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Mechanisms of Defense against Intracellular Pathogens Mediated by Human Macrophages

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  • Authors: Barry R. Bloom1, Robert L. Modlin2
  • Editor: Siamon Gordon3
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Harvard School of Public Health, Boston, MA 02115; 2: David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095; 3: Oxford University, Oxford, United Kingdom
  • Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0006-2015
  • Received 12 April 2015 Accepted 14 August 2015 Published 06 May 2016
  • Barry R. Bloom, bbloom@hsph.harvard.edu
image of Mechanisms of Defense against Intracellular Pathogens Mediated by Human Macrophages
  • Abstract:

    The key question our work has sought to address has been, “What are the necessary and sufficient conditions that engender protection from intracellular pathogens in the human host?” The origins of this work derive from a long-standing interest in the mechanisms of protection against two such paradigmatic intracellular pathogens, and , that have brilliantly adapted to the human host. It was obvious that these pathogens, which cause chronic diseases and persist in macrophages, must have acquired subtle strategies to resist host microbicidal mechanisms, yet since the vast majority of individuals infected with do not develop disease, there must be some potent human antimicrobial mechanisms. What follows is not a comprehensive review of the vast literature on the role of human macrophages in protection against infectious disease, but a summary of the research in our two laboratories with collaborators that we hope has contributed to some understanding of mechanisms of resistance and pathogenesis. While mouse models revealed some necessary conditions for protection, e.g., innate immunity, Th1 cells and their cytokines, and major histocompatibility complex class I-restricted T cells, here we emphasize multiple antimicrobial mechanisms that exist in human macrophages that differ from those of most experimental animals. Prominent here is the vitamin D-dependent antimicrobial pathway common to human macrophages activated by innate and acquired immune responses, mediated by antimicrobial peptides, e.g., cathelicidin, through an interleukin-15- and interleukin-32-dependent common pathway that is necessary for macrophage killing of .

  • Citation: Bloom B, Modlin R. 2016. Mechanisms of Defense against Intracellular Pathogens Mediated by Human Macrophages. Microbiol Spectrum 4(3):MCHD-0006-2015. doi:10.1128/microbiolspec.MCHD-0006-2015.

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Tumor Necrosis Factor alpha
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Adaptive Immune System
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Innate Immune System
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/content/journal/microbiolspec/10.1128/microbiolspec.MCHD-0006-2015
2016-05-06
2018-07-16

Abstract:

The key question our work has sought to address has been, “What are the necessary and sufficient conditions that engender protection from intracellular pathogens in the human host?” The origins of this work derive from a long-standing interest in the mechanisms of protection against two such paradigmatic intracellular pathogens, and , that have brilliantly adapted to the human host. It was obvious that these pathogens, which cause chronic diseases and persist in macrophages, must have acquired subtle strategies to resist host microbicidal mechanisms, yet since the vast majority of individuals infected with do not develop disease, there must be some potent human antimicrobial mechanisms. What follows is not a comprehensive review of the vast literature on the role of human macrophages in protection against infectious disease, but a summary of the research in our two laboratories with collaborators that we hope has contributed to some understanding of mechanisms of resistance and pathogenesis. While mouse models revealed some necessary conditions for protection, e.g., innate immunity, Th1 cells and their cytokines, and major histocompatibility complex class I-restricted T cells, here we emphasize multiple antimicrobial mechanisms that exist in human macrophages that differ from those of most experimental animals. Prominent here is the vitamin D-dependent antimicrobial pathway common to human macrophages activated by innate and acquired immune responses, mediated by antimicrobial peptides, e.g., cathelicidin, through an interleukin-15- and interleukin-32-dependent common pathway that is necessary for macrophage killing of .

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Figures

Image of FIGURE 1
FIGURE 1

Necessary conditions for protection in mice. Depletion of IFN-γ , TNF-α , or MHC class I results in increased susceptibility and death following challenge in C57BL/6 mice. B2M, beta-2 microglobulin; BCG, Bacillus Calmette–Guérin; GKO, IFN-gamma gene knock out; WT, wild type. Sources: references 1 3 .

Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0006-2015
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Image of FIGURE 2
FIGURE 2

Macrophages in leprosy lesions. Cellular infiltrates in tuberculoid and lepromatous leprosy lesions. The third panel shows an acid-fast stain, indicating the abundance of bacilli in lepromatous lesions. Courtesy of Thomas H. Rea.

Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0006-2015
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Image of FIGURE 3
FIGURE 3

Inducible NOS2 (iNOS) is essential for killing of by activated mouse macrophages but not for human monocyte-derived macrophages. L-NIL is an inhibitor of NOS2. Source: reference 17 .

Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0006-2015
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Image of FIGURE 4
FIGURE 4

TLR2-activated human monocyte-derived macrophages are able to kill , whereas activated DCs (derived by culture of monocytes with GM-CSF and IL-4) were unable to kill under the same conditions. ** ≤ 0.01. Source: reference 18 .

Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0006-2015
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Image of FIGURE 5
FIGURE 5

Failure of TLR2-activated human macrophages to induce cathelicidin (Cath.) mRNA in culture with sera from African Americans can be reversed by addition of 25-hydroxyvitamin D. IFN-γ activates human macrophages to produce cathelicidin to a comparable extent as the innate response to TLR2 agonists. Production of cathelicidin mRNA is dependent on vitamin D and inhibited by VAZ, a VDR antagonist. Vitamin D is essential for human macrophages activated by either TLR2 or IFN-γ to kill . FC, fold change. Sources: references 18 , 29 .

Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0006-2015
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Image of FIGURE 6
FIGURE 6

Inhibition of the effect of IFN-γ in stimulating induction of cathelicidin (Cath) mRNA by IFN-β is mediated by IL-10. FC, fold change. * ≤ 0.05. Source: reference 50 .

Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0006-2015
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Image of FIGURE 7
FIGURE 7

Common activation pathway for human macrophages stimulated through the innate receptor TLR2 or the acquired immune activator IFN-γ. IFN-β suppresses that activation through IL-10 by inhibiting induction of both CYP27B1 and the VDR. Source: reference 50 .

Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0006-2015
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Image of FIGURE 8
FIGURE 8

IL-15 defense response network links IL-32 to the vitamin D antimicrobial pathway. The IL-15-induced host defense network reveals IL-32 as a hub gene, connected to sets of genes involved in host defense, including the vitamin D antimicrobial pathway. The color of each node depicts fold change (FC) induction by IL-15 at 24 h. Source: reference 56 .

Source: microbiolspec May 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0006-2015
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