PMN infiltration in B. abortus infected organs and increased and reduced bacterial replication in mice depleted of TNF-a or IL-10, respectively. A close examination shows, however, that most of the phenomena described in those studies correspond to late times, once adaptive immunity has initiated or been established, and that the cellular infiltrates in the organs are predominately mononuclear. It is also significant that the ability of macrophages to control intracellular B. abortus is affected by IL10 only at very high concentrations, and that IL-6 and TNFa have no major effect, in contrast to INF-c which is the key cytokine in the control of brucellosis. Therefore, our observations at the onset of B. abortus infection are not in contradiction with those made once the adaptive immunity has developed. Activated macrophages control Oxysophocarpine Brucella efficiently, an effect noted even before the term ”activated macrophage”was coined. Since then, it has remained an unsolved problem how Brucella is able to persist in the infected host despite macrophage activation and a patently active and long lasting adaptive immunity. Furthermore, it has been noted that elimination of NADPH oxidase or nitric oxide synthase activity in mice does not affect the recovery of B. abortus in these animals, suggesting that these and possibly other crucial functions of activated cells are not relevant in brucellosis. Therefore, a very significant observation was that, once established in na?��ve macrophages, subsequent activation did not lead to Brucella clearance. It has been also shown that virulent B. abortus induces less macrophage activation than attenuated strains, as estimated by in situ esterase staining of mononuclear cells in vivo. Live Brucella does not release cytotoxic substances and it seems to prolong the survival of macrophages independently of TLR4, TLR2, IL-1b or IL-18. These properties enable Brucella to replicate without generating obvious cell damage, a characteristic that may be essential for establishing long lasting chronic infections. Some dependence, however, was observed when both TLRs were absent, suggesting that signaling by at least one of these receptors is required to prologue survival. Similarly, Brucella infected epithelial cells are able to cycle and consequently remain as reservoirs for the bacteria in vivo. Dendritic cells have been shown to sustain Brucella replication and thus may participate in immunity or serve as reservoirs, a hypothesis that deserves experimental testing. Other cells such as lymphocytes, which are crucial for mounting an efficient adaptive immunity at later times, may not play a significant role at the onset of the infection. It seems, therefore, that a crucial step in Brucella pathogenesis is to sneak to its replicating niche without cell activation or cell cycle interruption. Once there, macrophages are unable to destroy intracellular replicating Brucella, not because they are refractory to activation, but rather because their niche becomes unsuitable for fusion with lysosomes. Finally, the apoptosis inhibition may be also linked to the absence of caspases mediating proinflammatory activation. It is not known whether Brucella containing Butenafine hydrochloride vacuoles fail to fuse with lysosomes because they are part of the endoplasmic reticulum, because these vacuoles are modified in such a way that they do not have the appropriate docking molecules, or both. In this connection, the lack of significant involvement of TLR4 and TLR2 in the initial steps of B. abortus infection is remarkable. It has been demonstrated that, whereas early involvement of TLR4 and TLR2 promotes an inducible mode of phagocytosis characterized by a rapid fusion with lysosomes.