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Nat Rev Microbiol. Author manuscript; available in PMC Nov 22, 2011.
Published in final edited form as:
PMCID: PMC3221965

Evasion of innate immunity by Mycobacterium tuberculosis: is death an exit strategy?


Virulent Mycobacterium tuberculosis inhibits apoptosis and triggers necrosis of host macrophages to evade innate immunity and delay the initiation of adaptive immunity. By contrast, attenuated M. tuberculosis induces macrophage apoptosis, an innate defence mechanism that reduces bacterial viability. In this Opinion article, we describe how virulent M. tuberculosis blocks production of the eicosanoid lipid mediator prostaglandin E2 (PGE2). PGE2 production by infected macrophages prevents mitochondrial damage and initiates plasma membrane repair, two processes that are crucial for preventing necrosis and inducing apoptosis. Thus, M. tuberculosis-mediated modulation of eicosanoid production determines the death modality of the infected macrophage, which in turn has a substantial impact on the outcome of infection.

As one of the most important bacterial pathogens, Mycobacterium tuberculosis infects and persists in normal healthy individuals1. The chronic nature of this infection implies that M. tuberculosis has developed strategies to avoid both the innate and adaptive immune responses2,3. Manipulation of macro phage death pathways is one of the complex mechanisms used by M. tuberculosis to evade these host defences.

Subversion of the death modality of macro phages, the principal host cells infected by M. tuberculosis, is a common feature of several other intracellular pathogens. Various bacteria and intracellular parasites induce apoptosis or necrosis following infection. Legionella pneumophila, Listeria monocytogenes, Shigella flexneri, Yersinia pestis and Salmonella enterica subsp. enterica serovar Typhimurium all induce pyroptosis, which is a form of necrosis that requires caspase 1 activation4,5. S. enterica induces pyroptosis through the recruitment of ice protease-activating factor (IPAF; also known as NLRC4), an apoptotic protease-activating factor 1 (APAF1)-related NOD-like receptor protein4,69. In general, caspase 1-knockout mice are more susceptible to infection with these bacteria, suggesting that pyroptosis leads to pathogen clearance. However, as caspase 1 is crucial for the processing of mature interleukin-1β (IL-1β) and IL-18, two cytokines that are important for inflammation and host defence, the various consequences of caspase 1 activation are difficult to dissociate. Nonetheless, the detailed study of these different pathogens is instructive. For example, virulent S. Typhimurium induces apoptosis in gastrointestinal epithelial cells, which could prevent inflammation during bacterial penetration of the gut (Table I). Subsequently, infection of macrophages by S. Typhimurium induces pyroptosis, which leads to the release of pro-inflammatory mediators, including IL-1β, and activates host immunity. Crucially, the timing of macro phage pyroptosis seems to be modulated by bacterial virulence factors. By delaying macrophage pyroptosis, S. Typhimurium can parasitize the macrophage, replicate in a protected niche and use the cell to facilitate systemic dissemination10. Although stimulation of the host inflammatory response by pyroptosis is ultimately detrimental to the pathogen, these examples show that the pathogen’s ability to manipulate the timing of host cell death is sufficient to create conditions that allow it to establish a systemic infection8.

Table 1
Benefits of cell death following a host–pathogen interaction

Pyroptosis might have a crucial role in macrophage defence against M. tuberculosis infection under certain circumstances, as it has been shown that M. tuberculosis prevents inflammasome activation and IL-1β processing, which normally lead to improved mycobacterial clearance and a lower bacterial burden in the lungs of aerosol-infected mice11. However, it should be noted that macrophages infected with M. tuberculosis produce IL-1β in a manner that is dependent on bacterial virulence12,13. Furthermore, a recent study shows that although a major role for IL-1β in host resistance to M. tuberculosis clearly exists, the production of IL-1β in mice infected with M. tuberculosis can occur by mechanisms other than caspase 1 and inflammasome activation14.

By contrast, the obligate intracellular parasite Leishmania major, which is transmitted by an infected sand fly bite, is phagocytosed by neutrophils recruited to the skin. However, neutrophils are ineffectual at killing L. major and eventually undergo apoptosis. Myeloid cells, which are also recruited to the site of infection, phagocytose the infected apoptotic neutrophils15 and, analogous to the Greeks hiding in the Trojan Horse, the parasite gains entry into the macrophage unannounced16,17. This enables the parasite to undergo intracellular replication without triggering an innate response. Thus, in this example, the pathogen takes advantage of apoptotic death to avoid inflammation and detection by the host’s immune system.

Finally, like M. tuberculosis, several pathogens inhibit macrophage apoptosis, including L. pneumophila, Coxiella burnetii, Brucella spp., Neisseria spp. and Streptococcus spp. Although the microbial effectors and host targets have been defined in some cases, the assumption that the inhibition of apoptosis is a bacterial evasion mechanism has not always been clearly demonstrated. An exception to this is a study showing that the fates of macrophages and dendritic cells (DCs) differ following L. pneumophila infection18. Although L. pneumophila inhibits macrophage apoptosis, infected DCs undergo rapid apoptosis, which is less permissive for bacterial replication. Thus, similarly to M. tuberculosis, virulent L. pneumophila inhibits macrophage apoptosis and, instead, leads to necrosis.

Other investigations have shown that the type of macrophage death following infection with M. tuberculosis determines whether a successful antimycobacterial defence mechanism is activated. Infection with attenuated M. tuberculosis induces apoptosis1924. Virulent M. tuberculosis induces necrosis of both human and mouse macrophages, a property that is not shared with non-pathogenic mycobacterial species2426; this allows the bacteria to evade host defence mechanisms by inducing cellular lysis and spreading of the infection24 (FIG. 1). The concept that virulent M. tuberculosis actively inhibits the induction of macrophage apoptosis27 is supported by the identification of mutants that induce apoptosis instead of necrosis28,29.

Figure 1
The fate of infected macrophages affects host resistance to Mycobacterium tuberculosis infection

Thus, the death modality of infected macrophages should be considered an innate defence mechanism. Dissection of the cellular pathways that are altered by virulent M. tuberculosis has exposed a key role for host eicosanoid biosynthesis pathways in regulating the death modality of infected macrophages2426. Here, we discuss the selective production of specific eicosanoids that have important functional consequences for the innate control of intracellular M. tuberculosis infection.

Host lipids modulate macrophage death

Apoptosis and the concomitant antimycobacterial activity of human macrophages can be triggered by M. tuberculosis through the activity of cytosolic phospholipase A2γ (CPLA2γ; also known as PLA2G4C), a group IV CPLA2 that catalyses the release of arachidonic acid from the sn-2 position of membrane phospholipids20. Arachidonic acid and its diverse products regulate death in several cell types30. This is thought to be due to the fact that arachidonic acid products are second messengers in tumour necrosis factor-induced apoptosis31 and the fact that oxygen radicals, which are produced during lipoxygenation of arachidonic acid, induce the production of reactive oxygen species and are involved in the induction of cell death32. Arachidonic acid also activates sphingo myelinase, leading to ceramide production and apoptosis33. However, it is not clear which of these mechanisms are important in vivo34.

One area of research in this field focuses on the roles of the eicosanoids prostaglandin E2 (PGE2) and lipoxin A4 (LXA4) in the regulation of programmed macrophage death2426. The cyclooxygenases COX1 (also known as PTGS1) and COX2 (also known as PTGS2) convert arachidonic acid into the central intermediate PGH2 35, which is converted by specific synthases into a diverse range of prostanoids36. Interaction of these prostanoid species (which include the prostaglandins PGD2, PGE2, PGF2α, PGI2 and thromboxane) with an array of specific prostanoid receptors plays a part in several cellular pathways. In the case of PGE2, interactions with four PGE2 receptors, EP1, EP2, EP3 and EP4 (also known as PTGER1, PTGER2, PTGER3 and PTGER4, respectively) trigger intracellular pathways that either promote or inhibit inflammation37. Importantly, the functional specificity of PGE2 is largely determined by its interaction with these specific receptors37. EP1 mediates the elevation of intracellular Ca2+. By contrast, EP2, which is involved in joint inflammation and neutrophil recruitment, and EP4, which induces cell migration in tumour invasion, are both involved in the upregulation of intracellular cyclic AMP levels. EP2 activates protein kinase A (PKA), and EP4 activates adenylyl cyclase and phospho inositide 3-kinase. Triggering EP3 downregulates cAMP concentrations and is known to mediate fever and angiogenesis.

Lipid bodies form at distinct cytoplasmic sites following infection of mouse macrophages with the attenuated strain Mycobacterium bovis bacille Calmette-Guérin (BCG); these lipid bodies are the sites of COX2 activity and PGE2 generation38. Indeed, PGE2 production has been a consistent finding following M. bovis BCG infection of mouse macrophages39. Macrophages infected with other attenuated M. tuberculosis strains also activate PGE2 production, which prevents necrosis and leads to apoptosis instead26 (FIG. 2a). By contrast, virulent M. tuberculosis strains, such as M. tuberculosis str. H37Rv or M. tuberculosis str. erdman, are much weaker inducers of PGE2 production by macrophages26. This raises the possibility that virulent M. tuberculosis actively inhibits PGE2 production. Thus, an important strategy that M. tuberculosis exploits to induce or avoid apoptotic cell death is the subversion of host eicosanoid biosynthesis pathways25,26.

Figure 2
The balance of prostaglandin E2 and lipoxin A4 determine the cellular fate of macrophages infected with Mycobacterium tuberculosis

Lipoxins are also generated from arachidonic acid but require the action of different enzymes, including 5-lipoxygenases and 15-lipoxygenases40. Lipoxins are anti-inflammatory molecules and modulate chemokine and cytokine expression, monocyte trafficking and efferocytosis41. In contrast to the attenuated M. tuberculosis str. H37Ra, which is a weak LXA4 inducer, virulent M. tuberculosis strongly induces the synthesis of LXA4, which inhibits COX2 production and thus effectively shuts down PGE2 biosynthesis25,26 (FIG. 2b). In a PGE2-poor microenvironment, the macrophage cannot prevent mitochondrial damage or enable the repair of plasma membrane disruptions effectively2426, and both of these processes are required to prevent necrosis and induce apoptosis25,26. Virulent M. tuberculosis in pre-necrotic macrophages continues to replicate and, after the cells are lysed, propagates the infection by spreading to uninfected macrophages. Thus, the balance of PGE2 and LXA4 production by the infected macrophage regulates the relative amount of apoptosis and necrosis following M. tuberculosis infection and has important functional consequences for innate control of intracellular M. tuberculosis infection.

The idea that lipoxin production by M. tuberculosis-infected macrophages is associated with increased bacterial replication and greater virulence was strengthened by the recent genetic analysis of zebrafish (Danio rerio) susceptibility to Mycobacterium marinum infection42. Multiple mutant classes of D. rerio with different innate susceptibilities to M. marinum were identified42, and a hypersusceptible zebrafish mutant was found with a mutation that mapped to the lta4h locus, which encodes leukotriene A4 hydrolase (Lta4h), an enzyme that is required for the final step of leukotriene B4 (LTB4) synthesis. Although Lta4h deficiency results in the loss of LTB4 production, the addition of LTB4 did not complement the genetic defect nor increase host resistance. In the absence of Lta4h, its substrate (LTA4) accumulates and can lead to redirected eicosanoid synthesis and increased lipoxin synthesis. Therefore, it has been suggested that the increased susceptibility of the zebrafish lta4h mutant is due to an increase in lipoxin production. The same study presents human genetic data showing that polymorphisms in the LTA4H gene are associated with susceptibility to pulmonary and meningeal tuberculosis42. Thus, from fish to humans, the eicosanoids seem to have an unexpected role in susceptibility to tuberculosis.

Mitochondrial damage and death

The induction of LXA4 by virulent M. tuberculosis inhibits PGE2 production and triggers the mitochondrial permeability transition (MPT), leading to irreversible mitochondrial damage26 (FIG. 3c). By triggering LXA4 production in the host macrophage, virulent M. tuberculosis inhibits prostanoid production by blocking COX2 mRNA accumulation. By contrast, attenuated M. tuberculosis induces the synthesis of only minimal amounts of LXA4 and, instead, causes the production of substantial amounts of PGE2. When macrophages are infected with attenuated M. tuberculosis, PGE2 actively suppresses perturbations of the mitochondrial inner membrane26 (FIG. 3b).

Figure 3
The antinecrotic action of prostaglandin E2 is mediated through the induction of membrane repair and the protection of mitochondria

The MPT shuts down oxidative phosphorylation, leading to a loss of mitochondrial ATP production and the accumulation of reactive oxygen species, which in turn results in necrosis of the infected macrophage43,44 (FIG. 3c). The MPT is accompanied by permeabilization of the mitochondrial inner membrane and dissipation of the mitochondrial membrane potential (ΔΨm)44,45. This event is usually irreversible and is frequently associated with mitochondrial outer-membrane permeabilization (MOMP). After macrophage infection with attenuated M. tuberculosis, a reversible MOMP is triggered, leaving the mitochondrial inner membrane intact24,26. This leads to the transient release of cytochrome c, which results in only moderate activation of caspase 3 and caspase 9, leading to the induction of apoptosis (FIG. 3b). If macrophages infected with virulent M. tuberculosis are treated with cyclosporin A, an inhibitor of the MPT, cytochrome c release is substantially reduced46. As cytochrome c release is a consequence of MOMP, this indicates that during infection with virulent M. tuberculosis excessive MOMP is driven by the MPT.

Cumulatively, these studies suggest that the infection of macrophages with virulent M. tuberculosis causes mitochondrial inner membrane disruption and irreversible MOMP, leading to necrosis. By contrast, the transient MOMP caused by avirulent M. tuberculosis results in apoptosis.

Blocking plasma membrane repair

The interaction of a mycobacterium with a host macrophage results in plasma membrane microdisruptions. Microdisruptions induced by attenuated M. tuberculosis are rapidly resealed by plasma membrane repair mechanisms that include recruitment of lysosomal and Golgi-derived vesicles to the lesions on the macrophage surface25,47,48. Recruitment of these vesicles to the plasma membrane can be assessed by measuring lysosome-associated membrane glycoprotein 1 (LAMP1) or α-mannosidase II translocation to the macrophage surface49,50. Active membrane repair prevents necrosis and is required for the induction of apoptosis. By contrast, if resealing of the plasma membrane microdisruptions is inhibited, as is the case with virulent M. tuberculosis infection, necrosis ensues.

Ca2+ sensors are of crucial importance for the recruitment of both lysosomes and Golgi vesicles to the membrane lesions (FIG. 3b). Gene silencing of the lysosomal Ca2+ sensor synaptotagmin 7 (SYT7) impairs the recruitment of lysosomes, but not Golgi-derived vesicles, to the cell surface25,51. The recruitment of Golgi-derived vesicles, which occurs independently of lysosome recruitment, requires the expression of neuronal calcium sensor 1 (NCS1), a protein that is particularly abundant in the Golgi25,52. Silencing NCS1 expression or adding brefeldin A, a Golgi-specific transport inhibitor, inhibits translocation of Golgi vesicles. These data show that both lysosomal and Golgi-derived membranes are involved in plasma membrane repair and that they are recruited independently to plasma membrane lesions in infected macrophages (FIG. 3b).

Plasma membrane resealing is cAMP dependent53, and the addition of forskolin, an activator of adenylyl cyclase, results in greater translocation of lysosomal membranes to the cell surface25. The protective effect of PGE2 on mitochondrial stability is mediated through the PGE2 receptor EP226, and PGE2 binding to either EP2 or EP4 causes increased cAMP accumulation54. Consistent with this, PGE2 treatment of human macrophages infected with virulent M. tuberculosis str. H37Rv reconstitutes plasma membrane repair mediated by lysosomal membranes. By contrast, PGE2 does not affect Golgi-mediated repair25. Although the protective effects of PGE2 on mitochondria require EP2, PGE2-dependent lysosomal membrane translocation also requires phosphoinositide 3-kinase activation, which indicates that signalling through EP4 is involved25.

These findings have important functional consequences for the control of intracellular mycobacterial replication. It was found that arachidonate 5-lipoxygenase-knockout (Alox5−/−) mice, which are unable to produce LXA4 and other ALOX5-dependent products, survive longer than wild-type mice after low-dose aerosol infection with virulent M. tuberculosis55. Conversely, PGE synthase-knockout (Ptges−/−) mice, which are unable to produce PGE2, succumb earlier than wild-type mice (S.M.B., M.D. and H.R., unpublished observations). However, as many cell types produce eicosanoids, these results do not provide information about the role of eicosanoids during innate immunity. In experiments using macrophages from Ptges−/− and Alox5−/− mice, it was found that Ptges−/− macro phages were unable to control intracellular M. tuberculosis infection, whereas Alox5−/− macrophages limited M. tuberculosis replication better than wild-type macrophages25. This phenotype was replicated in vivo when Ptges−/−, Alox5−/− and wild-type macrophages infected with M. tuberculosis were adoptively transferred into the lungs of V(D)J recombination-activating protein 1-deficient (Rag1−/−) mice. Mice that received infected Alox5−/− macrophages had a substantially lower mycobacterial lung burden than recipients that received infected Ptges−/− or wild-type macrophages. As Rag1−/− mice lack B cells and T cells, the greater capacity of Rag1−/− mice to control pulmonary infection following the transfer of M. tuberculosis-infected Alox5−/− macrophages must be attributed to either an intrinsic property of Alox5−/− macrophages or a unique interaction between Alox5−/− macrophages and the innate immune system25.

One conceivable explanation for the role of PGE2 in fostering membrane repair is that PGE2 is required for the generation of SYT7, the lysosomal Ca2+ sensor essential for plasma membrane repair. As discussed, virulent M. tuberculosis stimulates LXA4 production in macrophages, which inhibits PGE2 production by downregulating COX2 mRNA accumulation26. Indeed, it was found that, unlike transcription of Lamp1, transcription of SYT7 mRNA is specifically induced by PGE2 25. Likewise, Alox5−/− macrophages infected with virulent M. tuberculosis express more SYT7 than wild-type or Ptges−/− macrophages25. Collectively, these data indicate that PGE2 is an essential modulator of SYT7 expression — although it is not known how this modulation occurs — and is therefore of crucial importance for the prevention of necrosis and induction of apoptosis. Cumulatively, these studies show that the balance of PGE2 and LXA4 production by infected macrophages affects the outcome of infection in the microenvironment of the lung.

A new model for pathogenesis

These findings establish causal relationships between the ability of the infected macrophage to restrict mycobacterial growth and both the protection of mitochondria and the resealing of plasma membrane lesions. The protection that is promoted by macrophage apoptosis seems to be based on sequestration of the pathogens in apoptotic bodies. Subsequent phagocytosis of apoptotic infected macrophages by other uninfected phagocytes could contribute to innate control of infection; however, the role of efferocytosis in bacterial killing is not well understood. An additional property of apoptotic macrophages is that the bacterial antigens that they contain are efficiently cross-presented by DCs, thus promoting a protective T cell response56 (FIG. 1a). Conversely, by inducing LXA4 production, which blocks PGE2 synthesis, virulent M. tuberculosis causes irreversible mitochondrial damage and inhibits plasma membrane repair25. Both of these factors contribute to necrosis, which releases M. tuberculosis from the lysed macrophages into the surrounding tissue, fosters de novo infection of uninfected bystander macrophages and spreads the infection (FIG. 3c). Furthermore, pre-necrotic infected macrophages and necrotic ghosts do not engender DC cross-priming of antigen-specific T cells, which leads to a substantially delayed T cell response and impairment of antimycobacterial defence mechanisms.

Recent work has identified M. tuberculosis genes that inhibit apoptosis, which supports our hypothesis that apoptosis is an innate defence mechanism that is actively suppressed by virulent M. tuberculosis28. However, the induction of necrosis must be a regulated process, as it would not be advantageous for the bacterium to destroy its niche before it has the chance to replicate. Therefore, we propose a new model of host–pathogen interaction for M. tuberculosis infection. We postulate that virulent M. tuberculosis postpones programmed cell death during the initial phase of intracellular replication to maintain an advantageous environment for growth. We further suggest that when intracellular conditions are no longer conducive to bacterial replication, virulent M. tuberculosis uses an active mechanism to induce necrosis and exit the phagosome and the macrophage (FIG. 3c). Under these conditions it is crucially important for M. tuberculosis to spread and infect other cells. Virulent M. tuberculosis induces the production of LXA4 by infected macrophages, which inhibits COX2 and prostanoid production, leading to a decline in the levels of PGE2 and a decrease in the expression of PGE2-regulated genes (for example, Syt7), thus impairing membrane repair by lysosomes. It has been demonstrated that this process leads to plasma membrane damage, but we propose that the same process also damages the phagosomal membrane and facilitates bacterial translocation from the phagosome into the cytosol. Bacterial translocation from the phagosome into the cytosol is a late event occurring 4 days after infection in human cells57 and even later in mouse macrophages (S.M.B., P. Peters, M. Skold and N. van der wel, unpublished observations). Virulent M. tuberculosis has been shown to escape from the phagosome into the cytosol, and we suggest that this is only the initial step in bacterial exit from the macrophage57.

Although M. tuberculosis has been reported to replicate in the cytosol during the late phase of infection57, the stage has already been set for the induction of cellular necrosis at this point. In the absence of PGE2, mitochondrial damage occurs and inhibits the recruitment of lysosomes to the plasma membrane, leading ultimately to necrosis. As recruitment of Golgi-derived vesicles to the cell surface is associated with phosphatidylserine flopping and annexin 1 deposition, two events that are necessary to form the apoptotic envelope, blockade of the Golgi-mediated repair pathway by virulent M. tuberculosis impairs the formation of the apoptotic envelope and leads to necrosis. Following necrosis, extracellular M. tuberculosis can infect other cells to initiate another cycle of replication and necrosis (a ‘boom and bust’ cycle). Although bacterial translocation into the cytosol has been proposed as an immune evasion strategy that prevents entry of M. tuberculosis antigens into the major histocompatibility complex (MHC) class II processing pathway57,58, M. tuberculosis antigens that were translocated into the cytosol would then be more prone to presentation by MHC class I molecules. We think that, instead of modulating antigen presentation, the translocation of M. tuberculosis into the cytosol induces macrophage necrosis, functions as an exit mechanism for the bacterium and ultimately allows M. tuberculosis to infect other cells.

Our model integrates many experimental findings, but it also raises additional questions. Although we have concentrated on the early stages of innate immunity, ultimately M. tuberculosis induces granuloma formation, which is the pathological hallmark of tuberculosis. During M. marinum infection in zebrafish, early granuloma formation was shown to be beneficial to bacterial replication42,59. It remains to be determined whether eicosanoids affect this process, but their pleiotropic effects, including functioning as chemokines, make it likely that the answer will be yes. By contrast, the formation of pulmonary granulomas in M. tuberculosis-infected mice is closely associated with the initiation of T cell immunity60, and mammalian granulomas are widely thought to be associated with containment of the infection, even if sterilization does not occur. The role of eicosanoids during these later stages of infection requires elucidation. A better understanding of their role is important, as it is known that prostaglandins can have both pro-inflammatory and anti-inflammatory effects, and some investigators have found that prostaglandins can impair antimicrobial immunity61,62. In this context, it will be particularly interesting to determine how eicosanoids affect acquired immunity and whether their effect on innate immunity influences the development of T cell immunity.


H.R.G. and S.M.B. are supported by the US National Institutes of Health (grant R01 AI073774).


A type of programmed cell death defined by chromatin condensation (pyknosis) and fragmentation, blebbing of the plasma membrane and formation of apoptotic bodies. The plasma membrane of an apoptotic cell remains intact and contains proteins that are cross-linked by transglutaminases such as annexin 1.
The uptake of apoptotic cells or apoptotic bodies by phagocytic cells.
A lipid mediator that is derived from arachidonic acid. Eicosanoids include prostaglandins, lipoxins, leukotrienes, prostacyclins, thromboxanes and hydroxyeicosatetraenoic acid compounds.
Mitochondrial membrane potential
The electrochemical gradient across the mitochondrial membranes, given the symbol ΔΨm. Complexes I, III and IV of the electron transport system in the inner mitochondrial membrane pump protons against their concentration gradient from the mitochondrial matrix into the inter-membrane space, making the matrix more negative.
Mitochondrial permeability transition
An increase in the permeability of the mitochondrial membranes to molecules of less than 1,500 daltons.
A form of cell death that is characterized by swelling of cytoplasmic organelles, including the mitochondria, and a loss of plasma membrane integrity.
Plasma membrane microdisruption
A pore formed by damage of the plasma membrane, as determined by measuring the diffusion of fluorescent dextran, an inert impermeant molecule.
A lipid metabolite of arachidonic acid that is a product of the cyclooxygenase cascade and of specific prostanoid synthases.
sn-2 position
The second (that is, middle) carbon atom in the glycerol backbone of phospholipids, providing a link for fatty acids.


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