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: Bacterial Fitness within the Host Macrophage

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  • Authors: Lu Huang1, Evgeniya V. Nazarova2, David G. Russell3
  • Editors: Pascale Cossart4, Craig R. Roy5, Philippe Sansonetti6
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853; 2: Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853; 3: Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853; 4: Institut Pasteur, Paris, France; 5: Yale University School of Medicine, New Haven, Connecticut; 6: Institut Pasteur, Paris, France
  • Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.BAI-0001-2019
  • Received 12 September 2018 Accepted 10 January 2019 Published 08 March 2019
  • David G. Russell, [email protected]
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  • Abstract:

    has evolved to become the single greatest cause of death from an infectious agent. The pathogen spends most of its infection cycle in its human host within a phagocyte. The bacterium has evolved to block the normal maturation and acidification of its phagosome and resides in a vacuole contiguous with the early endosomal network. Cytokine-mediated activation of the host cell can overcome this blockage, and an array of antimicrobial responses can limit its survival. The survival of in its host cell is fueled predominantly by fatty acids and cholesterol. The ability of to degrade sterols is an unusual metabolic characteristic that was likely retained from a saprophytic ancestor. Recent results with fluorescent reporter strains demonstrate that bacterial survival differs with the host macrophage population. Tissue-resident alveolar macrophages, which are biased towards an alternatively activated, M2-like phenotype, are more permissive to bacterial growth than monocyte-derived, inflammatory, M1-like interstitial macrophages. The differential growth of the bacterium in these different phagocyte populations appears to be linked to host cell metabolism.

  • Citation: Huang L, Nazarova E, Russell D. 2019. : Bacterial Fitness within the Host Macrophage. Microbiol Spectrum 7(2):BAI-0001-2019. doi:10.1128/microbiolspec.BAI-0001-2019.

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/content/journal/microbiolspec/10.1128/microbiolspec.BAI-0001-2019
2019-03-08
2019-03-23

Abstract:

has evolved to become the single greatest cause of death from an infectious agent. The pathogen spends most of its infection cycle in its human host within a phagocyte. The bacterium has evolved to block the normal maturation and acidification of its phagosome and resides in a vacuole contiguous with the early endosomal network. Cytokine-mediated activation of the host cell can overcome this blockage, and an array of antimicrobial responses can limit its survival. The survival of in its host cell is fueled predominantly by fatty acids and cholesterol. The ability of to degrade sterols is an unusual metabolic characteristic that was likely retained from a saprophytic ancestor. Recent results with fluorescent reporter strains demonstrate that bacterial survival differs with the host macrophage population. Tissue-resident alveolar macrophages, which are biased towards an alternatively activated, M2-like phenotype, are more permissive to bacterial growth than monocyte-derived, inflammatory, M1-like interstitial macrophages. The differential growth of the bacterium in these different phagocyte populations appears to be linked to host cell metabolism.

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FIGURE 1

() Schematic illustration of the potential outcomes of infection with . In most hosts, exhibits rapid expansion of the bacterial burden during the first 3 to 4 weeks of infection. At this point, the acquired immune response has developed and controls the bacterial burden at a subclinical level but is unable to clear the infection. In vaccinated hosts, this transition to control of the bacterial burden is achieved at around 1 log fewer bacilli. While resolution of infection is theoretically possible, it is virtually impossible to demonstrate. Progression from latent disease to active disease appears to occur in the face of a robust systemic immune response that is Th1 dominant. While there are candidate indicators of early disease progression, the field lacks immunological markers to detect vaccine-induced protection. Published previously in reference 10 . () The main features of the human TB granuloma. A fully formed human TB granuloma is an extremely stratified structure. The center of the granuloma is caseous and rich in lipids, thought to be derived from the lipids present in foamy macrophages. The caseum is surrounded by a macrophage-rich layer that contains foamy macrophages, multinucleated giant cells, and epithelioid macrophages. bacilli are observed in many of these cells. This structure is frequently encased in a fibrous capsule of collagen and other extracellular matrix proteins. Lymphocytes tend to be restricted to the periphery of the granuloma outside the fibrous outer layer. Published previously in reference 77 .

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.BAI-0001-2019
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FIGURE 2

Usefulness of the ′::GFP reporter strain in assessing and reporting on the localized induction of inducible nitric oxide synthase at the site of infection. Phosphate-buffered saline-immunized (naïve) mice and mice vaccinated with heat-killed (vac) were infected with an ′::GFP ′:: mCherry Erdman reporter strain. Fluorescence induction of the promoter-dependent GFP is higher at 14 days in the vaccinated animals, as assessed by confocal microscopy of thick tissue sections (), which were scored subsequently by Volocity (). () The thick tissue sections were probed with antibodies against murine NOS2 (magenta), demonstrating the colocalization between GFP induction and NOS2 expression at the site(s) of infection. N.S., not significant. Data are from reference 5 ).

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.BAI-0001-2019
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FIGURE 3

Selective depletion of AMs and IMs results in a decrease and an increase in bacterial burden, respectively. Mice were treated with clodronate (Clodro.) liposomes delivered either intranasally (i.n.) () or intravenously (i.v.) () to deplete the AMs or the circulating monocytes, which depleted the recruited IMs. Neither treatment impacted the neutrophil population within the infected lung tissue. Interestingly, depletion of AMs led to a reduction in bacterial burden, while depletion of IMs led to an increase in bacterial burden. The data demonstrate how modulation of the relative dimensions of the permissive (AM) and controller (IM) macrophage populations directly impacts bacterial burden. Data are from reference 44 .

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.BAI-0001-2019
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FIGURE 4

Models of macrophage reprogramming and preprogramming. How macrophages function in the reprogramming model (Model 1) is determined by immune signaling within the tissue niche. In the proposed preprogramming model (Model 2), the function of coexisting macrophage lineages in the lung in infection is determined, in large part, by the origin of the macrophage. Mtb, ; IL, interleukin; FAO, fatty acid oxidation. Published previously in reference 44 .

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.BAI-0001-2019
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FIGURE 5

Major classes of cholesterol-dependent anti- compounds identified in a screen against intracellular (M.tb). The primary screen of 340,000 compounds identified 300 hits with 50% inhibitory concentrations (IC 50) less than 5 μM, 50% of which showed activity only against intracellular bacteria and had no activity against in rich broth. However, the majority of these compounds recovered their activity when was grown in medium with cholesterol or fatty acids as the limiting carbon source. Major targets or functions inhibited by the compounds are shown. Activators of an adenylate cyclase (rv1625c [Cya]) were shown to be involved in regulation of cholesterol utilization, as well as specific inhibitors of the enzymes HsaAB and PrpC, which are involved in cholesterol breakdown or propionyl coenzyme A (propionyl-CoA) detoxification. Data are from reference 70 .

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.BAI-0001-2019
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FIGURE 6

infection leads to retention of the foamy macrophage phenotype and facilitates bacterial access to host-derived lipids. () Murine bone marrow-derived macrophages were induced to form foamy cells through incubation with 400 μM oleate for 24 h. The cells were subsequently infected with or left uninfected. At 0 h and 48 h after infection (t=0 and t=48), cells were fixed and stained with BODIPY 493/503. organisms are displayed in red, BODIPY 493/503 is displayed in green, and DAPI (4′,6-diamidino-2-phenylindole)-stained nuclei are shown in blue. The absence of green stain in uninfected cells at 48 h indicates loss of oleate-induced lipid droplets. () Visualization of trafficking of host-acquired lipids into intracellular . Murine bone marrow-derived macrophages were infected with for 5 days and treated with 400 μM oleate for 24 h. The cells were incubated with the fluorescent fatty acid BODIPY FL-C16 for 60 min prior to analysis by confocal microscopy. organisms are displayed in red, BODIPY FL-C16 is displayed in green, and colocalization of with the fluorescent lipid appears in yellow. Data from reference 78 .

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.BAI-0001-2019
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