- Email: [email protected]
The dynamic pathogen–host response interface
Drug Discovery Today: Disease Mechanisms
DRUG DISCOVERY
TODAY
Vol. 4, No. 4 2007
Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Charles Lowenstein – The John Hopkins School of Medicine, Baltimore, USA
DISEASE Infectious diseases MECHANISMS
EDITORIAL
The dynamic pathogen–host response interface W. Conrad Liles University Health Network/University of Toronto, 200 Elizabeth Street, 13N-220, Toronto, Ontario M5G 2C4, Canada. Email: [email protected]
Conventional therapeutic strategies for the management of infectious diseases have focused primarily on the use of antimicrobial agents to eradicate the causative microbial pathogen(s). Although invasion by a pathogen per se is a necessary component in the pathogenesis of an infectious disease, it is not the only part of the equation that defines the clinical phenotype that results from host invasion by a microbial pathogen. It has become increasingly clear that the host response to an invading pathogen plays an important role in defining the severity of illness, the clinical manifestation(s), and the clinical outcome in a given infectious disease. Recent advances in our understanding of the dynamic pathogen–host response interface, and its role in disease pathogenesis, progression, and clinical outcome, are the subject of this issue of Drug Discovery Today: Disease Mechanisms. The topics covered in this issue span the spectrum of infectious diseases, from malaria to anthrax. The diseases and syndromes discussed include some of the most important causes of morbidity and mortality in both the developing world (i.e. malaria, tuberculosis, HIV, and sepsis) and developed world (i.e. sepsis). The common feature of these seemingly diverse infectious diseases, caused by diverse microbial pathogens ranging from protozoan pathogens to viruses, is that the host response plays a major determinant in the associated clinical phenotype. In the first manuscript published in this issue, Finney et al. review recent progress in our understanding of pro-inflammatory responses in malaria and propose the hypothesis that malaria syndromes can be classified along a clinical spectrum that culminates in two poles of disease, defined by the host immune response and inflammation. The implications of this conceptualization of malaria pathology on potential immunomodulatory therapeutic approaches to change clinical outcome in severe malaria are discussed. Using cerebral malaria 1740-6765/$ ß 2008 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddmec.2008.02.005
Box 1. Section Editor W. Conrad Liles W. Conrad Liles, MD, PhD received his undergraduate education at Williams College (Williamstown, MA, USA), then entered the National Institutes of Health (NIH)-sponsored MD-PhD program (Medical Scientist Training Program) at the University of Washington and graduated in 1987 with an MD and PhD in pharmacology. Following residency in Internal Medicine at Massachusetts General Hospital from 1987 to 1990, he returned to the University of Washington where he served as Chief Medical Resident in 1991 and as a Fellow in Infectious Diseases from 1992 to 1995. In 1996, he was named to the faculty at the University of Washington as Assistant Professor of Medicine in the Division of Allergy and Infectious Diseases and rose to the rank of Professor of Medicine and Adjunct Professor of Pathology. In March 2006, Dr Liles moved to the University of Toronto to assume the positions of Vice-Chair of Medicine and Director, Division of Infectious Diseases. He was attracted to the University of Toronto by the opportunities to build translational research programs in sepsis, emerging infectious diseases and infectious diseases of public health importance, including malaria. He is the recipient of a Canada Research Chair (Tier 1) in Inflammation and Infectious Diseases and a member of the McLaughlin Centre for Molecular Medicine, the McLaughlin-Rotman Centre for Global Health, and the Toronto General Research Institute. As author of more than 130 peer-reviewed manuscripts and 30 book chapters, Dr Liles maintains an active translational research program in host defense, inflammation, innate immunity, sepsis, immunodeficiency disorders, and immunomodulatory therapy, while serving as a chartered member of the Immunity and Host Defense Study Section of the NIH. In 2004, Dr Liles received the Outstanding Investigator Award from the Western Society for Clinical Investigation (WSCI). He has been elected to Fellowship in the American College of Physicians (ACP) and the Infectious Diseases Society of America (IDSA). 205
Drug Discovery Today: Disease Mechanisms | Infectious diseases
(the most severe and pro-inflammatory form of human malaria) as an example, the following paper by Silver et al. reviews recent evidence that implicates a critical role for endothelial activation and dysregulation in the pathogenesis of end-organ injury and dysfunction in infectious diseases associated with systemic inflammation. The role of apoptosis in the immunopathogenesis of sepsis is the subject of the review by Perl et al. Recent findings implicating programmed cell death of lymphocytes, resulting in a state of sepsis-induced ‘immunoparalysis’, are reviewed, and the potential contribution of apoptosis to sepsis-related morbidity and mortality is examined in detail. The authors also discuss the development of several experimental antiapoptotic therapeutic strategies designed to improve clinical outcome in sepsis – a condition that remains a major public health problem in both the developing and developed worlds. Like malaria, tuberculosis (caused by infection with the mycobacterium, Mycobacterium tuberculosis) remains as one of the most important causes of infection-related morbidity and mortality worldwide. The paper by Arentz and Hawn highlights recent advances in our understanding of the innate immune response to M. tuberculosis and describes recent discoveries in host immunogenetics. Insights gained from these findings may have important ramifications for new vaccine development to prevent tuberculosis and/or development of immunomodulatory strategies to reduce tuberculosis-related morbidity and mortality. The possible role of sexually transmitted infections (STIs), especially genital herpes, in HIV transmission has received a large amount of attention recently, both in the biomedical scientific literature and the lay media. Rebbapragada and Kaul discuss recent findings in this field of investigation and discuss the potential mechanisms by which STIs might render the host more susceptible to HIV infection and/or more likely to transmit HIV to sexual partners.
206
www.drugdiscoverytoday.com
Vol. 4, No. 4 2007
Invasive fungal infections represent an emerging group of infectious diseases. Recent pivotal advances in our understanding of innate immune recognition of pathogenic fungi and initiation of antifungal host defense are reviewed in the paper by Goodridge and Underhill. Anthrax, caused by infection with the Gram-positive bacterium Bacillus anthracis, is recognized as an important potential microbial agent in bioterrorism. The final paper by Mogridge discusses recent advances in our understanding B. anthracis virulence factors, with an emphasis on how these factors allow the organism to evade the host innate immune response and cause progressive, and potentially fatal, disease. For many infectious diseases, effective antimicrobial therapy is already readily available. In many instances, simple pathogen eradication may not be sufficient to significantly reduce infection-related morbidity/mortality and improve clinical outcome. It is clear that the host response plays a critical role in the pathogenesis of infection-related disease, defined by the spectrum and magnitude of end-organ injury and dysfunction. Understanding the complex dynamic of the pathogen–host response interface may lead to the development of innovative immunomodualtory strategies for the management of diverse clinically important infectious diseases. These novel strategies would be employed as adjunctive therapy for the treatment of infectious diseases that are currently associated with poor outcome despite administration of ‘effective’ conventional antimicrobial agents. Further advances in our understanding of the immunpathogenesis, and associated deleterious host defense responses, of specific infectious diseases may lead to breakthroughs in the clinically management of infectious diseases of major public health importance worldwide. In infection, it’s not just the pathogen that counts! With best wishes, W. Conrad Liles
DRUG DISCOVERY
TODAY
Vol. 4, No. 4 2007
Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Charles Lowenstein – The John Hopkins School of Medicine, Baltimore, USA
DISEASE Infectious diseases MECHANISMS
EDITORIAL
The dynamic pathogen–host response interface W. Conrad Liles University Health Network/University of Toronto, 200 Elizabeth Street, 13N-220, Toronto, Ontario M5G 2C4, Canada. Email: [email protected]
Conventional therapeutic strategies for the management of infectious diseases have focused primarily on the use of antimicrobial agents to eradicate the causative microbial pathogen(s). Although invasion by a pathogen per se is a necessary component in the pathogenesis of an infectious disease, it is not the only part of the equation that defines the clinical phenotype that results from host invasion by a microbial pathogen. It has become increasingly clear that the host response to an invading pathogen plays an important role in defining the severity of illness, the clinical manifestation(s), and the clinical outcome in a given infectious disease. Recent advances in our understanding of the dynamic pathogen–host response interface, and its role in disease pathogenesis, progression, and clinical outcome, are the subject of this issue of Drug Discovery Today: Disease Mechanisms. The topics covered in this issue span the spectrum of infectious diseases, from malaria to anthrax. The diseases and syndromes discussed include some of the most important causes of morbidity and mortality in both the developing world (i.e. malaria, tuberculosis, HIV, and sepsis) and developed world (i.e. sepsis). The common feature of these seemingly diverse infectious diseases, caused by diverse microbial pathogens ranging from protozoan pathogens to viruses, is that the host response plays a major determinant in the associated clinical phenotype. In the first manuscript published in this issue, Finney et al. review recent progress in our understanding of pro-inflammatory responses in malaria and propose the hypothesis that malaria syndromes can be classified along a clinical spectrum that culminates in two poles of disease, defined by the host immune response and inflammation. The implications of this conceptualization of malaria pathology on potential immunomodulatory therapeutic approaches to change clinical outcome in severe malaria are discussed. Using cerebral malaria 1740-6765/$ ß 2008 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddmec.2008.02.005
Box 1. Section Editor W. Conrad Liles W. Conrad Liles, MD, PhD received his undergraduate education at Williams College (Williamstown, MA, USA), then entered the National Institutes of Health (NIH)-sponsored MD-PhD program (Medical Scientist Training Program) at the University of Washington and graduated in 1987 with an MD and PhD in pharmacology. Following residency in Internal Medicine at Massachusetts General Hospital from 1987 to 1990, he returned to the University of Washington where he served as Chief Medical Resident in 1991 and as a Fellow in Infectious Diseases from 1992 to 1995. In 1996, he was named to the faculty at the University of Washington as Assistant Professor of Medicine in the Division of Allergy and Infectious Diseases and rose to the rank of Professor of Medicine and Adjunct Professor of Pathology. In March 2006, Dr Liles moved to the University of Toronto to assume the positions of Vice-Chair of Medicine and Director, Division of Infectious Diseases. He was attracted to the University of Toronto by the opportunities to build translational research programs in sepsis, emerging infectious diseases and infectious diseases of public health importance, including malaria. He is the recipient of a Canada Research Chair (Tier 1) in Inflammation and Infectious Diseases and a member of the McLaughlin Centre for Molecular Medicine, the McLaughlin-Rotman Centre for Global Health, and the Toronto General Research Institute. As author of more than 130 peer-reviewed manuscripts and 30 book chapters, Dr Liles maintains an active translational research program in host defense, inflammation, innate immunity, sepsis, immunodeficiency disorders, and immunomodulatory therapy, while serving as a chartered member of the Immunity and Host Defense Study Section of the NIH. In 2004, Dr Liles received the Outstanding Investigator Award from the Western Society for Clinical Investigation (WSCI). He has been elected to Fellowship in the American College of Physicians (ACP) and the Infectious Diseases Society of America (IDSA). 205
Drug Discovery Today: Disease Mechanisms | Infectious diseases
(the most severe and pro-inflammatory form of human malaria) as an example, the following paper by Silver et al. reviews recent evidence that implicates a critical role for endothelial activation and dysregulation in the pathogenesis of end-organ injury and dysfunction in infectious diseases associated with systemic inflammation. The role of apoptosis in the immunopathogenesis of sepsis is the subject of the review by Perl et al. Recent findings implicating programmed cell death of lymphocytes, resulting in a state of sepsis-induced ‘immunoparalysis’, are reviewed, and the potential contribution of apoptosis to sepsis-related morbidity and mortality is examined in detail. The authors also discuss the development of several experimental antiapoptotic therapeutic strategies designed to improve clinical outcome in sepsis – a condition that remains a major public health problem in both the developing and developed worlds. Like malaria, tuberculosis (caused by infection with the mycobacterium, Mycobacterium tuberculosis) remains as one of the most important causes of infection-related morbidity and mortality worldwide. The paper by Arentz and Hawn highlights recent advances in our understanding of the innate immune response to M. tuberculosis and describes recent discoveries in host immunogenetics. Insights gained from these findings may have important ramifications for new vaccine development to prevent tuberculosis and/or development of immunomodulatory strategies to reduce tuberculosis-related morbidity and mortality. The possible role of sexually transmitted infections (STIs), especially genital herpes, in HIV transmission has received a large amount of attention recently, both in the biomedical scientific literature and the lay media. Rebbapragada and Kaul discuss recent findings in this field of investigation and discuss the potential mechanisms by which STIs might render the host more susceptible to HIV infection and/or more likely to transmit HIV to sexual partners.
206
www.drugdiscoverytoday.com
Vol. 4, No. 4 2007
Invasive fungal infections represent an emerging group of infectious diseases. Recent pivotal advances in our understanding of innate immune recognition of pathogenic fungi and initiation of antifungal host defense are reviewed in the paper by Goodridge and Underhill. Anthrax, caused by infection with the Gram-positive bacterium Bacillus anthracis, is recognized as an important potential microbial agent in bioterrorism. The final paper by Mogridge discusses recent advances in our understanding B. anthracis virulence factors, with an emphasis on how these factors allow the organism to evade the host innate immune response and cause progressive, and potentially fatal, disease. For many infectious diseases, effective antimicrobial therapy is already readily available. In many instances, simple pathogen eradication may not be sufficient to significantly reduce infection-related morbidity/mortality and improve clinical outcome. It is clear that the host response plays a critical role in the pathogenesis of infection-related disease, defined by the spectrum and magnitude of end-organ injury and dysfunction. Understanding the complex dynamic of the pathogen–host response interface may lead to the development of innovative immunomodualtory strategies for the management of diverse clinically important infectious diseases. These novel strategies would be employed as adjunctive therapy for the treatment of infectious diseases that are currently associated with poor outcome despite administration of ‘effective’ conventional antimicrobial agents. Further advances in our understanding of the immunpathogenesis, and associated deleterious host defense responses, of specific infectious diseases may lead to breakthroughs in the clinically management of infectious diseases of major public health importance worldwide. In infection, it’s not just the pathogen that counts! With best wishes, W. Conrad Liles