The Role of Neutrophils in Brucellosis

Abstract

SUMMARY Brucellosis is a bacterial disease of domestic animals and humans. The pathogenic ability of Brucella organisms relies on their stealthy strategy and their capacity to replicate within host cells and to induce long-lasting infections. Brucella organisms barely induce neutrophil activation and survive within these leukocytes by resisting microbicidal mechanisms. Very few Brucella-infected neutrophils are found in the target organs, except for the bone marrow, early in infection. Still, Brucella induces a mild reactive oxygen species formation and, through its lipopolysaccharide, promotes the premature death of neutrophils, which release chemokines and express “eat me” signals. This effect drives the phagocytosis of infected neutrophils by mononuclear cells that become thoroughly susceptible to Brucella replication and vehicles for bacterial dispersion. The premature death of the infected neutrophils proceeds without NETosis, necrosis/oncosis, or classical apoptosis morphology. In the absence of neutrophils, the Th1 response exacerbates and promotes bacterial removal, indicating that Brucella-infected neutrophils dampen adaptive immunity. This modulatory effect opens a window for bacterial dispersion in host tissues before adaptive immunity becomes fully activated. However, the hyperactivation of immunity is not without a price, since neutropenic Brucella-infected animals develop cachexia in the early phases of the disease. The delay in the immunological response seems a sine qua non requirement for the development of long-lasting brucellosis. This property may be shared with other pathogenic alphaproteobacteria closely related to Brucella. We propose a model in which Brucella-infected polymorphonuclear neutrophils (PMNs) function as “Trojan horse” vehicles for bacterial dispersal and as modulators of the Th1 adaptive immunity in infection.

Immunosuppressive Mechanisms in Brucellosis in Light of Chronic Bacterial Diseases

“…Brucella CβG does not show any toxicity or immunogenicity [80], crucial features for a pathogen aiming to persist for long periods of time. The transient activation of host immune pathways in the absence of toxicity may be beneficial for the bacteria, and the recruitment of myeloid cells might profit Brucella for dissemination as previously suggested [1,83]. β1,2gluco-oligosaccharides derived from Brucella CβG interact with the extracellular domain of DC-SIGN [84], suggesting that apart from its TLR4-dependency [80], Brucella CβG is recognised by the human DC-SIGN (Gorvel J.P. et al, unpublished); further investigations are nevertheless required to formally demonstrate this interaction and dissect its downstream transduction pathway.…”

A gene expression map of host immune response in human brucellosis

“…Recently, PMNs emerge as novel players during the initial stages of innate immune response against Brucella infection (10). Brucella resists the killing mechanisms of human PMNs and induces the early death of these cells promoting their phagocytosis by Mφ, which become vehicles for bacterial dispersion within the host (37).…”

“…Host protection against Brucella and prevention of its intracellular parasitism in macrophages depends on cell-mediated immunity, involving adequate Th1 immune response, with significant production of interferon gamma (IFN-γ) (8). Recent data support also an emerging key role of innate immunity and neutrophils in early proinflammatory responses against Brucella that may affect T-cell dynamics during infection (9,10). On the other hand, Brucella has developed various stealthy strategies to evade innate and adaptive immune responses, in order to establish intracellular long-term survival and replication (9,11).…”

Brucella: Reservoirs and Niches in Animals and Humans

“…Once inside, local professional phagocytes such as macrophages, dendritic cells, and neutrophils internalize the bacteria and move to the closest draining lymph nodes following the normal sampling of the immune system. This leads to subsequent dissemination to the different organs of the reticuloendothelial system, including lungs, spleen, liver, and bone marrow [ 33 ]. In pregnant animals, Brucella displays a strong tropism for placental trophoblasts [ 34 , 35 , 36 ] and also for mammary glands [ 37 ], in which it replicates extensively causing placentitis and abortion in the last trimester of pregnancy in ruminants [ 33 ].…”

“…This leads to subsequent dissemination to the different organs of the reticuloendothelial system, including lungs, spleen, liver, and bone marrow [ 33 ]. In pregnant animals, Brucella displays a strong tropism for placental trophoblasts [ 34 , 35 , 36 ] and also for mammary glands [ 37 ], in which it replicates extensively causing placentitis and abortion in the last trimester of pregnancy in ruminants [ 33 ]. In humans, brucellosis is a systemic infection and any organ can become infected, albeit with some predilection for joints and liver, and at lower levels for the brain and heart [ 38 ].…”