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Dynamic imaging of host–pathogen interactions in vivo

Key Points

  • Recent advances in microscopic imaging methods, together with the development of genetically encoded fluorescent reporters, have made it possible to directly visualize host–pathogen interactions in living tissues.

  • Time-lapse imaging studies have provided new insights into how immune cells function as sentinels for infection and tissue damage through active patrolling and sampling behaviour.

  • Recent imaging studies have revealed how pathogens may use the neutrophil response to their own benefit and the role of neutrophils in tissue remodelling following infection.

  • Dynamic imaging of Plasmodium spp. infection has provided important information regarding dissemination of the parasite from the site of infection, how Plasmodium spp. use Kupffer cells to access the liver and the strategies used by the parasite to avoid phagocytosis.

  • The immune response to pathogens in the subcapsular sinus of the lymph node has been studied in some detail. These studies revealed the importance of subcapsular sinus macrophages in trapping lymph-borne pathogens and in presenting antigen to B and T cells. These studies also reveal how intracellular pathogens can invade macrophages and how T cell contacts with invaded macrophages may expose T cells to direct invasion by pathogens.

  • T cell responses to pathogens in peripheral tissues have recently been imaged, revealing how T cells migrate within these tissues and interact with antigen-presenting cells.

Abstract

In the past decade, advances in microscopic imaging methods, together with the development of genetically encoded fluorescent reporters, have made it possible to directly visualize the behaviour of cells in living tissues. At the same time, immunologists have been turning their attention from the traditional focus on responses to model antigens to a new focus on in vivo infection models. Recently, these two trends have intersected with exciting results. Here we discuss how dynamic imaging of in vivo infection has revealed fascinating and unexpected details of host–pathogen interactions at a new level of spatial and temporal resolution.

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Figure 1: Examples of visualizing pathogens.
Figure 2: Dynamic imaging of Plasmodium spp. infection in mammals.
Figure 3: Dynamic imaging of immune responses in the lymph node subcapsular sinus.

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Acknowledgements

We thank J. Halkias for helpful comments. This work was supported by US National Institutes of Health grants AI065537 and AI065831 (E.A.R.). J.L.C. is a Sir Henry Wellcome Postdoctoral Fellow (Wellcome Trust grant: WT085494MA).

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Supplementary information

Supplementary information S1 (movie)

T cell invasion by parasites during contact with infected antigen-presenting cells in the lymph nodes. (MOV 1971 kb)

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Supplementary information S2 (movie)

Cyst rupture and release of parasites in the brain. (MOV 934 kb)

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Supplementary information S3 (movie)

Association of blood-borne mycobacteria with Kupffer cells in the liver. (MOV 9788 kb)

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Supplementary information S4 (movie)

Accumulation of vesicular stomatitis virus (VSV) particles on the floor of the subcapsular sinus. (MOV 2970 kb)

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Supplementary information S5 (movie)

Myelomonocytic extravasation accompanies a sustained loss in vascular integrity. (MOV 9000 kb)

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Supplementary information S6 (movie)

Sporozoite gliding in the skin. (MOV 3296 kb)

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Supplementary information S7 (movie)

Sporozoite passage into the liver parenchyma through Kupffer cells. (MOV 785 kb)

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Supplementary information S8 (movie)

Plasmodium berghei-infected hepatocyte and budding merosomes. (MOV 4451 kb)

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Supplementary information S9 (movie)

Two-stage neutrophil swarm formation. (MOV 1137 kb)

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Supplementary information S10 (movie)

Toxoplasma gondii egress corresponds to initiation of neutrophil swarming. (MOV 1475 kb)

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Supplementary information S11 (movie)

Accumulation of virus-specific B cells below and within the subcapsular sinus (SCS) floor. (MOV 3832 kb)

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Supplementary information S12 (movie)

T cells forming clusters around infected CD169+ cells. (MOV 2898 kb)

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Supplementary information S13 (movie)

T cell behaviour near isolated parasites and intact cysts. (MOV 4813 kb)

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Glossary

Confocal microscopy

A focused beam of light is scanned across the sample. Emitted light not from the focal point of the lens on the tissue is prevented from reaching the detector by a pinhole, reducing out-of-focus signal. The microscope obtains a series of in focus images at varying tissue depths, termed optical sectioning.

Two-photon laser-scanning microscopy

(TPLSM). An imaging method based on the excitation of uorophores by absorption of energy from two photons, with each photon contributing half of the energy required for excitation. Consequently, each photon is twice the wavelength that would be required for single photon excitation leading to deeper tissue penetration compared to other imaging methods.

Second harmonic signals

Signals that occur when two incident photons pass through a structure with no centre of symmetry and emerge as one photon with half the incident wavelength. In biological tissues this is mostly a property of collagen.

Bacille Calmette–Guérin

(BCG). A strain of live attenuated Mycobacterium bovis used for vaccination against Mycobacterium tuberculosis in humans.

Subcapsular sinus

The outer region of the lymph node where afferent lymph first enters the lymph node. It consists of a sponge-like network of reticular fibroblast cells encasing collagen fibres and is separated from the lymph node cortex by a layer of sinus-lining cells and a discontinuous basement membrane.

Liver sinusoids

Specialized blood vessels lined by a fenestrated endothelium and interspersed Kupffer cells.

Kupffer cells

A specialized population of macrophages that reside in the liver.

Granuloma

An organized structure containing macrophages and other immune cells.

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Coombes, J., Robey, E. Dynamic imaging of host–pathogen interactions in vivo. Nat Rev Immunol 10, 353–364 (2010). https://doi.org/10.1038/nri2746

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