Cell Host & Microbe
Previews sustains Trm. Depletion of cells expressing CD11b+, a marker for macrophages, led to a reduction in CD4+ (and CD8+) Trm as did blockade of the chemokine CCL5. Moreover, Iijima and Iwaski detected CD4+ Trm that produce a low level of IFN-g ex vivo without the need for restimulation with peptide. They propose a model where Trm-derived-IFN-g induces local macrophages to produce CCL5, which in turn prevents Trm from being expulsed into the vaginal lumen (Figure 1). Thus, Trm not only instruct innate immune cells upon infection but keep instructing them in order to maintain themselves at the initial site of infection. These three recent reports (Ariotti et al., 2014; Iijima and Iwasaki, 2014; Schenkel et al., 2014a) show the potential power and precision Trm may provide to protect against specific infections. In order to translate these findings into effective vaccine strategies, we will need a more comprehensive understanding of how to maximize the number of Trm and to prolong their longevity in a specific tissue. The complexity of Trm is substantial as
CD4+ and CD8+ T cells behave differently and the maintenance of Trm is very tissue specific. For instance, it is unlikely that expulsion into the lumen is a major concern for skin Trm, whereas the large surface area of the lung may require active repression of Trm shedding into the lung airways. On that note, the longevity of Trm appears to greatly differ between tissues as skin Trm are maintained in mice for over a year (Mackay et al., 2012), whereas lung Trm may only be detectable for a few months (Wu et al., 2013). Despite these challenges, vaccine-induced Trm could be worth the effort, particularly in the case of pathogens such as HIV, where rapid induction of an antiviral state by Trm could be pivotal to prevent systemic dissemination.
Iijima, N., and Iwasaki, A. (2014). Science. Published online August 28, 2014. http://dx.doi.org/ 10.1126/science.1257530. Jiang, X., Clark, R.A., Liu, L., Wagers, A.J., Fuhlbrigge, R.C., and Kupper, T.S. (2012). Nature 483, 227–231. Mackay, L.K., Rahimpour, A., Ma, J.Z., Collins, N., Stock, A.T., Hafon, M.L., Vega-Ramos, J., Lauzurica, P., Mueller, S.N., Stefanovic, T., et al. (2013). Nat. Immunol. 14, 1294–1301. Mackay, L.K., Stock, A.T., Ma, J.Z., Jones, C.M., Kent, S.J., Mueller, S.N., Heath, W.R., Carbone, F.R., and Gebhardt, T. (2012). Proc. Natl. Acad. Sci. USA 109, 7037–7042. Schenkel, J.M., Fraser, K.A., Beura, L.K., Pauken, K.E., Vezys, V., and Masopust, D. (2014a). Science. Published online August 28, 2014. http:// dx.doi.org/10.1126/science.1254536. Schenkel, J.M., Fraser, K.A., and Masopust, D. (2014b). J. Immunol. 192, 2961–2964. Skon, C.N., Lee, J.Y., Anderson, K.G., Masopust, D., Hogquist, K.A., and Jameson, S.C. (2013). Nat. Immunol. 14, 1285–1293.
REFERENCES Ariotti, S., Hogenbirk, M.A., Dijkgraaf, F.E., Visser, L.L., Hoekstra, M.E., Song, J., Jacobs, H., Haanen, J.B., and Schumacher, T.N. (2014). Science. Published online August 28, 2014. http://dx.doi.org/10. 1126/science.1254803.
Wakim, L.M., Woodward-Davis, A., and Bevan, M.J. (2010). Proc. Natl. Acad. Sci. USA 107, 17872–17879. Wu, T., Hu, Y., Lee, Y.T., Bouchard, K.R., Benechet, A., Khanna, K., and Cauley, L.S. (2013). J. Leukoc. Biol. 95, 215–224.
Lost but Not Forgotten David Sacks1,* 1Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, MD 20892, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.chom.2014.09.017
During its developmental transformation in the mammalian host, Trypanosma cruzi discards it flagellum into the cytoplasm of the host cell. In the current issue of Cell Host & Microbe, Kurup and Tarleton (2014) exploit the antigens made available by this process to develop a more effective vaccine strategy. The Kinetoplastid protozoan parasites that include African trypanosomes, Trypanosma cruzi, and various Leishmania sp. produce a spectrum of human and veterinary diseases that continue to pose enormous public health concerns throughout tropical and subtropical regions. Importantly, there are no effective vaccines against any of these vector-borne diseases. A major impediment to vaccine development is the complexity of the antigens that these eukaryotic pathogens offer as immunologic targets and their
remarkable adaptability to immunologic pressure. Thus, the large genome sizes and proteomes possessed by these parasites may preclude responses to anything but a few immunodominant epitopes encoded by genes that are driven to display extensive allelic or somatic polymorphisms. In the current studies, Kurup and Tarleton (2014) develop a strategy to identify invariant, subdominant, and early antigens targets that can be incorporated into a live, attenuated vaccine to potentiate a protective response.
Trypanosma cruzi is the causative agent of Chagas disease, which is the most prevalent cause of infectious myocarditis in Central and South America. The basic life cycle of Trypanosma cruzi was described by Carlos Chagas over one century ago (Chagas, 1909) and is summarized in Figure 1. Metacyclic trypomastigotes are the flagellated, extracellularstage parasites that are excreted by an infected reduviid bug. The excreta can contaminate the bite wound or mucous membranes, allowing the metacyclics to
Cell Host & Microbe 16, October 8, 2014 ª2014 Elsevier Inc. 423
Cell Host & Microbe
Previews
Figure 1. Life Cycle of Trypanosoma cruzi
Trypanosoma cruzi has a biphasic life cycle in which four developmental forms, epimastigotes (A), metacyclic trypomastigotes (B), amastigotes (C), and bloodstream trypomastigotes (D), alternate between the insect vector and the mammalian host. Epimastigotes and amastigotes are the replicative stages of the insect vector and mammalian host, respectively. Metacyclic and bloodstream trypomastigotes provide the source of the discarded flagellum and flagellar rod proteins for CD8+ T cell priming and recognition during their transformation to amastigotes in the cytoplasm of the host cell. Modified from Perez et al. (2014).
gain entry into the mammalian host, where they are able to infect a wide range of nucleated cells. The trypomastigotes rapidly escape the parasitophorous vacuole and transform in the cytoplasm into the amastigote stage, an ovoid form characterized by a short flagellum that does not extend beyond the flagellar pocket. Amastigotes replicate in the cytoplasm and give rise to bloodstream trypomastigotes that escape into the blood and invade new cells in a manner similar to metacyclic invasion. Given their cytoplasmic residence and the fact that many of the parasitized cells lack MHC class II molecules, protective immunity against T. cruzi infection is believed to be primarily CD8+ T cell dependent (Padilla et al., 2009). The natural CD8+ T cell response to T. cruzi infection in both mice and humans seems to be focused on epitopes encoded by genes of the large and strain-variant trans-sialidase gene family, which would require that a massive number of target epitopes be included in an effective vaccine (Martin et al., 2006).
In their search for strain-invariant epitopes that might elicit a protective response, Kurup and Tarleton (2014) reasoned that during the transformation of trypomastigotes to amastigotes in the host cell cytoplasm, the discarded flagellum might be a source of immunogenic, class I-restricted peptides for early CD8+ T cell priming. The unique availability of catabolized flagellar proteins for class I loading had been previously suggested (Michailowsky et al., 2003). Furthermore, it was already known that immunization with proteins present in the paraflagellar rod (PFR), which is the major structural component of the T. cruzi flagellum—and indeed all life stages of Kinetoplastida with the exception of amastigotes—confers protective immunity against T. cruzi infection in mice (Miller et al., 1997). The PFR is a latticelike arrangement of protein filaments that in T. cruzi is composed of four major proteins, PAR1–PAR4. By expressing a tagged form of PAR4, Kurup and Tarleton (2014) could directly visualize the loss and degradation of the flagellum in the host cell cytoplasm. This event was preceded by an asymmetrical division of the trypomastigote into two distinct daughter cells: one, a nucleated cell with a short flagellum that fully transforms into the first generation amastigote, and the other, an anucleate cell with an intact kinetoplast and elongate flagellum that disintegrates 9–12 hr postinfection, as visualized by the appearance of minute tagged particles in the cytosol of the infected macrophages. In vivo, a PAR4-specific CD8+ T cell response could be detected in T. cruzi-infected mice, and overexpression of PAR4 in the parasite enhanced the PAR4-specific response during infection. Most importantly, mice that were infected with the PAR4-overexpressing parasites and then drug cured had stronger protection against a challenge infection compared to mice drug cured of their wild-type parasites. Kurup and Tarleton (2014) also showed that the PARA4specific CD8+ T cells recognize the cognate epitope very quickly on infected cells, within a few hours after infection of fibroblasts in vitro. By linking a transsialidase epitope (TSKb20) to PARA4, they could accelerate the TSKb20-specific response, providing further evidence that flagellar degradation during stage transformation is an exceptional source
424 Cell Host & Microbe 16, October 8, 2014 ª2014 Elsevier Inc.
of immunogenic peptides for early CD8+ T cell priming and activation. Kurup and Tarleton (2014) argue that it is the rapid kinetics of the anti-PAR4 response, along with overexpression of the target epitope, that allowed the subdominant response to mediate stronger protection as compared to the still dominant but delayed response to the trans-sialidase proteins. Overexpression of additional PFR proteins—the PFR proteome consists of at least 30 proteins (Portman et al., 2009)—might further enhance the efficacy of a live, attenuated T. cruzi vaccine. How applicable might the potentiation of early T cell responses to flagellar proteins be to vaccination against other Kinetoplastid parasites? Whereas African trypanosomes retain an exclusive extracellular lifestyle as trypomastigote forms in the blood and tissues of their mammalian hosts, Leishmania sp. undergo rapid transformation to amastigotes following uptake of the flagellated, metacyclic stage promastigotes by neutrophils and macrophages in the skin at the site of delivery by sand fly bite. The impressive length of the metacyclic flagellum may provide an especially good source of material for early priming and detection by the immune response. As Leishmania do not escape the phagosome, the antigens made available by the discarded flagellum might be more relevant to CD4+ T cell responses, though endosomal processing of Leishmania-derived antigens for class I presentation has also been described (Bertholet et al., 2006). The more critical cell biological difference maybe that whereas reinvasion of cells by T. cruzi bloodstream trypomastigotes will probably provide a continuous source of flagellar proteins for boosting and for presentation by infected cells, the presentation of Leishmania flagellar proteins will be confined to only the earliest stage of infection by metacyclic promastigotes. Nonetheless, immunization with PFR-2 as a protein- and/or DNA-based vaccine succeeded in producing smaller lesions in hamsters challenged with L. panamensis or L. mexicana, suggesting that early T responses to even the most fleeting of antigens can be protective (Saravia et al., 2005). It is not clear that the approach so carefully developed in this report will ever achieve the sterilizing immunity that may be required of a prophylactic vaccine
Cell Host & Microbe
Previews for human Chagas disease, in which the myocarditis is associated with persistent infection. Nonetheless, the studies validate the selection of target antigens that are invariant, subdominant, and exposed early in the infectious cycle, as a general strategy to undermine the immune evasive capacity of vector borne parasites. REFERENCES Bertholet, S., Goldszmid, R., Morrot, A., Debrabant, A., Afrin, F., Collazo-Custodio, C., Houde,
M., Desjardins, M., Sher, A., and Sacks, D. (2006). J. Immunol. 177, 3525–3533.
Miller, M.J., Wrightsman, R.A., Stryker, G.A., and Manning, J.E. (1997). J. Immunol. 158, 5330–5337.
Chagas, C. (1909). Mem. Inst. Oswaldo Cruz 1, 159–218.
Padilla, A.M., Bustamante, J.M., and Tarleton, R.L. (2009). Curr. Opin. Immunol. 21, 385–390.
Kurup, S.P., and Tarleton, R.L. (2014). Cell Host Microbe 16, this issue, 439–449.
Perez, C.J., Lymbery, A.J., and Thompson, R.C.A. (2014). Trends Parasitol. 30, 176–182.
Martin, D.L., Weatherly, D.B., Laucella, S.A., Cabinian, M.A., Crim, M.T., Sullivan, S., Heiges, M., Craven, S.H., Rosenberg, C.S., Collins, M.H., et al. (2006). PLoS Pathog. 2, e77.
Portman, N., Lacomble, S., Thomas, B., McKean, P.G., and Gull, K. (2009). J. Biol. Chem. 284, 5610–5619.
Michailowsky, V., Luhrs, K., Rocha, M.O.C., Fouts, D., Gazzinelli, R.T., and Manning, J.E. (2003). Infect. Immun. 71, 3165–3171.
Saravia, N.G., Hazbo´n, M.H., Osorio, Y., Valderrama, L., Walker, J., Santrich, C., Corta´zar, T., Lebowitz, J.H., and Travi, B.L. (2005). Vaccine 23, 984–995.
A Delicate Balance: Maintaining Mutualism to Prevent Disease Daria Van Tyne1,2 and Michael S. Gilmore1,2,* 1Department
of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.chom.2014.09.019 2Department
The intestinal microbial ecosystem is complex, and few of the principles that contribute to homeostasis in health are well understood. Pham et al. (2014) show that a network including the epithelial interleukin-22 receptor protects against infection with the opportunistic pathogen Enterococcus faecalis through promotion of host-microbiota mutualism. The human gastrointestinal (GI) tract is a rich and highly complex ecosystem, where a wide variety of bacterial, fungal, and viral inhabitants coexist with one other and in symbiosis with their host. This diverse microbial community aids digestion, synthesizes vitamins, and protects the host against infection. But the microbiota exists in a delicate balance that is periodically disrupted, resulting in a state of microbial dysbiosis. The factors that precipitate microbial dysbiosis, and how to prevent or reverse it, are not well understood. Recent studies point to the complex interplay between diet, community complexity, and host immunity in maintaining GI tract microbial homeostasis (Turnbaugh et al., 2009; Jernberg et al., 2007; Deatherage Kaiser et al., 2013). Not surprisingly, diet is an important factor in determining GI community composition. When host diet shifts, the composition
of the GI microbial ecosystem also shifts (Turnbaugh et al., 2009). Over the past 50 years, antibiotic treatment has emerged as an important cause of microbial dysbiosis; broad-spectrum antimicrobials fundamentally change the composition of GI tract flora, and the effects can persist for years (Jernberg et al., 2007). Infection with a virulent pathogen such as Salmonella can also alter community structure and result in dysbiosis (Deatherage Kaiser et al., 2013). Finally, the host immune system plays a key role in maintaining a microbial homeostasis compatible with health. The immune system is ‘‘trained’’ as healthy flora are established during development and becomes capable of distinguishing between beneficial and harmful GI tract microbes. When working properly, the immune system is able to promote the occurrence of the former and suppress the latter. But when this training goes
awry, or when host immunity is disrupted, the GI tract ecosystem can tilt toward dysbiosis and disease (Figure 1). What are the key interactions between the host immune system and the GI tract microbial community that contribute to or prevent dysbiosis? In this issue, Pham and colleagues explore the role of the interleukin-22 receptor IL-22RA1 in maintaining microbial homeostasis in the mouse GI tract (Pham et al., 2014). Because intestinal inflammation can cause dysbiosis, the authors hypothesized that IL-22RA1 contributes to maintaining microbial homeostasis by restricting the overgrowth of opportunistic pathogens. In a series of experiments in mice lacking IL-22RA1, the authors demonstrate that during microbial dysbiosis, the opportunistic pathogen Enterococcus faecalis is able to expand in relative abundance in the intestinal tract and then translocate to the bloodstream
Cell Host & Microbe 16, October 8, 2014 ª2014 Elsevier Inc. 425
Previews sustains Trm. Depletion of cells expressing CD11b+, a marker for macrophages, led to a reduction in CD4+ (and CD8+) Trm as did blockade of the chemokine CCL5. Moreover, Iijima and Iwaski detected CD4+ Trm that produce a low level of IFN-g ex vivo without the need for restimulation with peptide. They propose a model where Trm-derived-IFN-g induces local macrophages to produce CCL5, which in turn prevents Trm from being expulsed into the vaginal lumen (Figure 1). Thus, Trm not only instruct innate immune cells upon infection but keep instructing them in order to maintain themselves at the initial site of infection. These three recent reports (Ariotti et al., 2014; Iijima and Iwasaki, 2014; Schenkel et al., 2014a) show the potential power and precision Trm may provide to protect against specific infections. In order to translate these findings into effective vaccine strategies, we will need a more comprehensive understanding of how to maximize the number of Trm and to prolong their longevity in a specific tissue. The complexity of Trm is substantial as
CD4+ and CD8+ T cells behave differently and the maintenance of Trm is very tissue specific. For instance, it is unlikely that expulsion into the lumen is a major concern for skin Trm, whereas the large surface area of the lung may require active repression of Trm shedding into the lung airways. On that note, the longevity of Trm appears to greatly differ between tissues as skin Trm are maintained in mice for over a year (Mackay et al., 2012), whereas lung Trm may only be detectable for a few months (Wu et al., 2013). Despite these challenges, vaccine-induced Trm could be worth the effort, particularly in the case of pathogens such as HIV, where rapid induction of an antiviral state by Trm could be pivotal to prevent systemic dissemination.
Iijima, N., and Iwasaki, A. (2014). Science. Published online August 28, 2014. http://dx.doi.org/ 10.1126/science.1257530. Jiang, X., Clark, R.A., Liu, L., Wagers, A.J., Fuhlbrigge, R.C., and Kupper, T.S. (2012). Nature 483, 227–231. Mackay, L.K., Rahimpour, A., Ma, J.Z., Collins, N., Stock, A.T., Hafon, M.L., Vega-Ramos, J., Lauzurica, P., Mueller, S.N., Stefanovic, T., et al. (2013). Nat. Immunol. 14, 1294–1301. Mackay, L.K., Stock, A.T., Ma, J.Z., Jones, C.M., Kent, S.J., Mueller, S.N., Heath, W.R., Carbone, F.R., and Gebhardt, T. (2012). Proc. Natl. Acad. Sci. USA 109, 7037–7042. Schenkel, J.M., Fraser, K.A., Beura, L.K., Pauken, K.E., Vezys, V., and Masopust, D. (2014a). Science. Published online August 28, 2014. http:// dx.doi.org/10.1126/science.1254536. Schenkel, J.M., Fraser, K.A., and Masopust, D. (2014b). J. Immunol. 192, 2961–2964. Skon, C.N., Lee, J.Y., Anderson, K.G., Masopust, D., Hogquist, K.A., and Jameson, S.C. (2013). Nat. Immunol. 14, 1285–1293.
REFERENCES Ariotti, S., Hogenbirk, M.A., Dijkgraaf, F.E., Visser, L.L., Hoekstra, M.E., Song, J., Jacobs, H., Haanen, J.B., and Schumacher, T.N. (2014). Science. Published online August 28, 2014. http://dx.doi.org/10. 1126/science.1254803.
Wakim, L.M., Woodward-Davis, A., and Bevan, M.J. (2010). Proc. Natl. Acad. Sci. USA 107, 17872–17879. Wu, T., Hu, Y., Lee, Y.T., Bouchard, K.R., Benechet, A., Khanna, K., and Cauley, L.S. (2013). J. Leukoc. Biol. 95, 215–224.
Lost but Not Forgotten David Sacks1,* 1Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, MD 20892, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.chom.2014.09.017
During its developmental transformation in the mammalian host, Trypanosma cruzi discards it flagellum into the cytoplasm of the host cell. In the current issue of Cell Host & Microbe, Kurup and Tarleton (2014) exploit the antigens made available by this process to develop a more effective vaccine strategy. The Kinetoplastid protozoan parasites that include African trypanosomes, Trypanosma cruzi, and various Leishmania sp. produce a spectrum of human and veterinary diseases that continue to pose enormous public health concerns throughout tropical and subtropical regions. Importantly, there are no effective vaccines against any of these vector-borne diseases. A major impediment to vaccine development is the complexity of the antigens that these eukaryotic pathogens offer as immunologic targets and their
remarkable adaptability to immunologic pressure. Thus, the large genome sizes and proteomes possessed by these parasites may preclude responses to anything but a few immunodominant epitopes encoded by genes that are driven to display extensive allelic or somatic polymorphisms. In the current studies, Kurup and Tarleton (2014) develop a strategy to identify invariant, subdominant, and early antigens targets that can be incorporated into a live, attenuated vaccine to potentiate a protective response.
Trypanosma cruzi is the causative agent of Chagas disease, which is the most prevalent cause of infectious myocarditis in Central and South America. The basic life cycle of Trypanosma cruzi was described by Carlos Chagas over one century ago (Chagas, 1909) and is summarized in Figure 1. Metacyclic trypomastigotes are the flagellated, extracellularstage parasites that are excreted by an infected reduviid bug. The excreta can contaminate the bite wound or mucous membranes, allowing the metacyclics to
Cell Host & Microbe 16, October 8, 2014 ª2014 Elsevier Inc. 423
Cell Host & Microbe
Previews
Figure 1. Life Cycle of Trypanosoma cruzi
Trypanosoma cruzi has a biphasic life cycle in which four developmental forms, epimastigotes (A), metacyclic trypomastigotes (B), amastigotes (C), and bloodstream trypomastigotes (D), alternate between the insect vector and the mammalian host. Epimastigotes and amastigotes are the replicative stages of the insect vector and mammalian host, respectively. Metacyclic and bloodstream trypomastigotes provide the source of the discarded flagellum and flagellar rod proteins for CD8+ T cell priming and recognition during their transformation to amastigotes in the cytoplasm of the host cell. Modified from Perez et al. (2014).
gain entry into the mammalian host, where they are able to infect a wide range of nucleated cells. The trypomastigotes rapidly escape the parasitophorous vacuole and transform in the cytoplasm into the amastigote stage, an ovoid form characterized by a short flagellum that does not extend beyond the flagellar pocket. Amastigotes replicate in the cytoplasm and give rise to bloodstream trypomastigotes that escape into the blood and invade new cells in a manner similar to metacyclic invasion. Given their cytoplasmic residence and the fact that many of the parasitized cells lack MHC class II molecules, protective immunity against T. cruzi infection is believed to be primarily CD8+ T cell dependent (Padilla et al., 2009). The natural CD8+ T cell response to T. cruzi infection in both mice and humans seems to be focused on epitopes encoded by genes of the large and strain-variant trans-sialidase gene family, which would require that a massive number of target epitopes be included in an effective vaccine (Martin et al., 2006).
In their search for strain-invariant epitopes that might elicit a protective response, Kurup and Tarleton (2014) reasoned that during the transformation of trypomastigotes to amastigotes in the host cell cytoplasm, the discarded flagellum might be a source of immunogenic, class I-restricted peptides for early CD8+ T cell priming. The unique availability of catabolized flagellar proteins for class I loading had been previously suggested (Michailowsky et al., 2003). Furthermore, it was already known that immunization with proteins present in the paraflagellar rod (PFR), which is the major structural component of the T. cruzi flagellum—and indeed all life stages of Kinetoplastida with the exception of amastigotes—confers protective immunity against T. cruzi infection in mice (Miller et al., 1997). The PFR is a latticelike arrangement of protein filaments that in T. cruzi is composed of four major proteins, PAR1–PAR4. By expressing a tagged form of PAR4, Kurup and Tarleton (2014) could directly visualize the loss and degradation of the flagellum in the host cell cytoplasm. This event was preceded by an asymmetrical division of the trypomastigote into two distinct daughter cells: one, a nucleated cell with a short flagellum that fully transforms into the first generation amastigote, and the other, an anucleate cell with an intact kinetoplast and elongate flagellum that disintegrates 9–12 hr postinfection, as visualized by the appearance of minute tagged particles in the cytosol of the infected macrophages. In vivo, a PAR4-specific CD8+ T cell response could be detected in T. cruzi-infected mice, and overexpression of PAR4 in the parasite enhanced the PAR4-specific response during infection. Most importantly, mice that were infected with the PAR4-overexpressing parasites and then drug cured had stronger protection against a challenge infection compared to mice drug cured of their wild-type parasites. Kurup and Tarleton (2014) also showed that the PARA4specific CD8+ T cells recognize the cognate epitope very quickly on infected cells, within a few hours after infection of fibroblasts in vitro. By linking a transsialidase epitope (TSKb20) to PARA4, they could accelerate the TSKb20-specific response, providing further evidence that flagellar degradation during stage transformation is an exceptional source
424 Cell Host & Microbe 16, October 8, 2014 ª2014 Elsevier Inc.
of immunogenic peptides for early CD8+ T cell priming and activation. Kurup and Tarleton (2014) argue that it is the rapid kinetics of the anti-PAR4 response, along with overexpression of the target epitope, that allowed the subdominant response to mediate stronger protection as compared to the still dominant but delayed response to the trans-sialidase proteins. Overexpression of additional PFR proteins—the PFR proteome consists of at least 30 proteins (Portman et al., 2009)—might further enhance the efficacy of a live, attenuated T. cruzi vaccine. How applicable might the potentiation of early T cell responses to flagellar proteins be to vaccination against other Kinetoplastid parasites? Whereas African trypanosomes retain an exclusive extracellular lifestyle as trypomastigote forms in the blood and tissues of their mammalian hosts, Leishmania sp. undergo rapid transformation to amastigotes following uptake of the flagellated, metacyclic stage promastigotes by neutrophils and macrophages in the skin at the site of delivery by sand fly bite. The impressive length of the metacyclic flagellum may provide an especially good source of material for early priming and detection by the immune response. As Leishmania do not escape the phagosome, the antigens made available by the discarded flagellum might be more relevant to CD4+ T cell responses, though endosomal processing of Leishmania-derived antigens for class I presentation has also been described (Bertholet et al., 2006). The more critical cell biological difference maybe that whereas reinvasion of cells by T. cruzi bloodstream trypomastigotes will probably provide a continuous source of flagellar proteins for boosting and for presentation by infected cells, the presentation of Leishmania flagellar proteins will be confined to only the earliest stage of infection by metacyclic promastigotes. Nonetheless, immunization with PFR-2 as a protein- and/or DNA-based vaccine succeeded in producing smaller lesions in hamsters challenged with L. panamensis or L. mexicana, suggesting that early T responses to even the most fleeting of antigens can be protective (Saravia et al., 2005). It is not clear that the approach so carefully developed in this report will ever achieve the sterilizing immunity that may be required of a prophylactic vaccine
Cell Host & Microbe
Previews for human Chagas disease, in which the myocarditis is associated with persistent infection. Nonetheless, the studies validate the selection of target antigens that are invariant, subdominant, and exposed early in the infectious cycle, as a general strategy to undermine the immune evasive capacity of vector borne parasites. REFERENCES Bertholet, S., Goldszmid, R., Morrot, A., Debrabant, A., Afrin, F., Collazo-Custodio, C., Houde,
M., Desjardins, M., Sher, A., and Sacks, D. (2006). J. Immunol. 177, 3525–3533.
Miller, M.J., Wrightsman, R.A., Stryker, G.A., and Manning, J.E. (1997). J. Immunol. 158, 5330–5337.
Chagas, C. (1909). Mem. Inst. Oswaldo Cruz 1, 159–218.
Padilla, A.M., Bustamante, J.M., and Tarleton, R.L. (2009). Curr. Opin. Immunol. 21, 385–390.
Kurup, S.P., and Tarleton, R.L. (2014). Cell Host Microbe 16, this issue, 439–449.
Perez, C.J., Lymbery, A.J., and Thompson, R.C.A. (2014). Trends Parasitol. 30, 176–182.
Martin, D.L., Weatherly, D.B., Laucella, S.A., Cabinian, M.A., Crim, M.T., Sullivan, S., Heiges, M., Craven, S.H., Rosenberg, C.S., Collins, M.H., et al. (2006). PLoS Pathog. 2, e77.
Portman, N., Lacomble, S., Thomas, B., McKean, P.G., and Gull, K. (2009). J. Biol. Chem. 284, 5610–5619.
Michailowsky, V., Luhrs, K., Rocha, M.O.C., Fouts, D., Gazzinelli, R.T., and Manning, J.E. (2003). Infect. Immun. 71, 3165–3171.
Saravia, N.G., Hazbo´n, M.H., Osorio, Y., Valderrama, L., Walker, J., Santrich, C., Corta´zar, T., Lebowitz, J.H., and Travi, B.L. (2005). Vaccine 23, 984–995.
A Delicate Balance: Maintaining Mutualism to Prevent Disease Daria Van Tyne1,2 and Michael S. Gilmore1,2,* 1Department
of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.chom.2014.09.019 2Department
The intestinal microbial ecosystem is complex, and few of the principles that contribute to homeostasis in health are well understood. Pham et al. (2014) show that a network including the epithelial interleukin-22 receptor protects against infection with the opportunistic pathogen Enterococcus faecalis through promotion of host-microbiota mutualism. The human gastrointestinal (GI) tract is a rich and highly complex ecosystem, where a wide variety of bacterial, fungal, and viral inhabitants coexist with one other and in symbiosis with their host. This diverse microbial community aids digestion, synthesizes vitamins, and protects the host against infection. But the microbiota exists in a delicate balance that is periodically disrupted, resulting in a state of microbial dysbiosis. The factors that precipitate microbial dysbiosis, and how to prevent or reverse it, are not well understood. Recent studies point to the complex interplay between diet, community complexity, and host immunity in maintaining GI tract microbial homeostasis (Turnbaugh et al., 2009; Jernberg et al., 2007; Deatherage Kaiser et al., 2013). Not surprisingly, diet is an important factor in determining GI community composition. When host diet shifts, the composition
of the GI microbial ecosystem also shifts (Turnbaugh et al., 2009). Over the past 50 years, antibiotic treatment has emerged as an important cause of microbial dysbiosis; broad-spectrum antimicrobials fundamentally change the composition of GI tract flora, and the effects can persist for years (Jernberg et al., 2007). Infection with a virulent pathogen such as Salmonella can also alter community structure and result in dysbiosis (Deatherage Kaiser et al., 2013). Finally, the host immune system plays a key role in maintaining a microbial homeostasis compatible with health. The immune system is ‘‘trained’’ as healthy flora are established during development and becomes capable of distinguishing between beneficial and harmful GI tract microbes. When working properly, the immune system is able to promote the occurrence of the former and suppress the latter. But when this training goes
awry, or when host immunity is disrupted, the GI tract ecosystem can tilt toward dysbiosis and disease (Figure 1). What are the key interactions between the host immune system and the GI tract microbial community that contribute to or prevent dysbiosis? In this issue, Pham and colleagues explore the role of the interleukin-22 receptor IL-22RA1 in maintaining microbial homeostasis in the mouse GI tract (Pham et al., 2014). Because intestinal inflammation can cause dysbiosis, the authors hypothesized that IL-22RA1 contributes to maintaining microbial homeostasis by restricting the overgrowth of opportunistic pathogens. In a series of experiments in mice lacking IL-22RA1, the authors demonstrate that during microbial dysbiosis, the opportunistic pathogen Enterococcus faecalis is able to expand in relative abundance in the intestinal tract and then translocate to the bloodstream
Cell Host & Microbe 16, October 8, 2014 ª2014 Elsevier Inc. 425
