Modulation of phagocytic function of bovine mononuclear phagocytes byHaemophilus somnus

Gomis, Susantha; Godson, Dale L.; Beskorwayne, Terry; Wobeser, Gary A.; Potter, Andrew

doi:10.1006/mpat.1996.0086

Cited by 30 publications

(20 citation statements)

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“…In one study of macrophage-NTHI interactions, 82% of 33 clinical NTHI isolates persisted and remained viable intracellularly after having been ingested by phagocytes of a macrophage cell line (9). Haemophilus species also interact with macrophages to modulate phagocytosis and promote disease in nonhuman mammals (14,15). Collectively, these studies support a paradigm of NTHI interactions with human macrophages as a key source of persistent inflammatory responses.…”

Section: Discussionmentioning

confidence: 94%

Outer Membrane Protein P6 of NontypeableHaemophilus influenzaeIs a Potent and Selective Inducer of Human Macrophage Proinflammatory Cytokines

et al. 2005

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Interactions of nontypeable Haemophilus influenzae (NTHI) with human macrophages contribute to the pathogenesis of NTHI-induced infection in humans. However, the immunologic mechanisms that initiate and perpetuate NTHI-mediated macrophage responses have not been well explored. Outer membrane protein (OMP) P6 is a conserved lipoprotein expressed by NTHI in vivo that possesses a Pam 3 Cys terminal motif, characteristic of immunoactive bacterial lipoproteins associated with Toll-like receptor signaling. We theorized that OMP P6 is a potent immunomodulator of human macrophages. To test this hypothesis, we purified OMP P6 as well as OMP P2, the predominant NTHI outer membrane protein, and lipooligosaccharide (LOS), the specific endotoxin of NTHI, from NTHI strain 1479. Human blood monocyte-derived macrophages, purified from healthy donors, were incubated with each outer membrane constituent, and cytokine production of macrophage supernatants interleukin-1␤ (IL-1␤), tumor necrosis factor ␣ (TNF-␣), IL-10, IL-12, and IL-8 was measured. OMP P6 selectively upregulated IL-10, TNF-␣, and IL-8. While OMP P6 (0.1 g/ml for 8 h) elicited slightly greater concentrations of IL-10, it resulted in over ninefold greater concentrations of TNF-␣ and over fourfold greater concentrations of IL-8 than did OMP P2. OMP P6 at doses as low as 10 pg/ml was still effective at induction of macrophage IL-8, while OMP P2 and LOS were not. OMP P6 of NTHI is a specific trigger of bacteria-induced human macrophage inflammatory events, with IL-8 and TNF-␣ as key effectors of P6-induced macrophage responses.Nontypeable Haemophilus influenzae (NTHI) is a major cause of sinopulmonary infections, with a particular propensity for people with chronic obstructive pulmonary disease (COPD) (26,31). NTHI strains are the most common pathogenic bacteria isolated from the airways of patients with COPD, in both stable and exacerbated states (32). Outer membrane protein (OMP) P6 is a highly conserved 16-kDa lipoprotein of NTHI, expressed in vivo. Of 115 strains of NTHI tested by immunodot or Western blot, all expressed OMP P6 (21). P6 sequences are conserved among strains, making P6 a strong potential vaccine candidate. OMP P6 elicits bactericidal antibody responses and evokes proliferative lymphocyte responses in vitro that correlate with relative protection from COPD exacerbations in humans (1). OMP P6 possesses a tripalmitoyl (Cys-Pam 3 ) terminus, common to immunoregulatory bacterial lipoproteins (3, 16). As is characteristic of immunoactive bacterial lipoproteins, OMP P6 induces intracellular signaling by activation of NF-B (34).Increasing evidence supports a key role for macrophages in the pathogenesis of NTHI infections. Macrophages interact with NTHI to promote binding and phagocytosis (28,42). In fact, NTHI are capable of surviving macrophage phagocytosis in vivo and have been recovered, fully viable, from macrophages of hypertrophied adenoids and of explanted lungs of patients with COPD (11,24). The importance of macrophage function to NTHI infection is ...

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Section: Discussionmentioning

confidence: 94%

Outer Membrane Protein P6 of NontypeableHaemophilus influenzaeIs a Potent and Selective Inducer of Human Macrophage Proinflammatory Cytokines

et al. 2005

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“…(14,29,32,35). On the other hand, mechanisms of phagocytosis avoidance by extracellular pathogens have been described for some gram-negative bacteria such as Escherichia coli, Yersinia sp., and Helicobacter pylori (10).…”

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confidence: 99%

EncapsulatedStreptococcus suisInhibits Activation of Signaling Pathways Involved in Phagocytosis

2004

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Streptococcus suis capsular type 2 is an important zoonotic agent of meningitis. Previous studies reported that, in contrast to nonencapsulated mutants, encapsulated S. suis is able to resist phagocytosis. However, the mechanisms by which S. suis avoids phagocytosis are unknown. To elucidate the signaling pathway(s) involved in S. suis antiphagocytosis, we compared the ability of an encapsulated strain and its nonencapsulated mutant to induce the activation of Akt and protein kinase C (PKC), which are downstream kinases of the phosphatidylinositol 3-kinase (PI-3K) pathway, known to be involved in the phagocytosis processes. The results demonstrated high levels of Akt and PKC␣ phosphorylation after infection of J774 macrophages with the nonencapsulated mutant, whereas the encapsulated strain showed reduced activation of PI-3K/Akt/PKC␣ signaling pathway, as well as several protein tyrosine events. These results correlated with the number of intracellular bacteria. Macrophages pretreated with specific PI-3K or PKC inhibitors showed reduced levels of Akt and PKC␣ phosphorylation, resulting in 50% reduction of phagocytosis. The role of phosphatases in the antiphagocytic mechanisms was evaluated by using phosphatase inhibitors, as well as SHP-1-deficient macrophages. Only in the absence of SHP-1 did the phagocytosis of encapsulated S. suis significantly increase, leading to Akt phosphorylation levels similar to those observed with the nonencapsulated strain, indicating activation of this important SH2 domain-containing tyrosine phosphatase by encapsulated S. suis. Finally, when purified S. suis capsular polysaccharide (CPS) was added to macrophages, no phosphorylation events were observed. In addition, CPS and encapsulated S. suis were able to inhibit the uptake of the nonencapsulated mutant. These results suggest the importance of CPS in the mechanisms, whereby S. suis downmodulates phagocytosis.

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“…H. somnus organisms have also been shown to release guanosine-like compounds that inhibited the respiratory burst function of bovine peripheral blood PMNs (48). Intracellular survival of H. somnus organisms within bovine phagocytes (12,38) and modulation of phagocytic effector function (20,21,50) have also been described. The role of these and other H. somnus virulence factors in the development of vascular disease in vivo is not clear.…”

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confidence: 99%

Haemophilus somnusInduces Apoptosis in Bovine Endothelial Cells In Vitro

et al. 2001

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Haemophilus somnus causes pneumonia, reproductive failure, infectious myocarditis, thrombotic meningoencephalitis, and other diseases in cattle. Although vasculitis is commonly seen as a result of systemic H. somnus infections, the pathogenesis of vascular damage is poorly characterized. In this study, we demonstrated that H. somnus (pathogenic isolates 649, 2336, and 8025 and asymptomatic carrier isolates 127P and 129Pt) induce apoptosis of bovine endothelial cells in a time-and dose-dependent manner, as determined by Hoechst 33342 staining, terminal deoxynucleotidyl transferase-mediated dUTP-FITC nick end labeling, DNA fragmentation, and transmission electron microscopy. H. somnus induced endothelial cell apoptosis in as little as 1 h of incubation and did not require extracellular growth of the bacteria. Viable H. somnus organisms induced greater endothelial cell apoptosis than heat-killed organisms. Since viable H. somnus cells release membrane fibrils and blebs, which contain lipooligosaccharide (LOS) and immunoglobulin binding proteins, we examined culture filtrates for their ability to induce endothelial cell apoptosis. Culture filtrates induced similar levels of endothelial cell apoptosis, as did viable H. somnus organisms. Heat inactivation of H. somnus culture filtrates partially reduced the apoptotic effect on endothelial cells, which suggested the presence of both heat-labile and heat-stable factors. We found that H. somnus LOS, which is heat stable, induced endothelial cell apoptosis in a time-and dose-dependent manner and was inhibited by the addition of polymyxin B. These data demonstrate that H. somnus and its LOS induce endothelial cell apoptosis, which may play a role in producing vasculitis in vivo.Haemophilus somnus (24, 26) is a member of the family Pasteurellaceae, which causes bovine pneumonia (3,16,17,23,32), abortion (9, 58), thrombotic meningoencephalitis (TME) (24, 26, 52), myocarditis (24), infertility (43, 53), and arthritis (26). Vasculitis is a common finding during H. somnus infections (3,17,24,26). H. somnus also can be isolated from the urogenital tracts of male and female cattle in the absence of clinical disease (27,35,36). Most of these asymptomatic carrier isolates are sensitive to in vitro killing by bovine serum (8). Conversely, most pathogenic isolates of H. somnus are resistant to in vitro killing by bovine serum (8). Administration of pathogenic strains of H. somnus to cattle reproduces clinical respiratory disease and pulmonary vasculitis (17). In light of the propensity of H. somnus infections to cause septicemia and vasculitis, it is unfortunate that few investigators have examined the in vitro interactions of H. somnus with endothelial cells. Thompson and Little (57) first noted that pathogenic isolates of H. somnus adhered to endothelial cells from carotid arterial explants to a greater extent than Escherichia coli and Salmonella enterica serovar Typhimurium, as viewed with scanning electron microscopy. These authors observed that adherence of H. somnus cells cause...

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Modulation of phagocytic function of bovine mononuclear phagocytes byHaemophilus somnus

Cited by 30 publications

References 0 publications

Outer Membrane Protein P6 of NontypeableHaemophilus influenzaeIs a Potent and Selective Inducer of Human Macrophage Proinflammatory Cytokines

Outer Membrane Protein P6 of NontypeableHaemophilus influenzaeIs a Potent and Selective Inducer of Human Macrophage Proinflammatory Cytokines

EncapsulatedStreptococcus suisInhibits Activation of Signaling Pathways Involved in Phagocytosis

Haemophilus somnusInduces Apoptosis in Bovine Endothelial Cells In Vitro

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