Immunity to brucellosis - Semantic Scholar

Rev. sci. tech. Off. int. Epiz., 2013, 32 (1), 137-147

Immunity to brucellosis P. Skendros (1)* & P. Boura (2) (1) First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece (2) Clinical Immunology Unit, 2nd Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece *Corresponding author: [email protected]

Summary Resistance to intracellular bacterial pathogens such as Brucella spp. relies on cell-mediated immunity, which involves activation of the bactericidal mechanisms of antigen-presenting cells (macrophages and dendritic cells) and the subsequent expansion of antigen-specific CD4+ and CD8+ T-cell clones. Brucella antigens induce the production of T helper type 1 (Th1) cytokines, and an adequate Th1 immune response is critical for the clearance of Brucella infection. Studies on experimental and human brucellosis indicate that interferon-γ (IFNγ) is the principal cytokine active against Brucella infection. On the other hand, Brucella has evolutionarily developed diverse evasion strategies to avoid the host’s innate and adaptive immunity in order to establish an intracellular niche for long-term parasitism. Disturbances of the Th1 response and anergy have been described in patients with chronic brucellosis, and are associated with poor outcome. Accordingly, chronic brucellosis represents a challenge for the study of immune mechanisms against Brucella and the development of novel therapeutic or vaccination approaches. Keywords Anergy – Brucellosis – Brucella – IFNγ – Immunity – Immune response – Macrophage – T cell.

Background Classically, the host immune response is functionally divided into innate or non-specific and adaptive or specific immunity. The innate immune system is the first line of defence against invading pathogens. Its elements include anatomical barriers (skin and internal epithelial layers), secretory molecules (various chemokines and cytokines, complement system and opsonins) and cellular populations, such as phagocytes (neutrophils, monocytes/ macrophages, dendritic cells), and innate lymphocyte subsets (natural killer [NK] and γδ T cells). The other arm, adaptive immunity, consists of T lymphocytes, which are involved in cytokine production and cytotoxicity (cellular immunity), as well as antibody-producing B lymphocytes (humoral immunity) (56). Detection, in a non-specific manner, of microbial structures called pathogen-associated molecular patterns (PAMPs) (e.g. lipopolysaccharide [LPS], peptidoglycan [PG], lipoproteins, DNA) by germline-encoded receptors of phagocytes that

are termed pattern recognition receptors (PRRs) (e.g. tolllike receptors [TLRs]), facilitates phagocytosis of microbes. This leads to the activation of innate immune cells, and the expression of pro-inflammatory mediators and costimulatory molecules that initiate adaptive immunity (32). Macrophages and dendritic cells represent the professional antigen-presenting cells (APCs). Upon activation, they perform pathogen uptake and process the antigenic material into peptides, presenting them in association with major histocompatibility (MHC) class II and I molecules to CD4+ T helper (Th) lymphocytes and CD8+ cytotoxic T lymphocytes (CTLs), respectively. T cells recognise peptide–MHC complexes via their specific receptors, T-cell receptors (TCRs). Collectively, innate immune responses aim initially to limit microbial spread using intracellular bactericidal mechanisms and, in parallel, to induce a dynamic adaptive immunity, which is mediated by antigenspecific lymphocyte clones responsible for the clearance of the infection (32, 56). Brucellosis is the commonest chronic bacterial zoonotic disease worldwide (55). It is caused by facultative

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intracellular pathogens of the genus Brucella that have domestic animals (cows, goats, sheep, pigs and dogs) and wild animals as natural reservoirs (54). Brucellosis has long been acknowledged as a model in the study of immunity against intracellular bacterial infections. For the first time, in 1958, Holland and Pickett demonstrated that Brucella spp. extensively replicated inside murine macrophages in a ‘silent mode’, without generating toxic effects (29). Later, Mackaness confirmed the cellular basis of immunity in brucellosis, suggesting the important role of the interaction between T lymphocytes and macrophages in defence against intracellular pathogens (41). It is noteworthy that, two decades later, brucellosis was again used as the model infection associated with interferon-γ (IFNγ) production in the description of the Th1/Th2 dichotomy concept by Mosmann (45). Since then, the pivotal role of cellular immunity and Th1 cytokines (IFNγ, tumour necrosis factor [TNF]␣) in the outcome of Brucella infection has been well

established not only in mice, but also in natural hosts and humans (27, 66, 76). Cross-talk between the host immune system and Brucella is essential either for the eradication of the pathogen, or for the development of intracellular parasitism and establishment of chronic disease. Host protection against Brucella depends on cell-mediated immunity, involving mainly activated professional APCs, Th1 cells, and CD8+ CTLs (66) (Fig. 1). On the other hand, Brucella has developed various strategies to evade innate and adaptive immune responses, aimed at establishment of an intracellular niche for longterm survival and replication (3, 33, 42). It should be mentioned that immune response mechanisms to brucellosis may diverge, and they are dependent on the host, and the species or strain of Brucella (27, 42). In this

Innate immmunity

B7 co-stimulation Antibody-mediated opsonisation

Cellular immmunity

Humoral immmunity

Ag: APC: B7: BCV: CTL: IFNγ:

antigen antigen-presenting cell CD80/CD86 co-stimulatory molecules Brucella-containing vacuole cytotoxic lymphocyte interferon gamma

IL: interleukin MHC II: major histocompatibility complex type II TCR: T-cell receptor TLR: Toll-like receptor TNFα: tumour necrosis factor alpha

Fig. 1 Simplified representation of immune response against Brucella Phagocytosis and/or pattern recognition receptor (e.g. TLR) signalling lead to the activation of APC and the priming of naïve CD4+ T lymphocytes towards a Th1 phenotype (innate immunity). The Th1 cytokines (TNFα, IFNγ) enhance the anti-Brucella mechanisms of macrophages (Mφ) and induce the CD8+ CTL-mediated cytotoxicity against Brucella-infected Mφ (specific cellular immunity). Innate lymphocytes are early producers of IFNγ, linking innate to specific immunity. The Th2 response activates B lymphocytes (B) for antibody production, facilitating the phagocytosis of Brucella through opsonisation (specific humoral immunity). The Th2 cytokines (e.g. IL-10) inhibit the action of Th1 cytokines (e.g. IFNγ) and vice versa

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paper the authors aim to summarise universal aspects of immunity against Brucella infection using selected examples of experimental models and human disease.

The innate immune system and Brucella Macrophages and dendritic cells Macrophages and dendritic cells (DCs) play a fundamental role in innate immunity, in recognition and in the induction of robust adaptive immunity against intracellular bacteria such as Brucella spp. Many lines of evidence support the bidirectional relationship between these two cell types and Brucella spp. Both cell types have various inducible mechanisms to eliminate bacteria (Table I), while bacteria can invade these phagocytic cells to avoid the cellular immune response and establish infections for prolonged periods. In order to establish chronic infection Brucella spp. express virulence factors or PAMPs that interfere with, or do not alert, the antimicrobial arsenal and antigen-presenting potential of the host macrophages/DCs (Table II) (3, 33, 42, 66, 72). This stealthy strategy, characterised by low stimulatory activity and toxicity for APCs, provides a ‘gap’ that permits the establishment of an intracellular replicative niche before the activation of Th1 immune responses. Brucella is uptaken via conventional zipper-like phagocytosis through lipid raft interactions using various phagocytosispromoting receptors (FcR, C3bR, scavenger receptors [SRs]). Following entry into macrophages and DCs, most of the bacteria (approximately 90%) are killed within the first few hours. However, some of them survive and reach their replicative niche (42, 58, 74). Brucella ensures its survival and virulence by diverting endocytic pathway trafficking, and forming special phagosomes of endoplasmic reticulum

(ER) origin called Brucella-containing vacuoles (BCVs) – these represent the intracellular replication compartments (Fig. 1). The BCVs escape fusion with late endosomes and lysosomes, before they move to ER and fuse with the ER membrane (12, 61). Autophagy is a dynamic cellular homeostatic process in which cytoplasmic targets are sequestered within double-membraned vesicles called autophagosomes and subsequently delivered to lysosomes for degradation (38). Recently, substantial evidence has demonstrated autophagy to be an important innate immune mechanism resulting in direct elimination of various intracellular pathogens through hydrolytic degradation in autophagolysosomes (xenophagy; see Table I) (38, 65). Pathogen engulfment by APCs, TLR signalling and IFNγ secretion by Th1 cells are potent inducers of the autophagic machinery against intracellular bacteria (65). Notably, recent experimental data on murine macrophages suggest that B. abortus and B. melitensis subvert autophagy or exploit autophagic machinery to their advantage. In particular, BCVs that display structural features of autophagy are required for B. abortus to complete their intracellular lifecycle and spread from cell to cell (70). Moreover, the pharmacological inhibition of autophagy in vitro has been shown to significantly reduce the intracellular replication of B. melitensis (28). Recognition and signalling by TLRs is crucial for the activation of APCs and the priming of adaptive immunity (see Fig. 1). The TLRs detect a wide range of bacterial PAMPs, including LPS, lipoproteins and nucleic acids, leading to the activation of the principal transcription factors nuclear factor (NF)-␬B, activator protein (AP)-1 and IFN regulatory factor (IRF)3/IRF7. Thus, TLR signalling mediates the production of several pro-inflammatory cytokines (TNFα, interleukin [IL]-12, IL-6, IL-1β, type I IFNs) and the expression of co-stimulation molecules (CD80, CD86), ultimately bridging innate and adaptive immunity (31). Various experimental models of TLR-deficient mice have

Table I Basic mechanisms of action of antigen-presenting cells against Brucella Effector mechanism

Mode of action

Phagocytosis and autophagy (xenophagy)

Degradation by hydrolytic enzymes of phagolysosomes/autophagolysosomes

Antimicrobial cationic peptides (defensins)

Direct killing

Oxidative burst

Direct killing by ROS

Cytokine production TNFα

Strong enhancement of the bactericidal activity of phagocytes

IL-12

Priming Th1 immune response, leading to the production of IFNγ, the principal cytokine against Brucella infection

Chemokine secretion (macrophages) MCP-1, RANTES, MIP1a/MIP1b

Migration of immune cells and maintenance of inflammation to limit infection

Antigen presentation

Priming of specific immune response, leading to IFNγ production and CTL-mediated killing (cytotoxicity)

CTL: IL: IFN: MCP:

cytotoxic lymphocyte interleukin interferon monocyte chemoattractant protein

MIP: RANTES: ROS: TNF:

macrophage inflammatory protein regulated and normal T cell expressed and secreted reactive oxygen species tumour necrosis factor

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Table II How Brucella avoids or manipulates host immunity to its own benefit Virulence factor or PAMP

Mode of action

Outcome

Type IV secretion system (virB)

Diversion of intracellular trafficking targeting to replicative niche

Establishment of intracellular parasitism

BvrS/BvrR regulatory system

Control of several systems essential for intracellular trafficking


Periplasmic β-cyclic glucan

BCV biogenesis


Proline racemase PrpA

T-independent B cell mitogen that stimulates IL-10 secretion

Suppression of cellular immunity (anergy)

Btp1/TcpB

Interfere with TLR2 and TLR4 signalling, blocking of MyD88-induced activation of NFkB

Subversion of innate immune recognition and pro-inflammatory response (stealthy strategy)

Inhibition of CTL cytotoxicity

Evasion of adaptive immunity

Flagellum

Poor inducer of its cognate receptor TLR5

Escape from innate immune recognition (stealthy strategy)

Lipopolysaccharide (LPS)

Attenuated endotoxic response

Escape from innate immunity and establishment of intracellular parasitism (stealthy strategy)

Inhibition of phagolysosome fusion


Inhibition of phagocytosis and bactericidal function

Subversion of innate immunity

Protection from complement attack

Subversion of innate immunity

Impairment of MHC II antigen presentation


Induction of IL-10 production

Suppression of cellular immunity (anergy)

Interference with TLR4/MD-2 recognition inhibiting DC maturation

Subversion of innate immunity, evasion of adaptive immunity

Inhibition of the expression of MHC-II molecules and antigen presentation to CD4+ T lymphocytes in human monocytes


Induction of human T-cell apoptosis


Lipoprotein Omp25

Down-regulation of TNFα production in human macrophages and DCs

Escape from innate immunity and establishment of intracellular parasitism (stealthy strategy)

?

Defective IFNγ signal transduction in infected human macrophages

Evasion from adaptive immunity

?

Subversion or exploitation of autophagy (xenophagy)

Subversion of innate immunity, establishment of intracellular parasitism and promotion of infection (cell-to-cell spreading)

Lipoprotein Omp19

BCV: CTL: DC: IL: MHC:

Brucella-containing vacuole cytotoxic lymphocyte dendritic cell interleukin major histocompatibility complex

been used in an attempt to describe the involvement of TLR signalling in the host immune response against brucellosis (3, 50). It seems that TLR9, in association with the MyD88 adaptor, has the most prominent role in host resistance, because it is required for the clearance of B. abortus and B. melitensis in infected macrophages and DCs. The TLR9 is expressed intracellularly within endosomal compartments and senses bacterial DNA rich in CpG motifs, leading to the production of IL-12, which drives the Th1 immune response (30, 40). Beyond TLRs, the role of other PRRs, important in resistance to intracellular bacteria (such as the NOD-like receptor family [NLR]), remains elusive and needs further clarification (50). Among the various PAMPs associated with innate immune recognition of Brucella, lipopolysaccharide (Br-LPS) is the most studied and best characterised. It is a non-canonical,

NF: nuclear factor Omp: outer membrane protein PAMP: pathogen-associated molecular pattern TLR: Toll-like receptor

non-endotoxic LPS, in comparison with classical LPS from Escherichia coli. The Br-LPS acts as an immunomodulating factor critical for the survival and replication of Brucella spp. in the host (11, 13). As demonstrated in Table II, Br-LPS has a unique dual role during the course of brucellosis: at early stages of infection it has low immunostimulatory activity, ‘masking’ the microbe from innate immune recognition, whereas at advanced stages, it negatively modulates the innate immune response to favour parasitism by the pathogen and development of chronic disease.

Neutrophils Neutrophils have a key role in innate immunity and are the first cells recruited in vast numbers to the site of inflammation. Neutrophils encounter and kill microbes intracellularly upon phagocytosis, when their antimicrobial

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granules fuse with the phagosome. Furthermore, they release lytic enzymes and reactive oxygen species (ROS) that destroy pathogens (46). It has been shown that B. abortus promptly activates human neutrophils and prolongs neutrophil survival in vitro. This effect is associated with lipidated outer membrane protein (L-Omp)19, indicating the proinflammatory role of lipoproteins in the innate immunity against brucellosis (80). Brucella does not replicate within neutrophils, although it seems to resist killing (4, 37).

Innate lymphocytes Innate lymphocytes are at the interface between innate and adaptive immunity, and include mainly natural killer (NK) cells, natural killer T (NKT) cells and γδ T cells. In comparison with conventional antigen-specific T cells (αβTCR CD4+ and CD8+ T lymphocytes), they are a smaller proportion of peripheral blood cell populations and recognise non-peptidic antigens (glycolipids and phospholipids) without MHC restriction. Many studies support the important role of innate lymphocytes as rapid and early producers of IFNγ in immunity to intracellular pathogens, before the expansion of specific Th1 responses (Fig. 1) (14, 39, 47, 60). Data suggest an early protective role for γδ T cells in murine, human and bovine brucellosis (6, 35, 68). This is quite interesting because, in contrast to mice and humans, in ruminants and neonatal calves γδ T cells are a major lymphocyte subset (68). In humans, Brucella phosphoantigens activate Vγ9Vδ2 T cells at early stages of infection (6). Moreover, peripheral blood Vγ9Vδ2 T cells increase significantly in patients with acute brucellosis and decline after treatment (35). It has been previously demonstrated that Vγ9Vδ2 T cells inhibit the growth of Brucella in autologous macrophages through a combination of contact-dependent and non-contactdependent mechanisms. These include granule- and Fas ligand-mediated cytotoxicity, macrophage activation, and bactericidal activity via IFNγ production and secretion of the potent bactericidal factors granulysin and cathelicidin (LL-37) (16, 49, 53). In addition, a recent study provides new data for the inductive role of the NKG2D receptor in the anti-Brucella effect of Vγ9Vδ2 T cells on infected human macrophages (8). In vitro studies on human cells have also indicated the contribution of NK and CD4+ invariant NKT cells (iNKT) to antibacterial immunity against Brucella through cytotoxic activity and IFNγ release (7, 15). Additionally, recent data from mice immunised with heat-killed B. abortus (HKBA) suggest a role for NK cells in the induction of polyclonal antibody production by B cells (23).

In humans, peripheral blood mononuclear cells (PBMCs) of patients with acute brucellosis transiently demonstrate deficient NK cytotoxicity but revert to normal function after effective treatment, suggesting that the efficiency of NK responses could be important for the evolution of brucellosis (62).

Adaptive immunity in brucellosis: the pivotal role of the Th1 response Specific T-cell immunity Adaptive immunity expands after the activation of innate immunity in order to mount and sustain an antigen-specific response aimed at eradicating bacteria and protecting the host. The Th1 nature of adaptive immunity in brucellosis is clearly demonstrated by: – the susceptibility to infection of mice deficient in key Th1 elements such as IFNγ, IFNγ regulatory factor-1 (IRF1) and IL-12 (10, 42) – the protection that is elicited in mice by the administration of Th1-related cytokines (IFNγ and IL-12) (42) – the predominant secretion of IFNγ by murine splenocytes and CD4+ T cells (21, 52, 79), bovine CD4+ T cells (75), and human PBMCs and T cells (24, 57, 78) after in vitro stimulation by various Brucella antigens – the display of Th1 responses in patients with brucellosis and the correlation between reduced Th1 responses and chronic/relapsing disease (1, 24, 57, 59) – human genetic studies that associate disease susceptibility or outcome with polymorphisms and mutations of molecules involved in Th1 cellular immunity (66). The Th1 immune response against Brucella leads to IFNγ secretion by antigen-specific T lymphocytes (see Fig. 1). Most studies indicate that CD4+ T lymphocytes are the major producers of IFNγ, although other cell subsets such as CD8+ T lymphocytes, γδ T lymphocytes and NK cells also participate in IFNγ production (3, 77). The IFNγ activates the bactericidal machinery of macrophages, promotes the expression of antigen-presenting and costimulatory molecules on APCs, stimulates CTL-mediatedcytotoxicity and potentiates the apoptotic death of infected macrophages (3, 66, 77). The bactericidal efficiency of IFNγactivated murine macrophages against Brucella is hampered by the Th2 cytokine IL-10. It has also been reported that Br-LPS induces the expression of IL-10 by human PBMCs

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(20, 34). Data suggest that Brucella disturbs IFNγ signal transduction in infected human macrophages, although the aetiological mechanism has not yet been clarified (9) (see Table II). Substantial evidence demonstrates the protective role of CD8+ CTLs in several models of experimental brucellosis. Activated CTLs contribute to protective immunity against Brucella through Fas- or perforin-mediated cytotoxicity and IFNγ secretion (Fig. 1) (17, 18, 51). Recent data obtained in IFNγ and IL-12/β2-microglobulin knockout mice demonstrate that lack of endogenous IFNγ is more important to control of brucellosis than CTLs (10). However, in the murine brucellosis model, CTLs were found to increase during the chronic stage of infection (22). In a similar manner, human clinical studies have also demonstrated increased numbers of CTLs in the peripheral blood of patients with chronic/relapsing brucellosis (43, 44, 63, 71). It could be presumed that this phenomenon is a compensatory effect for the defective CD4+ T-cell responses that are characteristic of chronic disease. Recent data from a murine model of chronic brucellosis indicate that CTLs also display a low quality responding capacity, characterised by suppression of Th1 cytokines (IFNγ, TNFα and IL-2). This deficit is associated with the B. melitensis Toll/IL-1 receptor (TIR)-domain-containing protein (TcpB), which inhibits CD8+ cytotoxic killing of target cells expressing antigenic peptides and constitutes a novel strategy for Brucella to evade adaptive immunity (18) (Table II).

B lymphocytes and Brucella infection The B lymphocytes govern the humoral arm of adaptive immunity, characterised by production of antigen-specific antibodies (see Fig. 1). In addition to their neutralising effect, antibodies act as opsonins that facilitate the phagocytosis of bacteria by APCs, activate complement and promote antibody-dependent cell-mediated cytotoxicity (ADCC) by macrophages, neutrophils and NK cells. Under certain circumstances, B cells perform antigen presentation which can activate cellular immunity (3). The role of humoral immunity against intracellular bacterial infections is limited and not protective. Antibody-mediated opsonisation (by immunoglobulin [Ig]M, IgG1, IgG2a and IgG3) enhances phagocytic uptake of bacteria, limiting the level of initial infection with Brucella (see Fig. 1), but has little effect on the intracellular course of Brucella infection (3, 5). From a clinical perspective, detection of antibodies against Br-LPS is commonly used for the diagnosis of brucellosis (using seroagglutination tests) in livestock and humans (2). Recently, a study of B-cell-deficient mice provided new insight into the regulatory role of B cells in brucellosis,


illustrating the critical role of Th1 responses in host resistance. During the early phase of disease, B cells produce IL-10 and transforming growth factor (TGF)β, which attenuate IFNγ-mediated Th1 responses and promote persistence of infection. Absence of B cells is associated with marked, antibody-independent resistance to Brucella (26). The proposed immunoregulatory role of B cells in brucellosis is supported by experimental data showing that: – opsonised B. abortus infects and survives inside primary murine B cells (25) – B. abortus expresses the virulence factor proline racemase PrpA, a strong B-cell mitogen that induces secretion of high levels of IL-10 (69).

Brucellosis-acquired cellular anergy: lessons from patients with chronic brucellosis Approximately 10% to 30% of patients with brucellosis develop chronic disease, characterised by an atypical clinical picture, high frequency of complications (focal disease), chronic fatigue syndrome and relapses (63, 64). Patients with chronic brucellosis display defective Th1 responses and T-cell anergy, probably due to modulation of host cellular immunity by Brucella spp. (Table II) (19, 24, 36, 57, 63, 64, 67). In particular, several clinical studies have reported: – disturbance of phagocytosis and migration against nonspecific and disease-specific antigens – reduced skin reactivity to bacterial antigens – protracted resistance of monocytes and lymphocytes to apoptosis – low proliferative responses of lymphocytes to mitogens or Brucella antigens – diminished in vitro production of Th1 cytokines (IFNγ, IL-2) by PBMCs, and elevated TGFβ1 in serum – reduced CD69+ early activated T lymphocytes – an increased proportion of CTLs (CD4/CD8 ratio inversion) (66). Related to the aforementioned data, patients with chronic relapsing brucellosis present a diminished percentage of CD4+ T lymphocytes expressing the IL-2 alpha receptor (CD25) in the peripheral circulation when compared with acute brucellosis cases (63), and they retain this ‘defect’ even after potent in vitro stimulation of PBMCs with mitogen and E. coli LPS (67). Interleukin-2 is a growth factor for antigenstimulated T lymphocytes and is critical for Th1 clonal expansion. Efficient priming of T cells by APCs also requires CD28/CD80 co-stimulation to enhance TCR signalling (see Fig. 1). However, patients with chronic brucellosis, as compared with those who are acutely infected, present

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low frequencies of CD4+/CD28+ T lymphocytes after stimulation of PBMC cultures with mitogen and E. coli LPS. In addition, stimulation of patients’ PBMCs with killed Brucella (HKBA) resulted in a significant, dose-dependent reduction in CD80+ monocytes (64, 67). Similarly, whole blood HKBA cultures resulted in significant reduction in T cells expressing IFNγ, followed by an increase in CD3+/ IL-13+ T cells during disease prolongation (Th2 switch) (57). Collectively, these data on human primary cell/HKBA cultures illustrate the immunosuppressive effects of Brucella PAMPs, which may contribute to chronicity of the disease.

Conclusions

mechanisms in order to ‘hide’ from, or manipulate, cellular immunity, and to achieve intracellular persistence (Table II). Brucella can cause asymptomatic latent disease and late reactivation (48, 73). Symbiosis of Brucella spp. with the host is related to T-cell unresponsiveness (anergy) caused by pathogen-mediated disturbances in cellular immunity. Despite the heterogeneous and protean phenotype of human brucellosis (54), chronic/relapsing disease remains a challenge for the study of protective immunity to intracellular pathogens such as Brucella spp. Understanding protective immunity against brucellosis could provide insights for the development of novel therapeutic and vaccination strategies for livestock and humans.

Over the last 50 years, brucellosis has served as a model for the study of cross-talk between host immunity and intracellular bacterial infections. Despite host- and pathogen-dependent differences in the immune responses against Brucella infection, APC activation and antigen-specific Th1 responses, characterised mainly by the production of IFNγ, are mandatory for overcoming disease (Table I and Fig. 1). Brucella has developed sophisticated evolutionary

L’immunité vis-à-vis de la brucellose P. Skendros & P. Boura Résumé La résistance aux bactéries pathogènes intracellulaires telles que Brucella spp. repose sur l’immunité à médiation cellulaire, qui consiste en une activation des mécanismes bactéricides propres aux cellules présentatrices d’antigènes (macrophages et cellules dendritiques) avec par la suite une prolifération de clones des cellules T CD4+ et CD8+ effectrices spécifiques de l’antigène. Les antigènes de Brucella induisent une production de cytokines T helper de type 1 (TH1). Cette réponse immune TH1 est cruciale pour venir à bout de l’infection à Brucella. Des travaux effectués sur la brucellose chez l’homme et sur la brucellose induite expérimentalement ont montré que l’interféron-γ (IFNγ) est la cytokine la plus active contre l’infection à Brucella. Cela étant dit, Brucella a développé au cours de son évolution plusieurs stratégies d’évitement visant à contourner l’immunité innée et acquise de l’hôte et à établir une niche intracellulaire permettant d’installer un parasitisme de longue durée. Une perturbation de la réponse de type TH1 et une anergie ont été décrites chez des patients atteints de brucellose chronique et sont souvent associées à une issue défavorable. En conséquence, la brucellose chronique représente un défi pour l’étude des mécanismes de l’immunité vis-à-vis de Brucella et un enjeu pour la mise au point de méthodes thérapeutiques ou vaccinales innovantes. Mots-clés Anergie – Brucella – Brucellose – Cellule T – IFNγ – Immunité – Macrophage – Réponse immune.

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Inmunidad a la brucelosis P. Skendros & P. Boura Resumen La resistencia a patógenos bacterianos intracelulares como las brucelas pasa por mecanismos de inmunidad celular, que suponen la activación de los sistemas bactericidas de las células presentadoras de antígeno (macrófagos y células dendríticas) y la subsiguiente multiplicación de linajes clónicos de células específicas de antígeno que son los linfocitos T CD4+ y CD8+. Los antígenos de Brucella inducen la síntesis de citoquinas por los linfocitos T reguladores (helper) de tipo 1 (Th1). Para eliminar la infección por Brucella es indispensable una adecuada respuesta inmunitaria de estas células. Los estudios sobre brucelosis experimental y humana indican que el interferón gamma es la principal citoquina activa contra la brucelosis. Por otro lado, Brucella ha adquirido evolutivamente diversas estrategias de evasión para zafarse de la inmunidad tanto innata como adaptativa del hospedador y establecer un nicho intracelular de parasitismo duradero. En pacientes con brucelosis crónica se han descrito perturbaciones de la respuesta mediada por Th1 y estados de anergia, que se traducen en un débil rendimiento inmunitario. La brucelosis crónica representa en consecuencia un terreno de pruebas para estudiar los mecanismos inmunitarios contra Brucella y dar con nuevos planteamientos terapéuticos o de vacunación. Palabras clave Anergia – Brucella – Brucelosis – Inmunidad – Interferón gamma – Linfocito T – Macrófago – Respuesta inmunitaria.

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