Apparent killing of Mycobacterium tuberculosis by cytokine-activated human monocytes can be an artefact of a cytotoxic effect on the monocytes

Abstract

SUMMARY A protocol using combined exposure to interferon‐gamma (IFN‐γ), calcitriol and tumour necrosis factor‐alpha (TNF‐α) has been reported to activate human monocytes in vitro to kill Mycobacterium tuberculosis. We have attempted to repeat the findings in two laboratories, with negative results: treated cells were no different from untreated cells in this respect. However, the treated cells were more sensitive to a toxic effect of the bacteria. We suggest that the reported dramatic mycobacterial killing may have been an illusory consequence of the toxicity leading to cell lysis and loss of the liberated bacteria from the assay.

Mycobacterium tuberculosis Exploits Human Interferon γ to Stimulate Macrophage Extracellular Trap Formation and Necrosis

“…We found that IFN-γ synergized with ESX-1 to induce necrosis (Figure 3). IFN-γ is known to enhance cytotoxicity in M. tuberculosis –infected human macrophages [24, 36]. One report showed that IFN-γ enhanced necrosis in bacille Calmette-Guérin–infected macrophages, implying that ESX-1 was not involved [36].…”

“…Murine macrophage studies clearly show that IFN-γ induces M. tuberculosis killing [22, 23]. But a similar effect of IFN-γ in human macrophages remains controversial [24–26]. IFN-γ can even enhance M. tuberculosis replication during human macrophage infections [26].…”

In vitro infection of human cells with Mycobacterium tuberculosis

“…In spite of this, the efforts of other investigators to reproduce these results were unsuccessful 76,77 . In an attempt to make sense of these disparate results, we designed an experiment with very well defined experimental conditions in which we infected simultaneously monocyte derived macrophages and neutrophils from the same donors with both M. tuberculosis and M. gordonae, a nonpathogenic mycobacteria, in the presence of IFNγ.…”

Cytokines as Immunomodulators in Tuberculosis Therapy

“…Other modulators, such as calcitriol, have been claimed to activate monocytes against M. tuberculosis [23], but these results have not been confirmed by other groups [24,25]. It has also been observed that tumor necrosis factor-α (TNF-α) does not help monocytes to restrict the intracellular growth of bacteria [25].…”