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Pulmonary and Critical Care Medicine, Department of Medicine, and Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri
Correspondence and requests for reprints should be addressed to M. J. Holtzman, M.D., Washington University School of Medicine, Campus Box 8052, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail: holtzman{at}im.wustl.edu
The 20th annual Transatlantic Airway Conference (TAC) was aimed at the topic of "Airway Responses to Respiratory Viruses" and was developed with several goals in mind. First, we recognized that, despite the fact that respiratory viral infection is perhaps the most common malady of humankind, there is a great deal more to learn about the pathogenesis of acute and chronic airway disease induced by viral infection. In that regard, discovery on this topic is often left to microbiologists, who focus on the pathogenic determinants of respiratory viruses; infectious disease specialists, who focus on similar issues, often in conjunction with epidemiology; or pathologists, who focus on diagnostic and laboratory medicine issues. We therefore aimed to bring this expertise together with experts in lung disease. Second, there is renewed interest in the subject of emergent diseases with the discovery, just in the past two years, of new and devastating respiratory viral infections. Recent examples include the coronavirus associated with severe acute respiratory syndrome (SARS) and a new strain of avian influenza virus, as well as the newly discovered human metapneumovirus, which can also cause serious disease in the immunocompromised host. Third, there is a new appreciation of the possibility that even transient respiratory viral infections can have long-lasting, if not permanent, effects on the host, resulting in chronic airway disease. In that regard, experimental evidence has been provided to demonstrate a permanent switch to an asthmatic bronchitis phenotype in a susceptible genetic background. Thus, infection with common respiratory viruses may trigger disease itself, not just disease exacerbations. Finally, the world has become more receptive to the possibility of vaccine strategies to combat viral infection. Devastating side effects that developed during the initial application of a killed-virus vaccine to combat respiratory syncytial virus (RSV) in the 1960s are slowly being placed in the context of advances in modern molecular biology. It is now possible to more rapidly and perhaps more intelligently engineer recombinant viruses and corresponding antibodies to those viruses and so facilitate studies aimed at therapeutic development. These approaches are now applicable to acute infections, especially in high-risk populations, and to the occurrence of virus-induced chronic airway disease as well.
In view of this background, the TAC was organized to reflect the multidisciplinary approach needed to combat the most common human pathogens. Invited speakers and discussants from North America and Europe (and Australia) had backgrounds in virology, infectious diseases, immunology, genetics, and pathology, as well as in adult and pediatric pulmonary medicine. The articles that accompany this summary were provided by the TAC 2005 speakers and provide detailed examples of these perspectives. This summary will provide at least some rationale and linkage for those viewpoints and a hint of the ongoing discussion and themes in this field.
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Dr. Patrick Holt addressed the relatively undefined role of lung dendritic cells in antiviral host defense. This topic is also critical because of the presumed likelihood that dendritic cells orchestrate both primary and secondary adaptive immunity to inhaled antigens, including respiratory viruses. However, the dendritic cell response to viruses remains poorly defined, so much of the information on this topic is based on what we know about the response to inert protein antigen (i.e., allergen). At present, attention has been focused on the role of type I interferon (IFN) from plasmacytoid dendritic cells as well as the regulation of T-cell (particularly cytotoxic T-cell) responses to viral infection. Major issues remain unresolved, including the role of myeloid dendritic cells, development of the dendritic cell population during infancy, and the contribution of regulatory T cells to the dendritic cell phenotype. Nonetheless, viral infection appears to cause a long-lasting disturbance in dendritic cell homeostasis, and this time course provides a suitable substrate to explain chronic alterations in response to other antigens, including allergens, as a basis for chronic airway disease.
In concert with this possibility, Dr. Openshaw presented evidence that the morbidity associated with RSV infection coincided with the timing of the B-cell and T-cell response to the virus. Indeed, several speakers highlighted the notion that the price for viral clearance was the destruction caused by the adaptive immune system. This destructive and inflammatory aspect of the immune response can be worsened by prior sensitization with inactivated virus, especially at an early age. The possibilities that RSV infection can persist or can cause an atypical Th2 (instead of a typical Th1) response were also presented, but these possibilities remain uncertain as a cause of chronic airway disease in humans.
Dr. Holtzman indicated that it is equally likely that transient viral infection can cause a switch to a disease phenotype based on reprogramming of the adaptive immune system. In that regard, Dr. Woodland reviewed studies on airway memory T cells that may mediate substantial control of the secondary viral infection. His studies concentrated on a mouse model that uses influenza virus as well as a natural mouse pathogen (i.e., mouse parainfluenza virus), which was isolated from humans in Sendai, Japan. In these models (and others), pools of two types of memory T cells—so-called peripheral/effector memory and central memory T cells—are established, which persist for the life of the animal. Indeed, a surprisingly high level of effector memory cells remains quiescent in the airway tissue but can act as first-line defense when activated by a subsequent infection. Effective vaccine strategies may therefore need to target this population as well as the central memory T cells that arrive later at the site of infection.
The same Sendai virus model has been used by the Holtzman lab to define the relationship between acute and chronic responses to viral infection. In particular, we have shown that experimental viral infection can inflict a "hit and run" effect on the adaptive immune system to alter long-term airway behavior toward an asthmatic/bronchitis disease phenotype. My presentation also focused attention on the control of the acute infection by specific components of the innate immune system, especially the role of the airway epithelial IFN system and the macrophage CCL5/CCR5 signaling system. This work raises the possibility that control over the severity of initial infection can prevent long-term disease consequences for the host.
Dr. Braciale and Dr. Tripp presented further studies of the acute response to viral infection. Dr. Braciale returned to the impact of RSV infection on responding T cells and highlighted the capacity of RSV to suppress T-cell effector activity during acute infections. These findings were reminiscent of the immunosuppressive lung environment noted by Dr. Woodland and others. Dr. Braciale also covered the behavior of T cells during the development of vaccine-associated airway disease associated with an exaggerated CD4+ Th2 effector response. As noted by Dr. Openshaw, this phenomenon has been used to model the determinants for severe RSV infection and/or RSV-induced asthma, although there is increasing evidence that a Th2-skewed response may only be relevant to vaccinated individuals and, as noted by Dr. Holtzman, the innate immune system may also influence the development of severe disease. Nonetheless, Dr. Braciale's studies of RSV demonstrated peripheral and central effector memory T–cell behavior similar to that described by Dr. Woodland in response to influenza and Sendai virus. In follow-up, Dr. Tripp presented evidence that RSV can directly influence Th1 and Th2 traffic to the lungs by a variety of means, including the clever strategy of chemokine mimicry.
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SESSION ON THE RESPONSE IN HUMANS |
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This session concluded with Dr. Collins' description of recent work at the National Institutes of Health on the development of an RSV vaccine. This group (and others) has used reverse genetics to generate recombinant virus for use as a live intranasal vaccine against RSV. Current strategies aim to recover a high-titer attenuated virus with high-level immunogenicity as well as to place RSV-protective antigens in an attenuated parainfluenza virus backbone. A reverse genetics approach is also being used to develop vaccines for human parainfluenza virus serotypes 1, 2, and 3, as well as human metapneumovirus. The work highlights the possibility that RSV (and other respiratory viruses) could be eliminated in early childhood or in other high-risk populations, thus finally testing the cause-and-effect relationship between viral infection and asthma in the human population.
In summary, participants in the TAC 2005 brought a diverse and sophisticated set of brainpower and data to bear on the topic of airway responses to viruses. Perspectives generally aimed at two major issues: first, what are the mechanisms that control common respiratory viral infections; and second, whether these generally transient infections also cause long-term airway disease, especially asthma and chronic bronchitis/chronic obstructive pulmonary disease. In both cases, investigators have begun and continue to focus on identifying specific components of the virus as well as the mucosal immune system that trigger an aberrant antiviral response. This type of insight will be necessary to allow for adjusting the host response to improve short- and long-term outcomes after viral infection, a goal that is now reasonably set for accomplishment.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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(Received in original form June 6, 2005; accepted in final form June 7, 2005)
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