Finally, CC apparently include both uninfected and latently infected individuals: these latter represent infection
but not disease 18, 48, 50. Interestingly, in the PBMC data presented here, the HHC group typically lies between the TB and CC groups in terms of gene expression, with a few exceptions. This is consistent with the basal assumptions. Even more interesting, whole blood analysis of gene expression shows PLX-4720 research buy that those HHC with the strongest response to ESAT-6 (who are most likely to have progressive TB 49) resemble TB patients more than HHC with little or no ESAT-6 response, with significantly higher expression of TNF-α, (p<0.04) and Fas (p<0.006) than ESAT-non-responsive HHC. TNFRII, FasL and FLIPL are also elevated, though not significantly (data not shown). This suggests that the elevated expression of these pro-apoptotic markers in whole blood reflects ongoing infection, rather than latency: ESAT-6-responsive CC did not display this trend. However, the sample size for this study was not designed for sub-analyses within groups and is thus too
small for us to do more than note this trend: we hope to clarify it in larger, ongoing studies. Overall, the data from whole blood indicate that expression of multiple BIBW2992 concentration promoters of apoptosis via the extrinsic pathway is strongly upregulated in circulating peripheral cells from newly diagnosed TB patients. The prominent elevation of TNF-α and Fas/FasL expression suggests the mechanisms through which this cascade is activated and is consistent with multiple studies from human TB 38, 44, 51–53. These data are also consistent with the starting hypothesis that apoptosis is one of the methods used by the host for eliminating infected cells without releasing viable bacteria – and suggest that the TNF-α pathway plays an important role in this. This in turn provides a possible explanation as to why inhibiting TNF-α leads to the sudden outgrowth of bacteria in latently infected individuals 32, who have been able to contain the infection up to that point. This conclusion, however, is hard to reconcile with the many manuscripts showing
inhibition of apoptosis by virulent M. tuberculosis or M. tuberculosis-derived products 23–25, 27, 28 or with the fact that see more despite elevation of many markers of apoptosis, the TB patients are, by definition, not containing the infection efficiently. Fortunately, there are two findings that may explain the apparent paradox. It has been suggested that M. tuberculosis can subvert the apoptotic cascade by modulating expression of markers downstream of primary signaling 54, 55. We therefore analyzed expression of a number of apoptosis-modulating genes downstream of these markers and in selected cases, also at expression of these genes in CD14+ and CD14− compartments. Since the number of potential genes is substantial, we chose those for which evidence already existed of modulation by M.