Intracellular Bacteria: Catch me if you can
- Inserm U1111, Université Lyon 1, Ecole Normale Supérieure, CNRS UMR5308, France
Infectious diseases are one of the main causes of death worldwide. Several of the most deadly bacterial pathogens, such as Salmonella enterica and Listeria monocytogenes, cause disease by multiplying inside human cells. The human body is constantly patrolled by immune cells, and contains lots of antibodies and other molecules that can target and kill microbes, but the environment inside host cells provides a safe haven where certain pathogens can avoid detection by the immune system. However, each host cell can contain only a limited number of these intracellular bacteria so, after several rounds of replication, they need to leave the infected cell and invade other cells in order to continue multiplying. Until recently the details of how intracellular bacteria can spread between cells without being detected and killed by the immune system were poorly understood.
Now, in eLife, Tom Kawula of the University of North Carolina and colleagues – including Shaun Steele as first author – report how experiments on Francisella tularensis, a bacterium that causes a disease known as tularemia, have revealed more details about this process (Steele et al., 2016). F. tularensis replicates in the cytosol of immune cells called macrophages and hundreds of them can live inside a single host cell (Celli and Zahrt, 2013). Previous studies have revealed that some intracellular bacteria, including L. monocytogenes, grow an actin tail in order to move between epithelial cells (Figure 1; Welch and Way, 2013). However, F. tularensis is unable to form an actin tail so it must rely on a different mechanism to spread around the body.
Figure 1
Intracellular bacteria can spread between host cells in different ways.
The environment surrounding the host cells is full of immune cells as well as proteins from the complement system (orange), defensins (purple) and antibodies (grey). Top: After several rounds of replication in host cells, certain intracellular bacteria (green), including L. monocytogenes, have the ability to make an actin tail that can propel them from an infected cell (shown in blue) towards a neighbouring epithelial cell (yellow). This causes part of the infected cell membrane to bulge into the neighbouring cell, which eventually results in the bacteria being taken into the neighbouring cell surrounded by two layers of membrane (one from each cell). Bacteria then break down the two membranes to be released into the cytosol. Bottom: Steele et al. found that F. tularensis and S. enterica can transfer between macrophages through a trogocytosis-associated process. Uninfected macrophages (yellow) acquire bacteria from infected macrophages (blue) following temporary contact between the cells. Afterwards, the cells separate and the bacteria start to replicate in the acceptor cell (blue-yellow; the original blue donor cell is not shown). This bacterial cell-to-cell transfer is also associated with the exchange of membrane, membrane proteins and cytosol.
Using video-microscopy, Steele et al. observed that uninfected macrophages acquire F. tularensis from infected macrophages following a brief cell-to-cell contact. This process does not kill the cells involved, or expose the bacteria to immune responses outside the cells. Moreover, the exchange of materials between two macrophages is not restricted to pathogens that live in the cytosol: Steele et al. demonstrate that macrophages can also exchange latex beads and plasma membrane. The researchers also demonstrate that S. enterica – which lives inside host cell compartments called vacuoles – can be transferred between macrophages in the same way. The active exchange of plasma membrane and membrane proteins was first observed in other immune cells called lymphocytes over a decade ago and is called trogocytosis (from the Greek Trogo=to nibble; Joly and Hudrisier, 2003).
The process discovered by Steele et al. joins a list of strategies that bacteria, viruses and other intracellular pathogens are known to use to spread in their host (reviewed in Sattenau, 2008). These other strategies include the fusion of infected cells with surrounding cells, the use of membrane structures that bridge the gaps between cells (Sherer and Mothes, 2008), and the exploitation of the mechanism by which macrophages recognize and engulf dying cells (Czuczman et al., 2014).
Trogocytosis is a normal process that mainly involves macrophages and other immune cells, such as monocytes. It happens more often upon infection, specifically between infected macrophages and their donor cells. This observation suggests that trogocytosis is regulated by individual cells upon infection. A remarkable feature of this process is that membrane proteins that are exchanged between cells – such as the Major Histocompatibility Complex (MHC) molecules, which help to activate immune responses – continue to work properly in their new cell. Therefore, trogocytosis may serve as a surveillance mechanism for the immune system.
The molecular mechanisms underlying trogocytosis and the associated transfer of intracellular bacteria remain to be deciphered. This task will be particularly challenging since it is not currently possible to block trogocytosis with genetic techniques or specific inhibitor drugs. Further experiments are needed to visualize the cellular structures involved in the process, and to understand how the transfer of bacteria is regulated. It will also be important to understand the impact of trogocytosis-associated transfer on other processes, notably innate immune signaling (Ablasser et al., 2013), the presentation of antigens (including the possible transfer of the MHC between cells; Campana et al., 2015), and the spread of the bacteria within the host.
References
-
Cross-dressing: an alternative mechanism for antigen presentationImmunology Letters 168:349–354.https://doi.org/10.1016/j.imlet.2015.11.002
-
Mechanisms of Francisella tularensis intracellular pathogenesisCold Spring Harbor Perspectives in Medicine 3:a010314.https://doi.org/10.1101/cshperspect.a010314
-
What is trogocytosis and what is its purpose?Nature Immunology 4:815.https://doi.org/10.1038/ni0903-815
-
Avoiding the void: cell-to-cell spread of human virusesNature Reviews Microbiology 6:815–826.https://doi.org/10.1038/nrmicro1972
-
Cytonemes and tunneling nanotubules in cell–cell communication and viral pathogenesisTrends in Cell Biology 18:414–420.https://doi.org/10.1016/j.tcb.2008.07.003
-
Arp2/3-mediated actin-based motility: a tail of pathogen abuseCell Host & Microbe 14:242–255.https://doi.org/10.1016/j.chom.2013.08.011
Article and author information
Author details
Publication history
Copyright
© 2016, Bourdonnay et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 9,626
- views
-
- 491
- downloads
-
- 10
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Intracellular Bacteria: Catch me if you can
eLife 5:e14721.
https://doi.org/10.7554/eLife.14721
Further reading
-
- Immunology and Inflammation
Adipose tissue inflammation is now considered to be a key process underlying metabolic diseases in obese individuals. However, it remains unclear how adipose inflammation is initiated and maintained or the mechanism by which inflammation develops. We found that microRNA-802 (Mir802) expression in adipose tissue is progressively increased with the development of dietary obesity in obese mice and humans. The increasing trend of Mir802 preceded the accumulation of macrophages. Adipose tissue-specific knockout of Mir802 lowered macrophage infiltration and ameliorated systemic insulin resistance. Conversely, the specific overexpression of Mir802 in adipose tissue aggravated adipose inflammation in mice fed a high-fat diet. Mechanistically, Mir802 activates noncanonical and canonical NF-κB pathways by targeting its negative regulator, TRAF3. Next, NF-κB orchestrated the expression of chemokines and SREBP1, leading to strong recruitment and M1-like polarization of macrophages. Our findings indicate that Mir802 endows adipose tissue with the ability to recruit and polarize macrophages, which underscores Mir802 as an innovative and attractive candidate for miRNA-based immune therapy for adipose inflammation.
-
- Immunology and Inflammation
Chronic antigenic stimulation can trigger the formation of interleukin 10 (IL-10)-producing T-regulatory type 1 (TR1) cells in vivo. We have recently shown that murine T-follicular helper (TFH) cells are precursors of TR1 cells and that the TFH-to-TR1 cell transdifferentiation process is characterized by the progressive loss and acquisition of opposing transcription factor gene expression programs that evolve through at least one transitional cell stage. Here, we use a broad range of bulk and single-cell transcriptional and epigenetic tools to investigate the epigenetic underpinnings of this process. At the single-cell level, the TFH-to-TR1 cell transition is accompanied by both, downregulation of TFH cell-specific gene expression due to loss of chromatin accessibility, and upregulation of TR1 cell-specific genes linked to chromatin regions that remain accessible throughout the transdifferentiation process, with minimal generation of new open chromatin regions. By interrogating the epigenetic status of accessible TR1 genes on purified TFH and conventional T-cells, we find that most of these genes, including Il10, are already poised for expression at the TFH cell stage. Whereas these genes are closed and hypermethylated in Tconv cells, they are accessible, hypomethylated, and enriched for H3K27ac-marked and hypomethylated active enhancers in TFH cells. These enhancers are enriched for binding sites for the TFH and TR1-associated transcription factors TOX-2, IRF4, and c-MAF. Together, these data suggest that the TR1 gene expression program is genetically imprinted at the TFH cell stage.
