the phagosome in which TLR signaling has occurred [53, 54, 58, 59]. These activities increase the antimicrobial capacity of the phagosome, although some bacteria have actually cooped these signals to regulate their virulence programs. Expression and secretion of antimicrobial peptides (AMPs) such as β-defensins and cathelicidin can also be induced by TLRs upon detection of microbial ligands, which further supports the role of TLR-mediated detection in cell-intrinsic antimicrobial activity [60–62]. However, pathogens have evolved a variety of strategies to avoid TLR signaling such as altering their surface structures, interfering with TLR signaling pathways, and inhibiting, escaping, or subverting phagocytosis [52].
3.1. TLRs and Brucella infection
The involvement of TLR2 and TLR4 in recognizing
Maturation of dendritic cells and production of IL-12 and TNF-α in macrophages and dentritic cells are impaired [67], and levels of inflammatory chemokines RANTES (CCL5), MCP-1 (CCL2) and MIP-1α (CCL) are reduced in the absence of MyD88 protein during
3.2. Roles of individual TLRs in Brucella infection
3.2.1. TLR2
The role of TLR2 in
3.2.2. TLR4
The role of TLR4 in
3.3. TLR6
TLR6 is an important component that triggers an innate immune response against
3.4. TLR9
TLR9 plays a role in controlling
4. Conclusion
Throughout this chapter, we described the interaction between
Abbreviation
IFN-γ | Interferon gamma |
TNF-α | Tumor necrosis factor alpha |
DC | Dendritic cell |
MHC II | Major histocompatibility complex |
TLR | Toll-like receptor |
PRRs | Pattern recognition receptors |
NF-κB | Nuclear factor kappa-light-chain-enhancer of activated B cells |
MAPK | Mitogen-activated protein kinase |
APCs | Antigen-presenting cells |
BCVs |
|
LPS | Lipopolysaccharide |
IgG | Immunoglobulin |
ER | Endoplasmic reticulum |
GPI | Glycosylphosphatidylinositol |
GM1 | Monosialotetrahexosylganglioside |
CTB | Cholera toxin B |
PrpC | Cellular prion protein |
HSP60 | Heat shock protein 60 |
LAMP-1 | Lysosomal-associated membrane protein 1 |
IL | Intracellular Toll/interleukin |
TIR | Intracellular Toll/interleukin receptor |
LRRs | Leucine-rich repeats |
HMG | High mobility group |
NADPH | Nicotinamide adenine dinucleotide phosphate |
AMPs | Antimicrobial peptides |
Omp | Outer membrane protein |
RANTES | Regulated on activation, normal T cell expressed and secreted |
MCP-1 | Monocyte chemotactic protein 1 |
MIP-1α | Macrophage inflammatory protein 1 alpha |
Th | T helper |
JAK2 | Janus kinase 2 |
MALP-2 | Macrophage-activating lipopeptide-2 |
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