Macrophage cytoplasmic vesicle pH gradients and vacuolar H+-ATPase activities relative to virus infection.
A number of viruses replicate in macrophages, some having an obligate requirement for a macrophage host. This raised the question concerning the role of the macrophage endosomal/lysosomal compartment during such infections. Both lysosomotropic weak bases, amantadine and chloroquine, which interfere with endosomal/lysosomal pH gradients, and the macrolide antibiotic bafilomycin A1, which interferes with vacuolar H+-ATPase, inhibited African swine fever (ASF) virus replication in porcine macrophages. This inhibition was reversible: replenishment of bafilomycin, but not amantadine or chloroquine, maintained the inhibition. The characteristics of the inhibition, and the capacity of virus to escape and re-commence replication, related to the capacity of each drug to interfere with the endosomal/lysosomal proton pump. These results demonstrate that the virus actually requires macrophage endosomal/lysosomal activity for its replication. Therein, vacuolar H+-ATPase activity is particularly critical for successful virus replication, which is interesting considering the importance of this for endosomal/lysosomal activity and macrophage function.
Natale
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Institute of Virology and Immunoprophylaxis, Mittelhäusern, Switzerland.
McCullough
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KC
D000165:Acridine Orange / Q000493:pharmacokinetics; D000357:African Swine Fever / Q000097:blood* / Q000201:enzymology; D000358:African Swine Fever Virus / Q000502:physiology; D000547:Amantadine / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D003593:Cytoplasm / Q000201:enzymology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D016650:Fluorescein-5-isothiocyanate; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000201:enzymology / Q000378:metabolism; D018942:Macrolides; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism* / Q000821:virology*; D008297:Male; D054328:Proton Pump Inhibitors; D017494:Proton Pumps / Q000378:metabolism*; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013552:Swine; D014617:Vacuoles / Q000201:enzymology / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D015054:Zymosan
D000900:Anti-Bacterial Agents; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D018942:Macrolides; D054328:Proton Pump Inhibitors; D017494:Proton Pumps; D002738:Chloroquine; C040929:bafilomycin A1; D015054:Zymosan; D000547:Amantadine; D006180:Proton-Translocating ATPases; D000165:Acridine Orange; D016650:Fluorescein-5-isothiocyanate