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Title: Pathogenicity of Mycobacterium tuberculosis Is Expressed by Regulating Metabolic Thresholds of the Host Macrophage}
Article:
Abstract:
The success of Mycobacterium tuberculosis as a pathogen derives from its facile adaptation to the intracellular milieu of human macrophages. To explore this process, we asked whether adaptation also required interference with the metabolic machinery of the host cell. Temporal profiling of the metabolic flux, in cells infected with differently virulent mycobacterial strains, confirmed that this was indeed the case. Subsequent analysis identified the core subset of host reactions that were targeted. It also elucidated that the goal of regulation was to integrate pathways facilitating macrophage survival, with those promoting mycobacterial sustenance. Intriguingly, this synthesis then provided an axis where both host- and pathogen-derived factors converged to define determinants of pathogenicity. Consequently, whereas the requirement for macrophage survival sensitized TB susceptibility to the glycemic status of the individual, mediation by pathogen ensured that the virulence properties of the infecting strain also contributed towards the resulting pathology.
Introduction:
Pathogenicity of Mycobacterium tuberculosis( Mtb) has been attributed to the plasticity of its central carbon metabolism( CCM) machinery, which facilitates ready adaptation of pathogen to the intracellular milieu of the macrophage[1]. Emerging evidence, however, suggests that Mtb pathogenicity is also supported by engagement with metabolic pathways of the host cell. Thus while Mtb adaption to host requires the switch in bacterial CCM towards catabolism of host lipid substrates[2]–[5], optimal exploitation of this switch involves pathogen-induced promotion of lipid body( LB) accumulation by the host macrophage[6]–[8]. This ensures an abundant supply of the lipid substrates. To investigate how Mtb infection influences CCM of the host macrophage we examined time-dependent modulations in macrophage metabolism, after infection with mycobacterial strains that varied in both genotype and phenotype. The resulting data, describing the temporal effects against a gradient of mycobacterial virulence, confirmed that Mtb pathogenicity was indeed intimately linked to its capacity to regulate host cell metabolism. Further, we also discovered that expression of virulence required the pathogen to engage with a unique subset of host metabolic pathways. Characterization of these pathways revealed that metabolic thresholds governing host cell survival were tightly assimilated with mechanisms regulating intracellular survival of the bacilli. This synthesis then provided the framework for convergence of both host- and pathogen-derived factors, in dictating the pathology of Mtb infection.
Discussion:
The ability to control and/or manipulate the timing and mode of death of infected cells plays an important role in mycobacterial infection[36]–[41]. Control of death by the host generally initiates apoptosis. This then functions as an innate defense mechanism that restricts microbial spread and enhances the induction of adaptive immunity. It is generally believed that virMtb inhibits apoptosis early in infection and, instead, induces necrosis of the host cell at later time points. This outcome provides for release of viable bacteria from the infected cells thereby promoting re-infection and, ultimately, transmission of disease. In addition, necrosis of infected macrophages has also been implicated in granuloma formation and inflammatory tissue damage[30],[42]. Our present study substantially enriches this general view by elucidating the scheme employed by virMtb to regulate death pathways of the host macrophage. Significant in this context is the identification that this process was controlled at the level of host cell metabolism, with regulation also impacting on pathology of the disease. Resolution of the pathogenetic strategies employed by Mtb was aided by our study design, which specifically incorporated several distinctive features to enable this end. First was the inclusion of a mycobacterial panel that collectively presented a manifold of virulence traits. By complementing this with a time-series analytical protocol, we could distinguish between the macrophage metabolic response profiles that correlated with either the elimination of non-pathogenic bacteria, the curtailment of an attenuated strain, or even with the successful cooption of host cell function by virulent bacilli. Interrogation of the data with ODE models then helped identification of the key interference points that dictated expression of Mtb virulence. Our discovery that the capacity to modulate glycolytic flux of the host macrophage dictated Mtb pathogenicity provides a new perspective on host-pathogen crosstalk. As demonstrated, this ability facilitated pathogen survival by subverting apoptosis of the infected cell. Subsequent studies clarifying the sole dependence of macrophages on glycolysis for their bioenergetic needs then revealed the basis for this effect. Thus, modulation in glycolytic flux was alone sufficient to determine the balance between survival and apoptotic death of the host cell. Our ODE models subsequently identified that Mtb virulence in fact derived from the targeted perturbation of only two steps in the pathway. One of these involved augmentation of glucose uptake by the macrophage, while the other fostered this effect by increasing substrate availability for the payoff phase of glycolysis. As a result, the rate of ATP synthesis was markedly enhanced in virMtb-infected cells. Thus, whereas the default consequence of infection on the host macrophage was to impose an energy demand that breached the homeostatic barrier, manipulation of ATP synthesis by virMtb circumvented this to ensure that infected cells remained viable. In conjunction with suppression of host macrophage apoptosis, establishment of infection also requires that the pathogen tend to its own survival needs within the intracellular milieu[43]. Here again our study yielded important insights by delineating how the glycolysis-mediated inhibition of apoptosis was allied with downstream regulation of select mitochondrial pathways to drive FM differentiation. The LBs generated as a result are known to provide a privileged niche for the intracellular bacteria[2],[13],[25],[26],[30]. As shown, the proficiency of pathogen in this regard stemmed from its ability to stimulate the complementary host processes of de novo lipid synthesis to generate TAGs on the one hand, and production of 3HB to inhibit lipolysis on the other. The concerted functioning of these two pathways was confirmed by the fact that pharmacological inhibition of either one of them compromised FM differentiation of virMtb-infected cells. Thus, regulation of LB biogenesis constitutes an indispensable ingredient of Mtb pathogenicity. While FM differentiation facilitated stabilization of the infection, we also found that continued accumulation of TAG eventually led to necrotic death of the cells. That is, the control over macrophage metabolism by pathogen persisted up to the point of securing a mechanism for eventual escape of the bacteria from these cells. These latter findings add to the earlier results and highlight the fluidity with which the individual stages that contribute to pathogenesis are integrated, and governed, by the pathogen. Noteworthy here was that this was achieved through a parsimonious strategy of targeting only select reactions. In this connection we note that both the temporal and quantitative aspects of virMtb-induced host cell lipid synthesis varied significantly between the individual strains. Therefore, it will be interesting to determine if the end point of TAG-induced necrosis is also differentially regulated depending on the Mtb strain and/or the bacillary load. Diabetes is an established risk factor for TB[44]–[46], and at least one causal factor suggested is the compromised immunity of hyperglycemic individuals[47],[48]. Our present finding that circulating glucose levels also contribute to pathogenicity by influencing macrophage apoptosis, however, reveals an additional facet to this relationship. That is, the glycemic status of an individual also impacts on the innate defense mechanism that controls Mtb infection. Notably, there is emerging evidence to suggest that the link between glucose availability and fate of the infected macrophage has broader implications that extend beyond the case of Mtb infection alone. Thus, for example, it may explain earlier findings that glucose availability also sustains chronic Brucella abortus infection in macrophages[49]. Similarly, it may also rationalize the recent discovery that control of glucose levels in the airway surface liquid serves as a mechanism for maintaining sterility of the lung airways[50]. Our observation that virMtb strains differ in their capacity to promote uptake of glucose by the host macrophage is also pertinent as it adds a complimentary dimension to the issue of glucose-dependency of Mtb infection. As shown, this property syndicates glucose availability with the cellular glycolytic rate by scaling the rate of glucose uptake by the host cell. Thus, glycemic levels and macrophage glycolysis together constitute an axis that integrates properties derived from both host and pathogen, in deciding the course of infection. That is, the ensuing pathology in any Mtb-infected individual is likely a result of the integrated effects of the individual's glycemic status, and nature of the infecting strain. Further analysis of this relationship may provide insights into factors that determine susceptibility to TB. Additionally, it may also be worthwhile to explore whether necrosis of Mtb-laden FMs contribute to the observed link between TB and atherosclerosis, with the consequent risk potentiation of ischemic stroke[51]–[55]. The facility with which Mtb continues to persist and disseminate in the human population remains a daunting challenge[6]. Our predominant focus on host immunity as a determinant of disease susceptibility is yet to yield results in terms of an effective vaccine against TB, or even a less ambiguous description of the correlates of protection. A case may, therefore, be made for revisiting the existing paradigms for understanding Mtb pathogenicity. By highlighting the extent to which metabolic intervention dictates the pathology of TB, our present report would indeed support such a view. Significant in this context is our identification that chokepoint interactions do exist that may be indifferent to either genotype or phenotype of the Mtb strain. Such a scenario then, also raises the possibility of exploiting such interactions for the development of new therapeutic strategies.
Mycobacterium tuberculosis ( Mtb ) is a highly successful human pathogen , representing the leading bacterial cause of death worldwide . Mtb infects macrophages and it adapts to the hostile intracellular milieu of this cell by exploiting the plasticity of its central carbon metabolism machinery . While several studies have detailed the bacterial adaptations that accompany infection , it is still unclear whether this process also involves engagement with host metabolic pathways . We therefore profiled the kinetic flux of host cell metabolites in macrophages that were infected with differently virulent Mtb strains . Interestingly , we found that Mtb pathogenicity was indeed intimately linked to its capacity to regulate host cell metabolism . A unique subset of host pathways was targeted so as to integrate the glycolytic threshold governing macrophage viability with mechanisms ensuring intracellular bacterial survival . Perturbation of macrophage glycolytic flux was enforced through pathogen-induced enhancement in glucose uptake , which in turn was also influenced by the extracellular glucose concentration . This observation rationalizes the increased susceptibility of diabetic individuals to TB infection Interestingly , Mtb strains also differed in their capacities to stimulate macrophage glucose uptake . Consequently , the resulting pathology is likely dictated both by the individual's glycemic status , and the nature of the infecting strain .