Abstract
We investigated the contribution of host immune cells to bacterial killing in a whole-blood bactericidal activity (WBA) assay, an ex vivo model used to test efficacy of drugs against mycobacterium tuberculosis (Mtb). We performed WBA assays with immuno-magnetic depletion of specific cell types, in the presence or absence of rifampicin. Innate immune cells decreased Mtb growth in absence of drug, but appeared to diminish the cidal activity of rifampicin, possibly attributable to intracellular bacterial sequestration. Adaptive immune cells had no effect with or without drug. The WBA assay may have potential for testing adjunctive host-directed therapies acting on phagocytic cells.
Highlights
A variety of drugs with potential anti-mycobacterial activity require testing alone and in combinations, but there are limited options for initial screening in humans prior to launching expensive and laborious clinical trials [1]
We found that immune cells influence mycobacterial growth in the whole-blood bactericidal activity (WBA) assay, the relationship is complex, varying by cell type and by the presence or absence of rifampicin
The depletion of neutrophils from ex vivo whole blood has previously been found to enhance the growth of mycobacterium tuberculosis (Mtb), and as in our study, neutrophilic depletion had a greater impact on Mtb growth than the depletion of other immune cell subtypes [8, 9]
Summary
A variety of drugs (old/ re-purposed and new) with potential anti-mycobacterial activity require testing alone and in combinations, but there are limited options for initial screening in humans prior to launching expensive and laborious clinical trials [1]. The whole-blood bactericidal activity (WBA) assay is an established ex vivo model which tests the anti-mycobacterial efficacy of drugs, in the context of an additional contribution made by host immune cells found in whole blood [2,3,4]. Whilst this model has a theoretical advantage over testing in cell-free assays, the nature of the contribution of the host cells in controlling Mtb growth, with and without antibacterial drugs, has not been well described [5]. We performed this study to determine the magnitude of the contribution of immune cells to measured WBA in this assay
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