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Host–pathogen interactions
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Host–pathogen interactions Editorial overview Adolfo Garcı´a-Sastre and Philippe J Sansonetti Current Opinion in Immunology 2010, 22:425–427 This review comes from a themed issue on Host pathogen
0952-7915/$ – see front matter # 2010 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2010.06.005
Adolfo Garcı´a-Sastre Department of Microbiology, Department of Medicine and Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, NY 10029, USA e-mail: [email protected]
Adolfo Garcı´a-Sastre is a professor of microbiology, Fischberg professor of medicine, and director of the Global Health and Emerging Pathogens Institute at the Mount Sinai School of Medicine in New York. His work focuses on the molecular biology and pathogenesis of influenza viruses, viral vaccines and interactions of RNA viruses with the host innate response.
Philippe J Sansonetti Unite´ de Pathoge´nie Microbienne Mole´culaire et Unite´ INSERM 786, Institut Pasteur, 28 Rue du Docteur Roux, 75724 Paris Cedex 15, France
Philippe Sansonetti is a professor at the Colle`ge de France, Chair of Microbiology and Infectious Diseases, and Professor at Institut Pasteur where his research team works on the molecular and cellular pathogenesis of invasive bacterial pathogens, including how these microorganisms manipulate the host immune response.
The interactions of microbes with host immunity profoundly shape the outcome of infectious diseases. These interactions are not always detrimental, but can be beneficial through the stimulation of protective immune responses. On the other hand, alterations of normal host processes by pathogens, specific host genetic defects, and the subversion of innate and adaptive immune responses by pathogens can lead to severe chronic and acute diseases triggered by specific microbes. In this issue, we have reviewed recent developments in the area of host–pathogen interactions that impact the outcome of infection, and that may contribute to new means to develop novel therapies and vaccines not only against infectious disease agents, but also against other inflammatory and autoimmune diseases. The first step towards the induction of antimicrobial immune responses is the recognition of an invading pathogen. This is achieved by several families of pattern recognition molecules. A major issue here is discrimination between harmful commensal bacteria and aggressive pathogens, considering that they share similar PAMPs. How is danger actually sensed? In this context, Philpott and Girardin summarize novel concepts on recognition of cytosolic microbial threats in the vicinity of host membranes by the NLR family of pattern recognition receptors, which can lead to antimicrobial responses after interaction of bacteria with cell membranes leading to membrane damage or after internalization of bacteria and bacterial products in endosomes and phagolysosomes. The localization of NLRs in association with host membranes facilitates a rapid perception of danger and response to danger. Autophagy has emerged as one of the critical antimicrobial responses induced by NLRs, leading to bacterial destruction. While much is known about the adaptive immune system, only recently the complexity and sophistication of the innate immune system has been recognized. Di Santo et al. review the functions of newly identified innate lymphoid cells in the gut, which contribute to immune defense at the mucosal surface. Specifically, the recently described mucosal gut-associated NCR22 cells express the NK receptor NKp46, but lacks other NK markers. These NK-like cells of the gut produce high levels of IL-22 and contribute to immune defense against specific intestinal pathogens. Further investigations focusing in these and other novel innate immune cell players in the intestinal mucosa will contribute to expand our understanding of gut mucosal immunity and how innate responses contribute to protection against microbes that invade the gut. Chronic stimulation of host responses by pathogens can result in unexpected disease processes. Marusawa and Chiba discuss how Helicobacter
www.sciencedirect.com
Current Opinion in Immunology 2010, 22:425–427
426 Host pathogen
pylori-mediated chronic stimulation of the activationinduced cytidine deaminase (AID), which is involved in antibody diversity by inducing somatic hypermutations and class-switch, can lead to gastric cancer by promoting mutations in tumor-associated genes. On one hand, virulence genes encoded by the cag pathogenicity island found in H. pylori strains associated with cancer directly activate aberrant expression of AID in gastric epithelial cells through the NF-kB pathway. In addition, the chronic pro-inflammatory environment in H. pylori colonized stomachs also induces NF-kB activation and AID expression in the epithelial cells. AID mutagenic activity in gastric epithelial cells leads to the accumulation of genetic changes in these cells, contributing to the development of stomach cancer. Similar processes may also contribute to gastric lymphomas originated from mucosal-associated lymphoid tissue under H. pylori chronic stimulation. Moreover, the proposed model of cancer induction may apply to other infectious disease-triggered cancer processes. This is then an example of how chronic and aberrant stimulation of an enzyme that participates in host defense can lead to tumorogenesis and disease. But not all the bacteria–gut interactions are detrimental for the host. Two of the articles in this issue discuss recent insights on how gut commensal bacteria develop a symbiotic relationship with the host that shapes host immunity. For instance, Eberl and Bonecca discuss the beneficial effects of non-pathogenic H. pylori colonization of the stomach. H. pylori in the stomach enhances host innate and adaptive immune responses by stimulating chemokine and antimicrobial peptide secretion by gastric epithelial cells. H. pylori also stimulate Treg cells which may act not only locally but also systemically to prevent against asthma and allergies. Other bacterial symbionts on the gut contribute to activation and maturation of B and T cells and to the morphogenesis of gut-associated lymphoid tissues. This immune stimulation is triggered at least in part through the recognition by host receptors, such as the NLR receptors, of microbe-associated molecular patterns. In addition, Kasper summarizes how the analysis of the human gut microbiome has given insights on the symbiotic relationship between the gut microbiome and the host on modulation of immunity. Commensal bacteria induce steady state levels of expression of antimicrobial peptides by Paneth cells in the gut, which provide a layer of defense against bacterial penetration. In addition, the microbiota induces increased intestinal epithelial cell proliferation upon intestinal injury, contributing to maintenance of the epithelial barrier and to protection against gut injury. Fecal flora also contributes to the development of IgA production, Th17 and Treg cell responses, which on one hand contribute to potent antimicrobial responses and on the other hand protect the host from overreactions Current Opinion in Immunology 2010, 22:425–427
associated with immune disorders. Many genetically associated inflammatory disorders of the gut are associated with a disruption in the symbiotic relationship between the gut microbiota and the host. Continuing within the theme of mucosal immunity in the intestine against microbial pathogens, Dunay and Sibley describe recent advances on understanding the role of inflammatory monocytes in the control of infection by the protozoan parasite Toxoplasma gondii. These monocytes exit the bone marrow in response to circulating MCP-1 produced in response to inflammation, and home to the intestinal mucosa, where, among other immune mediators, they produce NO, which blocks intracellular replication of T. gondii. In addition, IFNg-mediated upregulation of immunity related GTPases interfere with the survival mechanism of this parasite within vacuoles, leading to its destruction. While inflammatory monocytes recruited to the lamina propria are critical for the control of T. gondii, an exacerbated neutrophil infiltration is associated with enhanced disease. Genetic defects in the host leading to increased pathologies caused by infectious agents have often given important clues on the immune responses required for protection against different pathogens. Puel et al. describe how mutations associated with chronic mucocutaneous candidiasis disrupt the immune system resulting in disease susceptibility. Deficiencies in STAT3 and in CARD9 lead to an impairment in Th17 development and to increased susceptibility to this disease caused by the yeast Candida albicans. Deficiencies in AIRE also result in enhanced disease susceptibility, in this case because of the development of neutralizing antibodies against IL-17 and IL-22, underscoring the role of these cytokines in preventing chronic mucocutaneous candidiasis. The host immune response against invading pathogens needs to be robust enough to eliminate the pathogen, but not too strong in order to prevent immunopathology. Influenza virus infections exemplify the problems associated with the regulation of this delicate balance. Peiris et al. summarize the similarities and differences between different strains of influenza viruses with different degrees of virulence, such as the highly pathogenic 1918 and H5N1 strains, and the new H1N1 pandemic influenza viruses, and how studies conducted with these viruses have contributed to a better understanding of immune-protective and immune-pathological factors that might be harnessed in antiviral therapies. Our understanding on the role of both viral factors and host factors in protecting against or in exacerbating disease caused by influenza viruses is also discussed. Subversion of host immune responses by pathogens has emerged as a major area of research that offers new www.sciencedirect.com
Editorial overview Garcı´a-Sastre and Sansonetti 427
insights on host immunity and on mechanisms of pathogenesis. Large DNA viruses, poxviruses and herpesviruses, encode a plethora of immune-regulators that are required for their survival and for disease induction. Specially interesting are their regulators of chemokinesignaling activity. Lira and Alcamı´ summarize the latest advances in the knowledge of modulation of immune responses and disease by virus-encoded chemokine receptors, chemokine ligands and chemokine-binding proteins. The authors also discuss the recently discovered chemokine-binding proteins found in ticks. These modulators of chemokine activity might be exploited for therapeutic purposes. All infectious disease agents induce a wide spectrum of disease severity in the host. Understanding how specific patients are able to better fight disease than others might
www.sciencedirect.com
give us the required clues to combat diseases for which there is no cure available. In this respect, Chakrabarti and Simon have summarized recent concepts concerning how innate and adaptive immune responses may contribute to control HIV in long-term non-progressors. Rare individuals who spontaneously control HIV replication appear to do it by a combination of different factors related with the rapid induction of highly active cellular immune responses. These include the interferon-mediated induction of HIV-restriction factors, such as tetherin, TRIM5a and APOBEC3, and the development of high-avidity T cells, which control HIV replication and confer long-term immune memory. In addition, specific MHC class I alleles have been associated with a better protection against AIDS development. These recent studies might help in the development of novel therapeutic and prophylaxis treatments against HIV.
Current Opinion in Immunology 2010, 22:425–427
Host–pathogen interactions Editorial overview Adolfo Garcı´a-Sastre and Philippe J Sansonetti Current Opinion in Immunology 2010, 22:425–427 This review comes from a themed issue on Host pathogen
0952-7915/$ – see front matter # 2010 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2010.06.005
Adolfo Garcı´a-Sastre Department of Microbiology, Department of Medicine and Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, NY 10029, USA e-mail: [email protected]
Adolfo Garcı´a-Sastre is a professor of microbiology, Fischberg professor of medicine, and director of the Global Health and Emerging Pathogens Institute at the Mount Sinai School of Medicine in New York. His work focuses on the molecular biology and pathogenesis of influenza viruses, viral vaccines and interactions of RNA viruses with the host innate response.
Philippe J Sansonetti Unite´ de Pathoge´nie Microbienne Mole´culaire et Unite´ INSERM 786, Institut Pasteur, 28 Rue du Docteur Roux, 75724 Paris Cedex 15, France
Philippe Sansonetti is a professor at the Colle`ge de France, Chair of Microbiology and Infectious Diseases, and Professor at Institut Pasteur where his research team works on the molecular and cellular pathogenesis of invasive bacterial pathogens, including how these microorganisms manipulate the host immune response.
The interactions of microbes with host immunity profoundly shape the outcome of infectious diseases. These interactions are not always detrimental, but can be beneficial through the stimulation of protective immune responses. On the other hand, alterations of normal host processes by pathogens, specific host genetic defects, and the subversion of innate and adaptive immune responses by pathogens can lead to severe chronic and acute diseases triggered by specific microbes. In this issue, we have reviewed recent developments in the area of host–pathogen interactions that impact the outcome of infection, and that may contribute to new means to develop novel therapies and vaccines not only against infectious disease agents, but also against other inflammatory and autoimmune diseases. The first step towards the induction of antimicrobial immune responses is the recognition of an invading pathogen. This is achieved by several families of pattern recognition molecules. A major issue here is discrimination between harmful commensal bacteria and aggressive pathogens, considering that they share similar PAMPs. How is danger actually sensed? In this context, Philpott and Girardin summarize novel concepts on recognition of cytosolic microbial threats in the vicinity of host membranes by the NLR family of pattern recognition receptors, which can lead to antimicrobial responses after interaction of bacteria with cell membranes leading to membrane damage or after internalization of bacteria and bacterial products in endosomes and phagolysosomes. The localization of NLRs in association with host membranes facilitates a rapid perception of danger and response to danger. Autophagy has emerged as one of the critical antimicrobial responses induced by NLRs, leading to bacterial destruction. While much is known about the adaptive immune system, only recently the complexity and sophistication of the innate immune system has been recognized. Di Santo et al. review the functions of newly identified innate lymphoid cells in the gut, which contribute to immune defense at the mucosal surface. Specifically, the recently described mucosal gut-associated NCR22 cells express the NK receptor NKp46, but lacks other NK markers. These NK-like cells of the gut produce high levels of IL-22 and contribute to immune defense against specific intestinal pathogens. Further investigations focusing in these and other novel innate immune cell players in the intestinal mucosa will contribute to expand our understanding of gut mucosal immunity and how innate responses contribute to protection against microbes that invade the gut. Chronic stimulation of host responses by pathogens can result in unexpected disease processes. Marusawa and Chiba discuss how Helicobacter
www.sciencedirect.com
Current Opinion in Immunology 2010, 22:425–427
426 Host pathogen
pylori-mediated chronic stimulation of the activationinduced cytidine deaminase (AID), which is involved in antibody diversity by inducing somatic hypermutations and class-switch, can lead to gastric cancer by promoting mutations in tumor-associated genes. On one hand, virulence genes encoded by the cag pathogenicity island found in H. pylori strains associated with cancer directly activate aberrant expression of AID in gastric epithelial cells through the NF-kB pathway. In addition, the chronic pro-inflammatory environment in H. pylori colonized stomachs also induces NF-kB activation and AID expression in the epithelial cells. AID mutagenic activity in gastric epithelial cells leads to the accumulation of genetic changes in these cells, contributing to the development of stomach cancer. Similar processes may also contribute to gastric lymphomas originated from mucosal-associated lymphoid tissue under H. pylori chronic stimulation. Moreover, the proposed model of cancer induction may apply to other infectious disease-triggered cancer processes. This is then an example of how chronic and aberrant stimulation of an enzyme that participates in host defense can lead to tumorogenesis and disease. But not all the bacteria–gut interactions are detrimental for the host. Two of the articles in this issue discuss recent insights on how gut commensal bacteria develop a symbiotic relationship with the host that shapes host immunity. For instance, Eberl and Bonecca discuss the beneficial effects of non-pathogenic H. pylori colonization of the stomach. H. pylori in the stomach enhances host innate and adaptive immune responses by stimulating chemokine and antimicrobial peptide secretion by gastric epithelial cells. H. pylori also stimulate Treg cells which may act not only locally but also systemically to prevent against asthma and allergies. Other bacterial symbionts on the gut contribute to activation and maturation of B and T cells and to the morphogenesis of gut-associated lymphoid tissues. This immune stimulation is triggered at least in part through the recognition by host receptors, such as the NLR receptors, of microbe-associated molecular patterns. In addition, Kasper summarizes how the analysis of the human gut microbiome has given insights on the symbiotic relationship between the gut microbiome and the host on modulation of immunity. Commensal bacteria induce steady state levels of expression of antimicrobial peptides by Paneth cells in the gut, which provide a layer of defense against bacterial penetration. In addition, the microbiota induces increased intestinal epithelial cell proliferation upon intestinal injury, contributing to maintenance of the epithelial barrier and to protection against gut injury. Fecal flora also contributes to the development of IgA production, Th17 and Treg cell responses, which on one hand contribute to potent antimicrobial responses and on the other hand protect the host from overreactions Current Opinion in Immunology 2010, 22:425–427
associated with immune disorders. Many genetically associated inflammatory disorders of the gut are associated with a disruption in the symbiotic relationship between the gut microbiota and the host. Continuing within the theme of mucosal immunity in the intestine against microbial pathogens, Dunay and Sibley describe recent advances on understanding the role of inflammatory monocytes in the control of infection by the protozoan parasite Toxoplasma gondii. These monocytes exit the bone marrow in response to circulating MCP-1 produced in response to inflammation, and home to the intestinal mucosa, where, among other immune mediators, they produce NO, which blocks intracellular replication of T. gondii. In addition, IFNg-mediated upregulation of immunity related GTPases interfere with the survival mechanism of this parasite within vacuoles, leading to its destruction. While inflammatory monocytes recruited to the lamina propria are critical for the control of T. gondii, an exacerbated neutrophil infiltration is associated with enhanced disease. Genetic defects in the host leading to increased pathologies caused by infectious agents have often given important clues on the immune responses required for protection against different pathogens. Puel et al. describe how mutations associated with chronic mucocutaneous candidiasis disrupt the immune system resulting in disease susceptibility. Deficiencies in STAT3 and in CARD9 lead to an impairment in Th17 development and to increased susceptibility to this disease caused by the yeast Candida albicans. Deficiencies in AIRE also result in enhanced disease susceptibility, in this case because of the development of neutralizing antibodies against IL-17 and IL-22, underscoring the role of these cytokines in preventing chronic mucocutaneous candidiasis. The host immune response against invading pathogens needs to be robust enough to eliminate the pathogen, but not too strong in order to prevent immunopathology. Influenza virus infections exemplify the problems associated with the regulation of this delicate balance. Peiris et al. summarize the similarities and differences between different strains of influenza viruses with different degrees of virulence, such as the highly pathogenic 1918 and H5N1 strains, and the new H1N1 pandemic influenza viruses, and how studies conducted with these viruses have contributed to a better understanding of immune-protective and immune-pathological factors that might be harnessed in antiviral therapies. Our understanding on the role of both viral factors and host factors in protecting against or in exacerbating disease caused by influenza viruses is also discussed. Subversion of host immune responses by pathogens has emerged as a major area of research that offers new www.sciencedirect.com
Editorial overview Garcı´a-Sastre and Sansonetti 427
insights on host immunity and on mechanisms of pathogenesis. Large DNA viruses, poxviruses and herpesviruses, encode a plethora of immune-regulators that are required for their survival and for disease induction. Specially interesting are their regulators of chemokinesignaling activity. Lira and Alcamı´ summarize the latest advances in the knowledge of modulation of immune responses and disease by virus-encoded chemokine receptors, chemokine ligands and chemokine-binding proteins. The authors also discuss the recently discovered chemokine-binding proteins found in ticks. These modulators of chemokine activity might be exploited for therapeutic purposes. All infectious disease agents induce a wide spectrum of disease severity in the host. Understanding how specific patients are able to better fight disease than others might
www.sciencedirect.com
give us the required clues to combat diseases for which there is no cure available. In this respect, Chakrabarti and Simon have summarized recent concepts concerning how innate and adaptive immune responses may contribute to control HIV in long-term non-progressors. Rare individuals who spontaneously control HIV replication appear to do it by a combination of different factors related with the rapid induction of highly active cellular immune responses. These include the interferon-mediated induction of HIV-restriction factors, such as tetherin, TRIM5a and APOBEC3, and the development of high-avidity T cells, which control HIV replication and confer long-term immune memory. In addition, specific MHC class I alleles have been associated with a better protection against AIDS development. These recent studies might help in the development of novel therapeutic and prophylaxis treatments against HIV.
Current Opinion in Immunology 2010, 22:425–427