© 2002 American Thoracic Society
Investigating Invasive AspergillosisDepartments of Internal Medicine and Microbiology/Immunology University of Michigan Ann Arbor, Michigan
In this issue of AJRCCM (pp. 1263–1268), Mehrad and colleagues (1) address the understudied issue of host defense against Aspergillus fumigatus using a very powerful technology to study localized versus systemic defenses. The authors examine host defense in the lungs using transgenic mice that overexpress the CXC chemokine KC in the lungs via the Clara cell–specific promoter CC10. Moreover, the transgene is inducible and is expressed only after treatment of the mice with a tetracycline analogue. Thus, the mice develop normally, and high-level KC expression in the lungs occurs only after doxycycline exposure. The advantages of this system are twofold. First, the transgene is expressed in a tissue-limited distribution (the lungs). Second, the immune system develops under the normal cytokine regulatory balances rather than in the presence of a constitutive high level of a particular cytokine. Using this system, Mehrad and colleagues (1) demonstrate that increased neutrophil influx into the lungs enhances clearance of Aspergillus conidia and increased expression of KC increases macrophage influx, production of interferon- Transgenic mice are extremely useful pools to dissect host defenses. The systemic overexpression of a gene, however, has yielded some unexpected consequences. For example, rather than increasing macrophage influx, transgenic expression of the CC chemokine monocyte chemoattractant protein-1 actually blocks the ability of these mice to recruit macrophages via monocyte chemoattractant protein-1 to a site of infection (2). Subsequent studies using tissue-specific transgenic monocyte chemoattractant protein-1 expression (3, 4) confirmed that monocyte chemoattractant protein-1 is a macrophage chemotactic factor in vivo that requires an expression gradient (3). Studies on both innate and adaptive immunity have demonstrated the importance of the response at the site of infection and underscore the importance of tissue-specific transgenic systems. Previous studies by Tsai and colleagues using constitutive CC10-KC transgenic mice have shown that expression of KC by itself will induce neutrophil influx into the lungs (5). Thus, the studies by Mehrad and colleagues (1) have the advantage that baseline neutrophil numbers were normal (low) before the infection. Future studies could address the importance of the timing of the neutrophil influx to assess the role of neutrophils in anticonidia versus antihyphal host defense. Another lung-specific transgenic system uses the surfactant protein C promoter (6, 7). The field of tissue-specific and inducible promoter transgenic technology is beginning to expand with reports on a number of other tissue-specific (brain, thymus, muscle, T cell, etc.) promoters being engineered onto transgenes. The advances in medical sciences that have increased the success of hematopoietic and solid-organ transplantation have brought with them a dark side: immunosuppression. One of the most common and devastating effects of immunodeficiency is fungal infection (8). The major lessons that we have learned from fungal infections in immunodeficient patients are as follows: host defense relies on the interaction of multiple systems within innate and adaptive immunity, and established fungal infections are difficult to eradicate. In hindsight, these observation should not be surprising because in the plant world, fungi are the plague/Ebola/smallpox of plants. Fungi have evolved efficient mechanisms to adapt to changes in the environment via a battery of virulence factors. These include phase transformation and production of soluble immunomodulatory factors, including cell wall components and fatty acid metabolites related to prostaglandins and leukotrienes (9). Fortunately, immunocompetent humans have a system of host defenses that effectively contain fungal infections. Unfortunately, in immunodeficient states, reconstitution of one or two lines of host defense does not usually reconstitute the network. In addition, host defense against infection is likely to be different from host defense against established infection because of the difference in the microbiology of the pathogen in those two settings. Although it is true that innate and adaptive immunity are required for antifungal defense, much remains to be determined on the precise mechanisms of the host defense network. Invasive aspergillosis is a common infection in immunocompromised patients, notably bone marrow transplant patients (8, 10, 11). Unfortunately, there is still a high degree of mortality in patients with invasive aspergillosis. Neutrophils are clearly the first line of defense against Aspergillus conidia; however, it is a simplistic underestimation to view host defense against Aspergillus as solely neutrophil mediated. Granulocyte colony-stimulating factor treatment of patients decreases the incidence of an early Aspergillus infection but does not eliminate the susceptibility of bone marrow transplant patients to Aspergillus infection (8, 10, 11). Thus, what other components of the immune system are required, and how do we study them? What role do neutrophils play in the host defense network? Do neutrophil reconstitution protocols alter other components of host defense? A number of reports indicate that this may be true. Future studies need to address the role of other leukocytes such as macrophages, dendritic cells, natural killer cells, T cells, and B cells. The future application of the tissue-specific inducible transgenic technology demonstrated by Mehrad and colleagues (1) will yield significant insight into lung-specific immune mechanisms and provide insight into the network of host defenses that underlie immunity to fungi. REFERENCES
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, and interleukin-12 production. These studies confirm the importance of localized neutrophil recruitment in host defense against Aspergillus but also suggest that KC may initiate a broader host defense network. 
