Pulmonary Host Defenses

Steve Nelson, M.D.

Theodore J. Standiford, M.D.

Infection of the respiratory tract continues to be a major health care problem. Indeed, pneumonia is the leading cause of death due to infectious disease, and the incidence of pneumonia is increasing. Several major shifts in the epidemiology of respiratory tract infection have made the treatment of these infections increasingly difficult. The past decade has brought with it the emergence of common respiratory pathogens that have developed new and worrisome patterns of antimicrobial resistance. Although this is particularly true for microbes encountered in the nosocomial setting, multidrug resistance is also being observed in pathogens acquired outside the hospital. Moreover, we are now faced with the emergence of new pathogens causing disease in both immunocompetent and especially immunocompromised patients. Examples include bacteria such as Stenotrophomonas and Acinetobacter, as well as fungi such as Fusarium and non-albicans species of Candida. Changes in the epidemiology of respiratory tract infection have been driven by the widespread use of antibiotics and by a burgeoning population of at-risk patients. These rather ominous trends in the epidemiology of lung infection underscore the need to gain a full understanding of mechanisms of immune host response in the lung, knowledge that can be directed toward the development of immunotherapies to augment protective responses.

The generation of an immune response in the setting of infectious challenge is a complex and dynamic process that is initiated by resident immune cells within the lung airspace and interstitium. Alveolar macrophages represent the first line of defense against inhaled microbes and as such are essential in the initial recognition, containment, and elimination of extracellular bacterial pathogens from the alveolus. The alveolar macrophage also has the ability to amplify innate responses in the lung, primarily by expressing signals that promote the recruitment and activation of neutrophils. The key roles of alveolar macrophages and neutrophils in lung innate immunity have been nicely summarized in articles by Dr. Twigg and by Dr. Wang and colleagues, respectively. The development of acquired immunity against intracellular pathogens is more complex and requires the cooperative efforts of dendritic cells, T and B lymphocytes, natural killer (NK) cells, and macrophages. Dendritic cells initiate the afferent limb of cell-mediated immunity by presenting antigen to regional T cells, which then express type 1 or type 2 cytokines and co-stimulatory molecules necessary to skew adaptive responses and stimulate B cells to produce antibody. The culmination of these events leads to enhanced effector cell functions of phagocytic cells within the lung, including macrophages and neutrophils. Cells and processes involved in the afferent and effector limbs of adaptive immune responses are reviewed in the articles by Herring and colleagues, Masten, and Twigg. The contribution of nonmyeloid lung cells to lung immunity should also be recognized because lung stromal/parenchymal cells, most notably airway and alveolar epithelial cells, can internalize bacteria, present antigen, and elaborate cytokines and other bioactive factors that contribute to lung host defense.

Bacterial infection of the respiratory tract represents a substantial cause of morbidity, mortality, and health care expenditures. Dr. Happel and associates discuss the principal cells and host-derived mediators that participate in the orchestration of lung antibacterial host defense. Moreover, mycobacteria and fungi remain frequent and difficult-to-treat respiratory pathogens, especially in the immunocompromised host. Innate and adaptive immune responses relevant to the pathogenesis of mycobacterial and fungal infection of the lung are reviewed in the articles by Mason and Ali and by Hernández and colleagues, respectively. Although a detailed chapter discussing specific lung antiviral immunity has not been included, the first three articles in this issue provide an overview of innate and acquired host defense mechanisms against respiratory viruses.

Certain acquired conditions impart a substantial toll on lung host defense. Although highly active antiretroviral therapy has clearly limited the carnage of human immunodeficiency virus (HIV) infection on host immune responses, HIV-infected patients continue to be at substantial risk for the development of pulmonary infection. Dr. Shellito discusses the specific defects in lung innate and acquired immunity that are altered by HIV, and the impact of these defects on the spectrum of lung infections in HIV-infected subjects. Another all too common cause of acquired immune deficiency in hospitalized patients is the immunosuppression of critical illness, most notably that mediated by sepsis. Drs. Frevert and Martin discuss mechanisms by which pulmonary infection modulates the systemic inflammatory response and, more importantly, how extrapulmonary causes of sepsis affect lung innate and acquired immune responses.

In the final article, Drs. Standiford and Deng provide a comprehensive review of experimental and currently used approaches to immunoadjuvant therapy for the prevention and treatment of lung infection. Although preventive immunization strategies are of proven efficacy in patients with intact immune systems, their effectiveness in the immunocompromised host is less certain. Conversely, it is likely that active immunotherapy approaches will be of greatest benefit in patients with specific defects in host immune responses. Given the pace of antimicrobial resistance and changes in host immune status, we cannot rely solely on the development of new classes of antibiotics. Rather, we must continue to search for novel approaches to immunotherapy that may serve as important adjuvants in the treatment of patients with severe bacterial, mycobacterial, fungal, and viral infection of the lung.