Intracellular Bacteria: Catch me if you can
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.
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
- Version of Record published: February 26, 2016 (version 1)
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
-
- 9,417
- views
-
- 480
- downloads
-
- 9
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
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)
Further reading
-
- Chromosomes and Gene Expression
- Immunology and Inflammation
Ikaros is a transcriptional factor required for conventional T cell development, differentiation, and anergy. While the related factors Helios and Eos have defined roles in regulatory T cells (Treg), a role for Ikaros has not been established. To determine the function of Ikaros in the Treg lineage, we generated mice with Treg-specific deletion of the Ikaros gene (Ikzf1). We find that Ikaros cooperates with Foxp3 to establish a major portion of the Treg epigenome and transcriptome. Ikaros-deficient Treg exhibit Th1-like gene expression with abnormal production of IL-2, IFNg, TNFa, and factors involved in Wnt and Notch signaling. While Ikzf1-Treg-cko mice do not develop spontaneous autoimmunity, Ikaros-deficient Treg are unable to control conventional T cell-mediated immune pathology in response to TCR and inflammatory stimuli in models of IBD and organ transplantation. These studies establish Ikaros as a core factor required in Treg for tolerance and the control of inflammatory immune responses.
-
- Evolutionary Biology
- Immunology and Inflammation
CD4+ T cell activation is driven by five-module receptor complexes. The T cell receptor (TCR) is the receptor module that binds composite surfaces of peptide antigens embedded within MHCII molecules (pMHCII). It associates with three signaling modules (CD3γε, CD3δε, and CD3ζζ) to form TCR-CD3 complexes. CD4 is the coreceptor module. It reciprocally associates with TCR-CD3-pMHCII assemblies on the outside of a CD4+ T cells and with the Src kinase, LCK, on the inside. Previously, we reported that the CD4 transmembrane GGXXG and cytoplasmic juxtamembrane (C/F)CV+C motifs found in eutherian (placental mammal) CD4 have constituent residues that evolved under purifying selection (Lee et al., 2022). Expressing mutants of these motifs together in T cell hybridomas increased CD4-LCK association but reduced CD3ζ, ZAP70, and PLCγ1 phosphorylation levels, as well as IL-2 production, in response to agonist pMHCII. Because these mutants preferentially localized CD4-LCK pairs to non-raft membrane fractions, one explanation for our results was that they impaired proximal signaling by sequestering LCK away from TCR-CD3. An alternative hypothesis is that the mutations directly impacted signaling because the motifs normally play an LCK-independent role in signaling. The goal of this study was to discriminate between these possibilities. Using T cell hybridomas, our results indicate that: intracellular CD4-LCK interactions are not necessary for pMHCII-specific signal initiation; the GGXXG and (C/F)CV+C motifs are key determinants of CD4-mediated pMHCII-specific signal amplification; the GGXXG and (C/F)CV+C motifs exert their functions independently of direct CD4-LCK association. These data provide a mechanistic explanation for why residues within these motifs are under purifying selection in jawed vertebrates. The results are also important to consider for biomimetic engineering of synthetic receptors.