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Virulence of the intracellular pathogen Brucella for humans is mainly associated with its lipopolysaccharide (LPS) phenotype, with smooth LPS phenotypes generally being virulent and rough ones not. The reason for this association is not quite understood. We now demonstrate by flow cytometry, electron microscopy, and ELISA that human peripheral blood monocytes interact both quantitatively and qualitatively different with smooth and rough Brucella organisms in vitro. We confirm that considerably higher numbers of rough than smooth brucellae attach to and enter the monocytes in nonopsonic conditions; but only smooth brucellae replicate in the host cells. We show for the first time that rough brucellae induce higher amounts than smooth brucellae of several CXC (GRO-alpha, IL-8) and CC (MIP-1alpha, MIP-1beta, MCP-1, RANTES) chemokines, as well as pro- (IL-6, TNF-alpha) and anti-inflammatory (IL-10) cytokines released by challenged monocytes. Upon uptake, phagosomes containing rough brucellae develop selective fusion competence to form spacious communal compartments, whereas phagosomes containing smooth brucellae are nonfusiogenic. Collectively, our data suggest that rough brucellae attract and infect monocytes more effectively than smooth brucellae, but only smooth LPS phenotypes establish a specific host cell compartment permitting successful parasitism. These novel findings link the LPS phenotype of Brucella and its virulence for humans at the level of the infected host cells. Whether this is due to a direct effect of the LPS molecules or to upstream bacterial mechanisms remains to be established.

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Chemokines are pro-inflammatory molecules with a diverse array of biological and biochemical functions. These molecules induce the migration of a number of leukocyte subsets including monocytes, neutrophils, and T-cells. The recent cloning of the IL-8, GRO, and MIP-1 alpha chemokine receptors revealed that these glycoproteins belong to the serpentine family of seven transmembrane G-protein-coupled receptors. Other members of this family include the chemotactic receptors for fMLP and C5a, indicating that a common pathway for eliciting the directional migration of leukocytes is probably transduced via G proteins. Ligand binding to chemokine receptors is complex, featured by multiple chemokines binding to a single receptor and multiple receptors binding a specific ligand. Future directions in this field appear to be focused on the cloning of novel receptors and the identification of ligands for orphaned receptors.

SummaryIt is characteristic for virus infections that monocytes/macrophages and lymphocytes infiltrate infected tissue while neutrophils are absent. To understand the mechanisms selectively attracting mononuclear cells in viral diseases, we examined in an influenza A virus model the expression and regulation of chemokines as candidate molecules responsible for the immigration of leukocytes into inflamed tissue. After influenza A virus infection of human monocytes, a rapid expression of the mononuclear cell attracting CC-chemokine genes MIP-1 , MCP-1, and RANTES occurred which was followed by the release ofchemokine proteins. In striking contrast to CC-chemokines, the expression of the prototype neutrophil CXC-chemoattractants IL-8 and GRO-oe was completely suppressed after influenza A infection. The release of other neutrophil chemotactic factors was excluded by nficrochemotaxis assays. These results suggest that the virus-specific induction of mononuclear cell-attracting chemokines accounts for the preferential influx ofmononuclear leukocytes into virus-infected tissue.A hallmark of tissue inflammation is the recruitment, immigration and activation of leukocytes. Gradients of chemotactic factors direct transendothelial migration and movement through the extracellular matrix (1). Most viral diseases are characterized by the development of a specific infiltration consisting predominantly of mononuclear leukocytes while neutrophils are absent as long as no complicating bacterial superinfection occurs. Previous reports show that exposure of monocytes or macrophages to virus results in the release of various proinflammatory cytokines (2-5). Along this line, we demonstrated that an infection of monocytes with influenza A or coxsackie B3 virus induced TNF-o~, IL-1, and IL-6 production (6-9). However, the induction of these proinflammatory cytokines cannot explain the development of characteristic mononuclear leukocyte infiltrations in virally infected tissue.In virus infections, little attention has been focused on the chemokine family and a systematic analysis is still missing. Chemokines are potent chemoattractant cytokines (10, 11) and have to be considered as the main candidate molecules responsible for the selective recruitment of distinct leukocyte populations. Members of the CC-chemokine subfamily, such as MIP-lcl 1 (macrophage inflammatory protein-lc~), MCP-1 (monocyte chemotactic protein-I), and RANTES (regulated upon activation, normal T cell expressed and secreted) preferentially attract monocytes and lymphocytes (12). The CXC-chemokines which contain an ELR-motifpreceding the first cysteine, such as IL-8 (interleukin-8) or GRO-ci (melanoma growth stimulatory activity) are major neutrophil chemoattractants (13).As a first step to study the mechanisms responsible for the generation of a typical virus-induced tissue infiltration consisting predominantly of mononuclear cells, we employed influenza A virus to infect human monocytes. Here we report the selective induction of mononuclear cell attracting chemokine...

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