Abstract
Most bacterial infections induce the activation of polymorphonuclear neutrophils (PMNs), enhance their microbicidal function, and promote the survival of these leukocytes for protracted periods of time. Brucella abortus is a stealthy pathogen that evades innate immunity, barely activates PMNs, and resists the killing mechanisms of these phagocytes. Intriguing clinical signs observed during brucellosis are the low numbers of Brucella infected PMNs in the target organs and neutropenia in a proportion of the patients; features that deserve further attention. Here we demonstrate that B. abortus prematurely kills human PMNs in a dose-dependent and cell-specific manner. Death of PMNs is concomitant with the intracellular Brucella lipopolysaccharide (Br-LPS) release within vacuoles. This molecule and its lipid A reproduce the premature cell death of PMNs, a phenomenon associated to the low production of proinflammatory cytokines. Blocking of CD14 but not TLR4 prevents the Br-LPS-induced cell death. The PMNs cell death departs from necrosis, NETosis and classical apoptosis. The mechanism of PMN cell death is linked to the activation of NADPH-oxidase and a modest but steadily increase of ROS mediators. These effectors generate DNA damage, recruitments of check point kinase 1, caspases 5 and to minor extent of caspase 4, RIP1 and Ca++ release. The production of IL-1β by PMNs was barely stimulated by B. abortus infection or Br-LPS treatment. Likewise, inhibition of caspase 1 did not hamper the Br-LPS induced PMN cell death, suggesting that the inflammasome pathway was not involved. Although activation of caspases 8 and 9 was observed, they did not seem to participate in the initial triggering mechanisms, since inhibition of these caspases scarcely blocked PMN cell death. These findings suggest a mechanism for neutropenia in chronic brucellosis and reveal a novel Brucella-host cross-talk through which B. abortus is able to hinder the innate function of PMN.
Highlights
Polymorphonuclear leukocytes (PMNs) represent a key cellular component of the host’s antibacterial arsenal
Examination of the Brucella infected bone marrow reveals granulomas and phagocytosis of myeloid cells. Based on these observations we explored the fate of native neutrophils during their interaction with Brucella
We found that the bacterium induces the premature cell death of neutrophils without inducing proinflammatory phenotypic changes
Summary
Polymorphonuclear leukocytes (PMNs) represent a key cellular component of the host’s antibacterial arsenal. The average lifespan of PMNs is close to 5.4 days, period after which they undergo spontaneous apoptosis [1] This is in frank contrast to the previously reported short lifespans of a few hours for these cells [2]. These dead PMNs are removed by phagocytic cells laying in the reticuloendothelial system, such as monocytes (Mo), macrophages (Mφ) and dendritic cells (DCs) [3]. PMNs are activated and migrate into tissues, where they may survive three to five days to perform their phagocytic, microbicidal and proinflammatory functions [1,5]. These events are part of the innate immune response commonly triggered by pathogen-associated molecular patterns (PAMPs) [6] or by danger signals that guide the PMNs response [7]
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