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Immunity to infection
465
Immunity to infection Editorial overview Barry Bloom* and Rolf Zinkernagelt Addresses *Department of Microbiology and Immunology, Albert Einstein College of Medicine, Forchheimer Building, 1300 Morris Park Avenue, Bronx, NY 10461, USA tlnstitute for Pathology, University of Zurich, Universitatsspital, Schmelzbergstrasse 12, 6091 Zurich, Switzerland Current
Opinion
in Immunology
1996, 8:465-466
0 Current Biology Ltd ISSN 0952-7915 Abbreviations cytotoxic T lymphocyte CTL interferon IFN interleukin IL
The series of opinions presented in this section concerning the role of immune mechanisms and resistance to infectious pathogens is rich in new insights and hypotheses. Of necessity it can survey only a limited number of selected examples, and these are best seen within the context of the previous series of current topics in this section last year and in the light of the advances made since then in understanding the interactions between infectious pathogens and the host immune system. The present reviews once again make clear that the balance between infectious agents and the host, including specific and nonspecific immunological defense mechanisms, reflects a wide variety of the evolutionary equilibria. While conventional live-attenuated or inactivated vaccines have been extremely successful in decreasing morbidity and mortality against a number of acute cytopathic and pathogenic infections, this is not the case for many persisting infections that may form the basis for chronic degenerative and immunopathological diseases. Without better understanding of these infections, both prophylaxis and postexposure therapy will be difficult, if not impossible, to develop. It is not quite by chance, therefore, that the organisms reviewed in this section include many infectious agents that tend to establish chronic, persistent or latent types of infection in which the infectious agents may reach varying balances between protection, pathogenesis and persistence. The complex relationships between viruses, bacteria or classical parasites and the vertebrate host are perhaps most clearly understood for viruses. In particular, pox and herpes viruses are big.viruses whose complexity approaches that of intracellular bacteria. They use a multiplicity of tricks to delay immune responses, as summarized by Smith (pp 467-471); some viral proteins bind various kinds of cytokines by using receptors with varying degrees of specificity, thereby interfering with immune responses and effector functions. The release of cytokines by CD8+
T cells infection
versus the action of perforin in the is the subject of two complementary
control of reviews
by Kagi and Hengartner (pp 472477) and Guidotti and Chisari (pp 478-483). Several murine models are providing evidence that supports the theory of direct contact-dependent perforin-mediated lysis of infected or tumor target cells by cytotoxic T lymphocytes (CTLs), particularly in response to infection by noncytopathic viruses (or in response to intracellular bacteria during secondary infections). Alternatively, evidence is also presented that interferon (IFN)-y production triggered by CTLs (independent of perforin) can inhibit transgenic hepatitis B gene expression and plays a key role in the control of several acute cytopathic viral infections. A few years ago many thought that cytolysis was the dominant antiviral T-cell effector mechanism; it is now clear that this is true against some viruses, while soluble cytokines etc.) that are able to factors (antibodies, extend protection beyond contact-dependent cell to cell mechanisms are crucial against many others. A special case of host-virus relationship is summarized by Frazer (pp 484-491). Papilloma viruses manage to keep beyond the usual reach of antigen-presenting cells and are ignored by lymphocytes for quite some time. An immune response is eventually induced, albeit with difficulty, because the virus uses several tricks to escape T-cell recognition. The initiation of a response is further impeded by the fact that effector T cells and antibodies have difficulties in reaching the peripheral sites of viral infection, The intricate relationship between viruses and B cells is the subject of the reviews by Rickenson et al. (pp 492-497) on Epstein-Barr virus (EBV) and by Luther and Acha-Orbea (pp 498-502) on mouse mammary tumor virus (MMTV); both of these infections feature the lymphoproliferation of infected B cells. In EBV infections, the process of T cells recognizing the infection and then regulating B-cell proliferation, as well as the many ways this process can be avoided, determines whether or not a tumor arises. MMTV also manipulates the immune system in order to survive in the host and to be able to spread; B cells infected by MMTV trigger T cells and somehow promote the transport of the virus to the mammary glands, where the virus locally infects mammary epithelial cells and is transmitted to offspring through the mothers’milk. The pathogenesis of Lyme disease provides an extraordinary example of the lengths to which a microbial pathogen, Born&a burgdorfen’, is able to go in order to evade the immune response. It employs multiple mechanisms to evade recognition and to persist for long periods of time within the host, frequently resulting in the development of devastating disease. Seiler and Weis (pp 503-509)
466
Immunity to infection
reveal within
the subtle mechanisms of antigenic modulation the parasite, the induction of nonspecific host defense mechanisms and the possible ways for the host immune system to control pathogenic infection and persistence. The emerging importance of nonclassical immunological presentation and recognition is emphasized by Porcelli eta/. (pp 510-516) in their elucidation of T-cell recognition of nonpeptide antigens that are presented by mycobacteria. One such class of antigen, the lipoglycans, is known to be present in many microbial pathogens and is often associated with virulence. Porcelli et a/. review the evidence for presentation of antigens by CD1 molecules which enables T cells to respond to chemically defined lipid and nonpeptide antigens. A new universe of potential antigens that may be involved in protection and pathogenesis is suggested. Bogdan et a/. (pp 517-525) critically re-evaluate the paradigm of the Thl/ThZ dichotomy in leishmanial infection of BALB/c mice; also presented is a broad analysis of the mechanisms involved in protection as well as in persistence. The key role of IL-4 is challenged and what emerges is a more complex and balanced picture of cytokine interactions and perhaps the primacy of IL-12. It is widely assumed that mechanisms involved in resistance to primary infection by Leihzania are likely to be the same ones that provide resistance to secondary challenge, although it is surprising how limited our knowledge is regarding differences between immunological mechanisms engaged in primary and secondary infections. Perhaps the best understood case involving cellular immunity is that of Listeria monoqytogenes, reviewed by Harty et al. (pp 526-530). It has emerged that IFN-y is an absolute necessity for protection against initial infection but that, in primed individuals, protection can be mediated largely by CDS+ T cells even in IFN-y knockout mice. Each study emphasizes the importance of characterizing the
secondary responses, as well as the initial ones, that are required to prevent infection, for example, the importance of antibodies and non-T-cell responses in Borrelia, or the importance of IFN-y in primary Listetia infection. They also suggest that renewed attention be given to the immune responses that are critical in the limitation, maintenance or elimination of the pathogen, as in the case of nitric oxide and the inducible nitric oxide synthase system and Leidmania persistence.
In recent years perhaps the most exciting development in vaccinology has been in the area of DNA vaccines, which are the subject of great hopes and expectations as well as great concerns. Ulmer et a/. (pp 531-536) review state-of-the-art DNA vaccines, provide compelling evidence of their remarkable effectiveness in animal systems and indicate why the detailed mechanisms of their actions remain poorly understood. They help to clarify the principles of antigen localization and transport, the induction of functional subsets of T cells and the role of CTLs specific for the antigens encoded by influenza virus, by papilloma virus and in malaria. While concerns remain about the potential of integration into chromosomal genes or the possibilities for producing autoreactivity, there is little question that, in the next few years, DNA vaccines will teach us a great deal about immune protection as well as very basic issues in immunology.
The selected infectious agents reviewed in this collection reveal progress in our understanding of immunity and immunopathology and illustrate the wonderfully complex and diverse subtleties of individual parasite-host interactions. New insight will not only help to improve vaccines and disease prevention in general but will also enrich our understanding of the fascinating biology of the interactions of infectious agents with their hosts.
Immunity to infection Editorial overview Barry Bloom* and Rolf Zinkernagelt Addresses *Department of Microbiology and Immunology, Albert Einstein College of Medicine, Forchheimer Building, 1300 Morris Park Avenue, Bronx, NY 10461, USA tlnstitute for Pathology, University of Zurich, Universitatsspital, Schmelzbergstrasse 12, 6091 Zurich, Switzerland Current
Opinion
in Immunology
1996, 8:465-466
0 Current Biology Ltd ISSN 0952-7915 Abbreviations cytotoxic T lymphocyte CTL interferon IFN interleukin IL
The series of opinions presented in this section concerning the role of immune mechanisms and resistance to infectious pathogens is rich in new insights and hypotheses. Of necessity it can survey only a limited number of selected examples, and these are best seen within the context of the previous series of current topics in this section last year and in the light of the advances made since then in understanding the interactions between infectious pathogens and the host immune system. The present reviews once again make clear that the balance between infectious agents and the host, including specific and nonspecific immunological defense mechanisms, reflects a wide variety of the evolutionary equilibria. While conventional live-attenuated or inactivated vaccines have been extremely successful in decreasing morbidity and mortality against a number of acute cytopathic and pathogenic infections, this is not the case for many persisting infections that may form the basis for chronic degenerative and immunopathological diseases. Without better understanding of these infections, both prophylaxis and postexposure therapy will be difficult, if not impossible, to develop. It is not quite by chance, therefore, that the organisms reviewed in this section include many infectious agents that tend to establish chronic, persistent or latent types of infection in which the infectious agents may reach varying balances between protection, pathogenesis and persistence. The complex relationships between viruses, bacteria or classical parasites and the vertebrate host are perhaps most clearly understood for viruses. In particular, pox and herpes viruses are big.viruses whose complexity approaches that of intracellular bacteria. They use a multiplicity of tricks to delay immune responses, as summarized by Smith (pp 467-471); some viral proteins bind various kinds of cytokines by using receptors with varying degrees of specificity, thereby interfering with immune responses and effector functions. The release of cytokines by CD8+
T cells infection
versus the action of perforin in the is the subject of two complementary
control of reviews
by Kagi and Hengartner (pp 472477) and Guidotti and Chisari (pp 478-483). Several murine models are providing evidence that supports the theory of direct contact-dependent perforin-mediated lysis of infected or tumor target cells by cytotoxic T lymphocytes (CTLs), particularly in response to infection by noncytopathic viruses (or in response to intracellular bacteria during secondary infections). Alternatively, evidence is also presented that interferon (IFN)-y production triggered by CTLs (independent of perforin) can inhibit transgenic hepatitis B gene expression and plays a key role in the control of several acute cytopathic viral infections. A few years ago many thought that cytolysis was the dominant antiviral T-cell effector mechanism; it is now clear that this is true against some viruses, while soluble cytokines etc.) that are able to factors (antibodies, extend protection beyond contact-dependent cell to cell mechanisms are crucial against many others. A special case of host-virus relationship is summarized by Frazer (pp 484-491). Papilloma viruses manage to keep beyond the usual reach of antigen-presenting cells and are ignored by lymphocytes for quite some time. An immune response is eventually induced, albeit with difficulty, because the virus uses several tricks to escape T-cell recognition. The initiation of a response is further impeded by the fact that effector T cells and antibodies have difficulties in reaching the peripheral sites of viral infection, The intricate relationship between viruses and B cells is the subject of the reviews by Rickenson et al. (pp 492-497) on Epstein-Barr virus (EBV) and by Luther and Acha-Orbea (pp 498-502) on mouse mammary tumor virus (MMTV); both of these infections feature the lymphoproliferation of infected B cells. In EBV infections, the process of T cells recognizing the infection and then regulating B-cell proliferation, as well as the many ways this process can be avoided, determines whether or not a tumor arises. MMTV also manipulates the immune system in order to survive in the host and to be able to spread; B cells infected by MMTV trigger T cells and somehow promote the transport of the virus to the mammary glands, where the virus locally infects mammary epithelial cells and is transmitted to offspring through the mothers’milk. The pathogenesis of Lyme disease provides an extraordinary example of the lengths to which a microbial pathogen, Born&a burgdorfen’, is able to go in order to evade the immune response. It employs multiple mechanisms to evade recognition and to persist for long periods of time within the host, frequently resulting in the development of devastating disease. Seiler and Weis (pp 503-509)
466
Immunity to infection
reveal within
the subtle mechanisms of antigenic modulation the parasite, the induction of nonspecific host defense mechanisms and the possible ways for the host immune system to control pathogenic infection and persistence. The emerging importance of nonclassical immunological presentation and recognition is emphasized by Porcelli eta/. (pp 510-516) in their elucidation of T-cell recognition of nonpeptide antigens that are presented by mycobacteria. One such class of antigen, the lipoglycans, is known to be present in many microbial pathogens and is often associated with virulence. Porcelli et a/. review the evidence for presentation of antigens by CD1 molecules which enables T cells to respond to chemically defined lipid and nonpeptide antigens. A new universe of potential antigens that may be involved in protection and pathogenesis is suggested. Bogdan et a/. (pp 517-525) critically re-evaluate the paradigm of the Thl/ThZ dichotomy in leishmanial infection of BALB/c mice; also presented is a broad analysis of the mechanisms involved in protection as well as in persistence. The key role of IL-4 is challenged and what emerges is a more complex and balanced picture of cytokine interactions and perhaps the primacy of IL-12. It is widely assumed that mechanisms involved in resistance to primary infection by Leihzania are likely to be the same ones that provide resistance to secondary challenge, although it is surprising how limited our knowledge is regarding differences between immunological mechanisms engaged in primary and secondary infections. Perhaps the best understood case involving cellular immunity is that of Listeria monoqytogenes, reviewed by Harty et al. (pp 526-530). It has emerged that IFN-y is an absolute necessity for protection against initial infection but that, in primed individuals, protection can be mediated largely by CDS+ T cells even in IFN-y knockout mice. Each study emphasizes the importance of characterizing the
secondary responses, as well as the initial ones, that are required to prevent infection, for example, the importance of antibodies and non-T-cell responses in Borrelia, or the importance of IFN-y in primary Listetia infection. They also suggest that renewed attention be given to the immune responses that are critical in the limitation, maintenance or elimination of the pathogen, as in the case of nitric oxide and the inducible nitric oxide synthase system and Leidmania persistence.
In recent years perhaps the most exciting development in vaccinology has been in the area of DNA vaccines, which are the subject of great hopes and expectations as well as great concerns. Ulmer et a/. (pp 531-536) review state-of-the-art DNA vaccines, provide compelling evidence of their remarkable effectiveness in animal systems and indicate why the detailed mechanisms of their actions remain poorly understood. They help to clarify the principles of antigen localization and transport, the induction of functional subsets of T cells and the role of CTLs specific for the antigens encoded by influenza virus, by papilloma virus and in malaria. While concerns remain about the potential of integration into chromosomal genes or the possibilities for producing autoreactivity, there is little question that, in the next few years, DNA vaccines will teach us a great deal about immune protection as well as very basic issues in immunology.
The selected infectious agents reviewed in this collection reveal progress in our understanding of immunity and immunopathology and illustrate the wonderfully complex and diverse subtleties of individual parasite-host interactions. New insight will not only help to improve vaccines and disease prevention in general but will also enrich our understanding of the fascinating biology of the interactions of infectious agents with their hosts.