PubMed · 9833438
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T Higuchi, A Komiyama. 1998. [Acquired neutrophil dysfunction].. https://pubmed.ncbi.nlm.nih.gov/9833438/
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Neutrophils kill bacteria by ingesting them into phagosomes where superoxide and cytoplasmic granule constituents, including myeloperoxidase, are released. Myeloperoxidase converts chloride and hydrogen peroxide to hypochlorous acid (HOCl), which is strongly microbicidal. However, the role of oxidants in killing and the species responsible are poorly understood and the subject of current debate. To assess what oxidative mechanisms are likely to operate in the narrow confines of the phagosome, we have used a kinetic model to examine the fate of superoxide and its interactions with myeloperoxidase. Known rate constants for reactions of myeloperoxidase have been used and substrate concentrations estimated from neutrophil morphology. In the model, superoxide is generated at several mm/s. Most react with myeloperoxidase, which is present at millimolar concentrations, and rapidly convert the enzyme to compound III. Compound III turnover by superoxide is essential to maintain enzyme activity. Superoxide stabilizes at approximately 25 microM and hydrogen peroxide in the low micromolar range. HOCl production is efficient if there is adequate chloride supply, but further knowledge on chloride concentrations and transport mechanisms is needed to assess whether this is the case. Low myeloperoxidase concentrations also limit HOCl production by allowing more hydrogen peroxide to escape from the phagosome. In the absence of myeloperoxidase, superoxide increases to >100 microM but hydrogen peroxide to only approximately 30 microM. Most of the HOCl reacts with released granule proteins before reaching the bacterium, and chloramine products may be effectors of its antimicrobial activity. Hydroxyl radicals should form only after all susceptible protein targets are consumed.
Haemophilus influenzae is subject to phase variation mediated by changes in the length of simple sequence repeat regions within several genes, most of which encode either surface proteins or enzymes involved in the synthesis of lipopolysaccharides (LPS). The translational repeat regions that have been described thus far all consist of tandemly repeated tetranucleotides. We describe an octanucleotide repeat region within a putative LPS biosynthetic gene, losA. Approximately 20 percent of nontypeable H. influenzae strains contain copies of losA and losB in a genetic locus flanked by infA and ksgA. Of 30 strains containing losA at this site, 24 contained 2 tandem copies of the octanucleotide CGAGCATA, allowing full-length translation of losA (on), and 6 strains contained 3, 4, 6, or 10 tandem copies (losA off). For a serum-sensitive strain, R3063, with losA off (10 repeat units), selection for serum-resistant variants yielded a heterogeneous population in which colonies with increased serum resistance had losA on (2, 8, or 11 repeat units), and colonies with unchanged sensitivity to serum had 10 repeats. Inactivation of losA in strains R3063 and R2846 (strain 12) by insertion of the cat gene decreased the serum resistance of these strains compared to losA-on variants and altered the electrophoretic mobility of LPS. We conclude that expression of losA, a gene that contributes to LPS structure and affects serum resistance, is determined by octanucleotide repeat variation.
Human Vgamma9Vdelta2 T cells play a crucial role in early immune response to intracellular pathogens. In brucellosis infection, this population of cells is drastically increased in the peripheral blood of patients during the acute phase of infection. In vitro, Vgamma9Vdelta2 T cells exhibit strong cytolytic activity against Brucella-infected cells and are able to impair intracellular growth of Brucella suis in autologous macrophages. In this study, we have investigated the relative importance of contact-dependent mechanisms versus soluble factors in the intracellular growth and viability of B. suis. We show that Vgamma9Vdelta2 T cells use contact-dependent mechanisms, such as the release of lytic granules and Fas-mediated signals, to decrease intracellular B. suis through lysis of infected macrophages, but these mechanisms have little impact on Brucella survival. Moreover, we demonstrate that soluble factors secreted by Vgamma9Vdelta2 T cells can directly affect B. suis survival through their potent bactericidal effects. From these results, we conclude that Vgamma9Vdelta2 T cells are able to use a combination of mechanisms that reduce the total numbers of B. suis and thus, may benefit the host by limiting the spread of this intracellular pathogen.