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Editorial overview: Host pathogens: the interplay between host innate and adaptive immune systems and pathogens
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ScienceDirect Editorial overview: Host pathogens: the interplay between host innate and adaptive immune systems and pathogens Paul Zhou and Zheng W Chen Current Opinion in Immunology 2016, 42:viii–x For a complete overview see the Issue Available online 20th August 2016 http://dx.doi.org/10.1016/j.coi.2016.08.001 0952-7915/# 2016 Elsevier Ltd. All rights reserved.
Paul Zhou
Unit of Anti-Viral Immunity and Genetic Therapy, Institut Pasteur of Shanghai, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China e-mail: [email protected] Paul Zhou received his Ph.D. in immunology in the State University of New York in Buffalo in 1989 and his postdoctoral training in the Mayo Clinic between 1989 and 1993. He was a senior staff fellow in the NIH between 1993 and 1998. Between 1998 and 2005 he was an Associate Scientist in the Southwest Foundation for Biomedical Research and an Adjunct Associate Professor in UT Health Science Center in San Antonio, Texas. Since 2005 he has been an Unit Chief and Full Professor in the Institut Pasteur of Shanghai, Chinese Academy of Sciences. Researches in Dr. Zhou’s Unit focus on ‘Development of Vaccines and Antibody-based Therapeutics against HIV and Influenza Virus’.
Current Opinion in Immunology 2016, 42:viii–x
Since we entered into the twenty first century, many newly emerging and reemerging pathogens, such as influenza H5N1 and H7N9, SARS and MERS, Ebola and Zika, have caused serious infections and casualties in humans. But such human infections and casualties caused by newly emerging and reemerging pathogens are still far less than those caused by human immunodeficiency virus type 1 (HIV-1), seasonal influenza viruses, hepatitis C virus (HCV), Mycobacterium tuberculosis (TB) and malaria. Currently, there are no licensed vaccines for HIV-1, HCV, and malaria. Vaccines for seasonal influenza and TB need significant improvement. No one has been cured of HIV-1 except for the Berlin patient, Timothy Brown. Thus, understanding the interplay between these pathogens and the host immune system is of paramount importance for vaccine development, immunotherapy and understanding pathogenesis. Nine reviews in this issue of Pathogens and Host focused on several recent advancement in innate and adaptive immunity against influenza viruses, HIV-1, HCV, TB and malaria and in the translation of these advancement into new vaccine designs and new immunotherapies. Current seasonal influenza vaccines are efficacious when vaccine strains are matched with circulating influenza strains. However, they need to be reformulated frequently to elicit protective antibody responses against viral variants and do not protect humans from pandemics and outbreaks of newly emerging strains. Thus, the holy grail of influenza vaccine research is to design immunogen(s) that not only protect current strains, but also future strains. Karlynn E. Neu et al. (pp. 48–55) review antibody responses to influenza virus, conserved protective epitopes on influenza hemagglutinin recognized by broadly reactive antibodies. In addition, they analyzed the occurrence of broadly neutralizing stalk-reactive antibodies and speculated about their role in extinction of previously circulating human influenza strains. Finally, they described how to boost stalk-reactive antibody responses from antigen-specific memory B cells as ways to develop stalkbased ‘universal’’ influenza virus vaccines. Along the same venue Huanhuan Ren and Paul Zhou (pp. 83–90) review epitope-focused vaccine design against influenza A and B viruses. They summarize conserved epitopes in the head (RBS as well as outside RBS) and the stem regions of HA recognized by broadly human and animal monoclonal antibodies and emphasize both stem-based vaccine design that aims to elicit cross-subtype (‘universal’) antibody responses and RBS-based vaccine design that aims to elicit HA subtype-specific antibody responses. Two tables in the review should be useful for readers to obtain detailed reference information in these studies. www.sciencedirect.com
Editorial overview Zhou and Chen ix
Zheng W Chen
Department of Microbiology and Immunology, Center for Primate Biomedical Research, University of Illinois College of Medicine Chicago, 909 South Wolcott Avenue, MC790, E704, Chicago, IL 60612, United States e-mail: [email protected] Dr. Chen started his career as a fellow at Harvard University in 1989. He then worked as Assistant Professor and Associate Professor of Medicine at Harvard from 1994 to 2004, running the NIH-funded research program since 1993. He took full professorship and directorship at University of Illinois in 2005. His research interests include cellular/molecular biology, immune responses and immunity of Ag-specific gd Tcell subset, CTL, Th1/Th22 subsets in TB, HIV/AIDS, malaria and other infectious diseases. For decades, his lab has remained a single group actively employing nonhuman primate models to investigate functions and immunity of the major human gd T-cell subset in TB and other infections.
Although highly active antiretroviral therapy (ART) has been proven to be a successful suppressive treatment for HIV-1, it fails to eradicate infection. Thus, successful vaccine and cure strategies are needed to further reduce the global incidence of new infections. Passive infusion with broadly neutralizing monoclonal antibodies has demonstrated efficacy as both preventive and therapeutic agents in humanized mouse and simian-human immunodeficiency virus (SHIV) rhesus macaque models, and more recently in chronic HIV-1 infected individuals. But so far, eliciting such broadly neutralizing antibody responses by active immunizations has been proven very difficult. Xueling Wu and Xiang-Peng Kong (pp. 56–64) review the antigenic landscape of HIV-1 envelope proteins recognized by many broadly neutralizing antibodies recently isolated from infected individuals and provide important insights into how these antibodies with high level of SHM, unusual HCDR3 length and specific mode of antigen recognition are generated in about 50% infected individuals. The information could be useful for vaccine design against HIV-1 envelope proteins. A very interesting feature of this review is to put the antigenic landscape in the context of recently developed soluble cleaved BG505 SOSIP trimer. Jason T. Kimata et al. (pp. 65–70) explain the science behind the HIV-1 latency and the challenges to eradicate HIV-1 reservoir with the ‘shock and kill’ strategy. They review several new strategies to enhance immune clearance such as adoptive T cell transfer and passive immunotherapy with broadly neutralizing antibodies and to sensitize latently infected cells with cell death inducing agents. The innate immune system detects pathogens via a group of pathogen recognition receptors (PRRs) expressed on the cell membranes or in the cytosol. These receptors can respond to almost all microorganisms since they recognize common molecular structures, including lipid, protein or nucleic acid components derived from microorganisms. In case of influenza virus, the group of RIG-I-like receptor (RLRs) plays an important role in innate defense. Michaele Webe-Gerlach and Friedemann Weber (pp. 71–75) provide a concise overview of anti-influenza virus activities of RIG-I, one of three RLRs. They emphasize that besides its well-known activity in the signaling chain that leads to IFN induction, RIG-I also has two additional antiviral activities. RIG-I promotes the disassembly of the viral polymerase complex by binding to the 50 ppp-dsRNA panhandle of PB2-627E mutant virus nucleocapsid. RIG-I stimulates the NF-kB mediated pro-IL-1b expression and at the same time associates with ASC and caspase-1 into the inflammasome. Caspase-1 in the complex cleaves pro-IL-1b into the bioactive IL-1b. Along the same venue Yongfen Xu and Jin Zhong (pp. 98–104) review innate immunity against HCV. Interestingly, different PRRs in different cell types (hepatocytes versus non-hepatocytes) recognize HCV molecules to mediate anti-HCV activities. Although many host innate effectors have been identified against HCV, the review mainly focuses on a recently identified ER-associated enzyme cholesterol-25-hydroxylase (CH25H) and its product 25-hydroxycholesterol (25HC). Finally, they review escape mechanisms used by HCV to evade innate immunity with emphasis on the cleavage of MAVS by NS3/4A and of STING by NS4B. TB has become a top killer among infectious diseases worldwide due to the epidemic of HIV/AIDS and multi-drug resistant TB. Controlling the spread of TB represents a significant challenge as we have TB drugs and the BCG vaccine. Developing an effective host-directed therapy (HDT) and better vaccine is therefore of central importance for global control of TB epidemics. Such vaccine/HDT efforts require targeting or leveraging of protective immune components. To date, protective components and mechanisms
www.sciencedirect.com
Current Opinion in Immunology 2016, 42:viii–x
x Host pathogens
against human TB remain unknown. It is noteworthy that a majority of humans do not develop TB after Mtb infection and that many individuals are not even infected after exposures to Mtb aerosols from active TB patients. Although adaptive immunity is critical for TB control, innate immunity components have been a recent focus on uncovering coordinative protection. gd T cells are usually considered as innate-like unconventional T cells, representing a minor population relative to the major population of ab CD4/CD8T cells. Despite discovery of gd T cells for >30 years, protection against infections by human gd T cells have not been defined. Dominant Vg2Vd2 (alsoVg9Vd2) T-cell subset constitute 65–90% of total circulating human gd T cells. This subset remains a sole gd T-cell subpopulation capable of recognizing phosphoantigen HMBPP from Mtb or selected pathogens, and exist only in humans or nonhuman primates (NHP). Now in the review article (pp. 105–112), Zheng W. Chen summarizes recent progress in understanding protective immune responses of Vg2Vd2T cells. The discussion is focused on the following aspects: (i) HMBPP is required for immune responses/functions of Vg2Vd2T cells during infections; (ii) broad cytokines involve effector functions of Vg2Vd2T cells in Mtb infection; (iii) early responses of Vg2Vd2T cells via immune intervention can increase resistance to Mtb infection. Concurrently, TLR2-driven innate immune responses during Mtb infection are reviewed by Archana Gopalakrishnan and Padmini Salgame (pp. 76–82). These experts efficiently cover the following topics: (i) TLR2 does not contribute to protection against acute Mtb
Current Opinion in Immunology 2016, 42:viii–x
infection; (ii) TLR2 has a significant role in protection against chronic Mtb infection; (iii) TLR2 controls immunopathology in chronic Mtb infection; (iv) Mtb hijacks TLR2 to evade macrophage effector mechanisms; and (v) TLR2 signaling is regulated to minimize host immunopathology. Since T cells play a major role in control of both blood and liver stage of plasmodium infection, it is important to exploit protective T-cell responses for malaria vaccine development. Drs. Van Braeckel-Budimir et al. (pp. 91– 97) review the potential interrelation or disconnection between vaccine-induced protection and malaria infection-driven CD8T cell responses. The review article discusses the following scientific points: (i) natural exposures do not induce stable CD8T cell memory response or sterilizing humoral immunity against liver or blood stages of plasmodium infection; (ii) immunization with radiation attenuated sporozoites (RAS), arrested during the early liver stage of infection, induces CD8T cell-mediated sterilizing protection in malaria naı¨ve individuals; (iii) the blood stage of malaria has immunoregulatory effects on T cell responses; (iv) functional exhaustion and induction of strong regulatory T cell (Treg) effector functions seem to be the main mechanism of blood stageinduced immunoregulation. In conclusion, this series of review articles updates recent advancement in the innate and adaptive immune responses to influenza, HCV, HIV-1, TB, and malaria. The reviews also spotlight some of the future challenges in development of vaccines for HIV, HCV and malaria or better vaccines for TB and influenza as well as therapeutic strategies to cure HIV-1 infection.
www.sciencedirect.com
ScienceDirect Editorial overview: Host pathogens: the interplay between host innate and adaptive immune systems and pathogens Paul Zhou and Zheng W Chen Current Opinion in Immunology 2016, 42:viii–x For a complete overview see the Issue Available online 20th August 2016 http://dx.doi.org/10.1016/j.coi.2016.08.001 0952-7915/# 2016 Elsevier Ltd. All rights reserved.
Paul Zhou
Unit of Anti-Viral Immunity and Genetic Therapy, Institut Pasteur of Shanghai, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China e-mail: [email protected] Paul Zhou received his Ph.D. in immunology in the State University of New York in Buffalo in 1989 and his postdoctoral training in the Mayo Clinic between 1989 and 1993. He was a senior staff fellow in the NIH between 1993 and 1998. Between 1998 and 2005 he was an Associate Scientist in the Southwest Foundation for Biomedical Research and an Adjunct Associate Professor in UT Health Science Center in San Antonio, Texas. Since 2005 he has been an Unit Chief and Full Professor in the Institut Pasteur of Shanghai, Chinese Academy of Sciences. Researches in Dr. Zhou’s Unit focus on ‘Development of Vaccines and Antibody-based Therapeutics against HIV and Influenza Virus’.
Current Opinion in Immunology 2016, 42:viii–x
Since we entered into the twenty first century, many newly emerging and reemerging pathogens, such as influenza H5N1 and H7N9, SARS and MERS, Ebola and Zika, have caused serious infections and casualties in humans. But such human infections and casualties caused by newly emerging and reemerging pathogens are still far less than those caused by human immunodeficiency virus type 1 (HIV-1), seasonal influenza viruses, hepatitis C virus (HCV), Mycobacterium tuberculosis (TB) and malaria. Currently, there are no licensed vaccines for HIV-1, HCV, and malaria. Vaccines for seasonal influenza and TB need significant improvement. No one has been cured of HIV-1 except for the Berlin patient, Timothy Brown. Thus, understanding the interplay between these pathogens and the host immune system is of paramount importance for vaccine development, immunotherapy and understanding pathogenesis. Nine reviews in this issue of Pathogens and Host focused on several recent advancement in innate and adaptive immunity against influenza viruses, HIV-1, HCV, TB and malaria and in the translation of these advancement into new vaccine designs and new immunotherapies. Current seasonal influenza vaccines are efficacious when vaccine strains are matched with circulating influenza strains. However, they need to be reformulated frequently to elicit protective antibody responses against viral variants and do not protect humans from pandemics and outbreaks of newly emerging strains. Thus, the holy grail of influenza vaccine research is to design immunogen(s) that not only protect current strains, but also future strains. Karlynn E. Neu et al. (pp. 48–55) review antibody responses to influenza virus, conserved protective epitopes on influenza hemagglutinin recognized by broadly reactive antibodies. In addition, they analyzed the occurrence of broadly neutralizing stalk-reactive antibodies and speculated about their role in extinction of previously circulating human influenza strains. Finally, they described how to boost stalk-reactive antibody responses from antigen-specific memory B cells as ways to develop stalkbased ‘universal’’ influenza virus vaccines. Along the same venue Huanhuan Ren and Paul Zhou (pp. 83–90) review epitope-focused vaccine design against influenza A and B viruses. They summarize conserved epitopes in the head (RBS as well as outside RBS) and the stem regions of HA recognized by broadly human and animal monoclonal antibodies and emphasize both stem-based vaccine design that aims to elicit cross-subtype (‘universal’) antibody responses and RBS-based vaccine design that aims to elicit HA subtype-specific antibody responses. Two tables in the review should be useful for readers to obtain detailed reference information in these studies. www.sciencedirect.com
Editorial overview Zhou and Chen ix
Zheng W Chen
Department of Microbiology and Immunology, Center for Primate Biomedical Research, University of Illinois College of Medicine Chicago, 909 South Wolcott Avenue, MC790, E704, Chicago, IL 60612, United States e-mail: [email protected] Dr. Chen started his career as a fellow at Harvard University in 1989. He then worked as Assistant Professor and Associate Professor of Medicine at Harvard from 1994 to 2004, running the NIH-funded research program since 1993. He took full professorship and directorship at University of Illinois in 2005. His research interests include cellular/molecular biology, immune responses and immunity of Ag-specific gd Tcell subset, CTL, Th1/Th22 subsets in TB, HIV/AIDS, malaria and other infectious diseases. For decades, his lab has remained a single group actively employing nonhuman primate models to investigate functions and immunity of the major human gd T-cell subset in TB and other infections.
Although highly active antiretroviral therapy (ART) has been proven to be a successful suppressive treatment for HIV-1, it fails to eradicate infection. Thus, successful vaccine and cure strategies are needed to further reduce the global incidence of new infections. Passive infusion with broadly neutralizing monoclonal antibodies has demonstrated efficacy as both preventive and therapeutic agents in humanized mouse and simian-human immunodeficiency virus (SHIV) rhesus macaque models, and more recently in chronic HIV-1 infected individuals. But so far, eliciting such broadly neutralizing antibody responses by active immunizations has been proven very difficult. Xueling Wu and Xiang-Peng Kong (pp. 56–64) review the antigenic landscape of HIV-1 envelope proteins recognized by many broadly neutralizing antibodies recently isolated from infected individuals and provide important insights into how these antibodies with high level of SHM, unusual HCDR3 length and specific mode of antigen recognition are generated in about 50% infected individuals. The information could be useful for vaccine design against HIV-1 envelope proteins. A very interesting feature of this review is to put the antigenic landscape in the context of recently developed soluble cleaved BG505 SOSIP trimer. Jason T. Kimata et al. (pp. 65–70) explain the science behind the HIV-1 latency and the challenges to eradicate HIV-1 reservoir with the ‘shock and kill’ strategy. They review several new strategies to enhance immune clearance such as adoptive T cell transfer and passive immunotherapy with broadly neutralizing antibodies and to sensitize latently infected cells with cell death inducing agents. The innate immune system detects pathogens via a group of pathogen recognition receptors (PRRs) expressed on the cell membranes or in the cytosol. These receptors can respond to almost all microorganisms since they recognize common molecular structures, including lipid, protein or nucleic acid components derived from microorganisms. In case of influenza virus, the group of RIG-I-like receptor (RLRs) plays an important role in innate defense. Michaele Webe-Gerlach and Friedemann Weber (pp. 71–75) provide a concise overview of anti-influenza virus activities of RIG-I, one of three RLRs. They emphasize that besides its well-known activity in the signaling chain that leads to IFN induction, RIG-I also has two additional antiviral activities. RIG-I promotes the disassembly of the viral polymerase complex by binding to the 50 ppp-dsRNA panhandle of PB2-627E mutant virus nucleocapsid. RIG-I stimulates the NF-kB mediated pro-IL-1b expression and at the same time associates with ASC and caspase-1 into the inflammasome. Caspase-1 in the complex cleaves pro-IL-1b into the bioactive IL-1b. Along the same venue Yongfen Xu and Jin Zhong (pp. 98–104) review innate immunity against HCV. Interestingly, different PRRs in different cell types (hepatocytes versus non-hepatocytes) recognize HCV molecules to mediate anti-HCV activities. Although many host innate effectors have been identified against HCV, the review mainly focuses on a recently identified ER-associated enzyme cholesterol-25-hydroxylase (CH25H) and its product 25-hydroxycholesterol (25HC). Finally, they review escape mechanisms used by HCV to evade innate immunity with emphasis on the cleavage of MAVS by NS3/4A and of STING by NS4B. TB has become a top killer among infectious diseases worldwide due to the epidemic of HIV/AIDS and multi-drug resistant TB. Controlling the spread of TB represents a significant challenge as we have TB drugs and the BCG vaccine. Developing an effective host-directed therapy (HDT) and better vaccine is therefore of central importance for global control of TB epidemics. Such vaccine/HDT efforts require targeting or leveraging of protective immune components. To date, protective components and mechanisms
www.sciencedirect.com
Current Opinion in Immunology 2016, 42:viii–x
x Host pathogens
against human TB remain unknown. It is noteworthy that a majority of humans do not develop TB after Mtb infection and that many individuals are not even infected after exposures to Mtb aerosols from active TB patients. Although adaptive immunity is critical for TB control, innate immunity components have been a recent focus on uncovering coordinative protection. gd T cells are usually considered as innate-like unconventional T cells, representing a minor population relative to the major population of ab CD4/CD8T cells. Despite discovery of gd T cells for >30 years, protection against infections by human gd T cells have not been defined. Dominant Vg2Vd2 (alsoVg9Vd2) T-cell subset constitute 65–90% of total circulating human gd T cells. This subset remains a sole gd T-cell subpopulation capable of recognizing phosphoantigen HMBPP from Mtb or selected pathogens, and exist only in humans or nonhuman primates (NHP). Now in the review article (pp. 105–112), Zheng W. Chen summarizes recent progress in understanding protective immune responses of Vg2Vd2T cells. The discussion is focused on the following aspects: (i) HMBPP is required for immune responses/functions of Vg2Vd2T cells during infections; (ii) broad cytokines involve effector functions of Vg2Vd2T cells in Mtb infection; (iii) early responses of Vg2Vd2T cells via immune intervention can increase resistance to Mtb infection. Concurrently, TLR2-driven innate immune responses during Mtb infection are reviewed by Archana Gopalakrishnan and Padmini Salgame (pp. 76–82). These experts efficiently cover the following topics: (i) TLR2 does not contribute to protection against acute Mtb
Current Opinion in Immunology 2016, 42:viii–x
infection; (ii) TLR2 has a significant role in protection against chronic Mtb infection; (iii) TLR2 controls immunopathology in chronic Mtb infection; (iv) Mtb hijacks TLR2 to evade macrophage effector mechanisms; and (v) TLR2 signaling is regulated to minimize host immunopathology. Since T cells play a major role in control of both blood and liver stage of plasmodium infection, it is important to exploit protective T-cell responses for malaria vaccine development. Drs. Van Braeckel-Budimir et al. (pp. 91– 97) review the potential interrelation or disconnection between vaccine-induced protection and malaria infection-driven CD8T cell responses. The review article discusses the following scientific points: (i) natural exposures do not induce stable CD8T cell memory response or sterilizing humoral immunity against liver or blood stages of plasmodium infection; (ii) immunization with radiation attenuated sporozoites (RAS), arrested during the early liver stage of infection, induces CD8T cell-mediated sterilizing protection in malaria naı¨ve individuals; (iii) the blood stage of malaria has immunoregulatory effects on T cell responses; (iv) functional exhaustion and induction of strong regulatory T cell (Treg) effector functions seem to be the main mechanism of blood stageinduced immunoregulation. In conclusion, this series of review articles updates recent advancement in the innate and adaptive immune responses to influenza, HCV, HIV-1, TB, and malaria. The reviews also spotlight some of the future challenges in development of vaccines for HIV, HCV and malaria or better vaccines for TB and influenza as well as therapeutic strategies to cure HIV-1 infection.
www.sciencedirect.com