Impairment of IntramacrophagicBrucella suisMultiplication by Human Natural Killer Cells through a Contact-Dependent Mechanism

Abstract

Brucellosis is a worldwide zoonosis that affects domestic animals and humans. The pathogenesis exhibited by this disease differs remarkably between humans and animals (35, 43). In domestic animals, brucellosis is mainly an abortive disease that results from a long-lasting often-unapparent infection. On the other hand, human brucellosis, also named Malta fever, is a complex disease that begins with a systemic infection that can be followed either by localized infection or chronic disease (15,29,43). Murine models are commonly used to study Brucella infection. Many strains of mice are sensitive to Brucella spp. but develop a disease quite different from that observed in domestic animals or in humans. Infection with Brucella does not modify pregnancy in mice, and acute infection results in a long-lasting presence of bacteria in the spleen and liver, predominantly. In humans, chronic infection is characterized by a specific bacterial localization within the body (spleen, liver, heart, bones, and brain) and a deleterious effect of the bacteria on these organs (43). The difference in pathogeny results most likely from differences in the immune responses in humans, domestic animals, and animal models (14). Some important differences between the immune responses of mice and humans have been reported. Brucella suis inhibits macrophage tumor necrosis factor alpha (TNF-␣) production in humans but not in mice (7,8) and this property is due to the outer membrane protein Omp25 (23). Furthermore, humans possess a specific type of circulating lymphocytes, called T␥9␦2, which is absent in mice. These lymphocytes proliferate importantly in human blood after Brucella infection (2) and impair intramacrophagic multiplication (36, 37).The mouse immune response has been widely studied (1, 19) although the reasons for the persistence of Brucella are not understood (22). The immune response in mammals can be divided into innate and adaptive immunity. Although the adaptive immunity is the most efficient response to eliminate infectious agents, it is widely accepted that innate response determines the behavior of specific response particularly in defining Th1 versus Th2 polarized response. Thus, the innate response is very important for the evolution of the infection. The importance of the Th1 cytokine gamma interferon (IFN-␥) in controlling infection in mice has been emphasized (1, 33). Among the cells involved in IFN-␥ production, NK cells play a particular role; they are the most important IFN-␥ producers in the beginning of infection. However, it has been clearly demonstrated that NK cells do not play a major role in the early control of Brucella abortus infection in mice (18). On the other hand, it was formally established that in the acute phase of the illness, the activity of the NK cells is impaired in humans developing brucellosis (40). Moreover, human NK cells were recently shown to mediate the intracellular killing of Mycobacterium tuberculosis (4). Therefore, in order to better understand the role of NK cells in bacterial deve...

Dominant Th1 cytokine production in early onset of human brucellosis followed by switching towards Th2 along prolongation of disease

“…It has been shown that NK cells cultured in the presence of infected macrophages are highly activated and secrete gamma interferon and tumor necrosis factor alpha. 28 It is also demonstrated that a nonpeptidic fraction of Brucella suis specifically can activate human Vgamma9 Vdelta2 T cells. Activated Vgamma9 Vdelta2 T cells impaired the multiplication of B. suis in THP-1 cells by inducing TNF-alpha and IFN-gamma release.…”

Release of LL-37 by Activated Human Vγ9Vδ2 T Cells: A Microbicidal Weapon against Brucella suis

“…These soluble factors could not be attributed to effects of proinflammatory cytokines (IFN-␥ and TNF-␣) nor granulysin, an antibacterial protein contained in lytic granules (9). Studies from Dieli et al (20) have shown that granulysin from V␥9V␦2 T cells can kill both intracellular and extracellular bacteria, Mycobacterium tuberculosis, but further studies showed that granulysin requires cell-to-cell contact and the observed extracellular effects came from recombinant granulysin that was added to supernatant or from strontium chloride treatments (21,22). Therefore, granulysin is not a potential soluble factor.…”

Vγ9Vδ2 T cells use a combination of mechanisms to limit the spread of the pathogenic bacteria Brucella

“…To investigate the exact role of granule exocytosis in the inhibition of Brucella development, we treated V␥9V␦2 T cells with strontium chloride, which induces degranulation and depletion of intracellular granule stores [27]. We tested several concentrations of strontium chloride and followed the depletion of intracellular granule stores by analyzing V␥9V␦2 T cells for levels of one of the granule proteins, perforin.…”