Chlorpromazine (CPZ) is one of several phenothiazines known to have antimicrobial properties. It can inhibit mycobacteria, and was reported in the early literature to improve tuberculosis clinically. CPZ was tested here for its ability to inhibit the replication of Mycobacterium tuberculosis and Mycobacterium avium in cultured normal human macrophages, as determined by counts of viable bacteria at 0,4, and 7 days after bacterial infection of the macrophages. CPZ inhibited the intracellular bacteria at a concentration range of 0.23-3.6 μg/ml, and was more effective intracellularly than extracellularly. It was further tested for its ability to cooperate with isoniazid, streptomycin, pyrazinamide, rifampin, rifabutin, penicillin and ethambutol (EMB) against intramacrophage M. tuberculosis and M. avium. CPZ enhanced the effectiveness of most of the drugs tested against intracellular mycobacteria. However, the combination of CPZ and EMB did not result in augmented antimycobacterial activity.
Recombinant human gamma interferon (rIFN-y) was examined for its ability to activate human peripheral blood monocyte-derived macrophages to kill tumor cells and to affect the replication of two phylogenetically distinct intracellular pathogens, Mycobacterium tuberculosis and Leishmania donovani. Macrophages preincubated overnight with doses of rIFN-y from 5 to 500 U/ml killed [3H]thymidine-labeled mouse L929 tumor targets, as measured by the release of [3H]thymidine into the supernatant after 48 h. Counts of macrophages initially infected with leishmania promastigotes showed that rIFN-y-pretreated macrophages could both inhibit the replication of and kill the resulting intramacrophage amastigotes over a 7-day period. However, rIFN-y pretreatment of macrophages actually enhanced mycobacterial replication over a 5-to 7-day period, as assessed by (i) counting acid-fast bacilli or (ii) lysing macrophages to release bacteria and determining the numbers of viable units. Mycobacterial growth was not affected by rIFN-y in the absence of macrophages. rIFN-y
Mycobacterium avium grows exponentially over 7 days in human macrophages when they are cultured in serumless medium. Normal serum inhibits this replication. When serum lipids were extracted using chloroform, the inhibitor was present in the lipid-free component. The lipid extract significantly enhanced M. avium replication. Iron (Fe2+) added at 8-80 micrograms/mL to infected macrophage cultures in serum resulted in enhanced mycobacterial replication. Serum-induced inhibition of bacterial growth in serumless medium could be duplicated with apotransferrin at 50-500 micrograms/mL. At 1000 micrograms/mL, apotransferrin no longer inhibited bacterial growth. Holotransferrin was not inhibitory, and at 500 micrograms/mL, it enhanced M. avium growth. Depletion of the transferrin in serum by affinity chromatography using goat anti-transferrin on protein G-Sepharose removed inhibitory activity. These results indicate that transferrin levels, transferrin saturation, iron levels, and serum lipids can profoundly alter the replication of M. avium in association with macrophages.
Human adult natural killer (NK) cells were recently demonstrated to inhibit herpes simplex virus (HSV) replication in vitro. In this study we compared the ability of newborn and adult NK cells to inhibit HSV replication. Cord blood mononuclear cells (MNCs) from healthy, term newborns and MNCs from adults were analyzed for their percentage of Leu-11+ cells and compared in vitro for their NK-cell activity against HSV-infected fibroblasts and the tumor cell line K562. Cord blood MNCs, compared with adult MNCs, had significantly lower percentages of Leu-11+ cells (5 vs 11%; P less than 0.01), less anti-K562 NK activity (6 vs 54 lytic units/10(7) cells; P less than 0.001), and less anti-HSV NK activity (5 vs 52% HSV plaque inhibition; P less than 0.02). Comparing individual neonates and adults with equal percentages of Leu-11+ cells, neonatal MNCs still had less NK activity against either target. When Leu-11+ MNCs were isolated using the fluorescence-activated cell sorter, neonatal Leu-11+ MNCs still inhibited HSV replication less than adult Leu-11+ MNCs (P less than 0.01). MNCs from some neonates had significant anti-K562 NK activity but poor anti-HSV NK activity, suggesting either nonidentical NK-cell subpopulations or specific suppression. Whereas neonatal NK activity against K562 was always augmented by prior exposure to either interferon (IFN) or interleukin-2 (IL-2), the neonatal NK activity against HSV-infected cells was only augmented for half of the neonates tested. Endogenous production of alpha-IFN and gamma-IFN by MNCs exposed to HSV-infected fibroblasts was the same for cells from neonates or from HSV-seronegative adults.(ABSTRACT TRUNCATED AT 250 WORDS)
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