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Infection and Immunity, December 2005, p. 8402-8406, Vol. 73, No. 12
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.12.8402-8406.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Intrapulmonary, Adenovirus-Mediated Overexpression of KARAP/DAP12 Enhances Fungal Clearance during Invasive Aspergillosis

Kristin J. Carpenter,1 Karen F. Buckland,1 Zhou Xing,2 and Cory M. Hogaboam1*

Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109,1 Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada L8N 3Z52

Received 13 May 2005/ Returned for modification 10 June 2005/ Accepted 12 July 2005


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ABSTRACT
 
Herein, we report that the intrapulmonary delivery of an adenovirus vector expressing KARAP/DAP12, an adaptor protein expressed in granulocytes and mononuclear cells, enhanced fungal clearance during experimental invasive pulmonary aspergillosis in neutropenic mice.


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TEXT
 
Invasive growth of Aspergillus fumigatus in the lung and other organs is clinically recognized as invasive aspergillosis (23). Invasive aspergillosis is a leading cause of nosocomial pneumonia and mortality in patients receiving immunosuppressive drug regimens for transplant or other medical conditions (12), and providing antifungal therapy to susceptible patients remains challenging and of limited effectiveness in most cases (25). Several defects in the immune response in the lung and other organs presumably accounts for the inability of the innate and acquired immune response to handle the presence of this ubiquitous mold. Decreases in neutrophil counts and/ or function are recognized as major factors in the ability of A. fumigatus to germinate and grow in immunocompromised patients (22), but more recently it has been shown that defects in natural killer (NK) (28), Th1 (9), and dendritic (10, 11) cell recruitment and/or activation may also account for Aspergillus infection in the immunocompromised host.

KARAP/DAP12 also known as TYRO-BP (31) is an immunoreceptor tyrosine-based activation motif-bearing adaptor protein that was first found in NK cells (13) and is now known to be expressed by a variety of other myeloid cells, including neutrophils, monocytes, macrophages, and dendritic cells (1, 6, 8, 33). Mice rendered deficient in KARAP/DAP12 by gene targeting exhibit NK defects that prevent adequate murine cytomegalovirus clearance (36) and fail to develop autoimmunity due to defective antigen presenting (4). Paradoxically, KARAP/DAP12–/– mice also show deficits in osteoclast and oligodendrocyte maturation, and hence, these mice exhibit osteopetrosis and demyelinization (29, 32). KARAP/DAP12-transgenic mice exhibit severe lymphopenia, neutrophilia, and lung infiltration by multinucleated macrophages (24). In myeloid cells, KARAP/DAP12 associates directly with a number of receptors in the C-type lectin and immunoglobulin (Ig) superfamilies (2). In the Ig superfamily, this adapter protein mediates the intracellular actions of the triggering receptors expressed on myeloid cells (TREM) (14).

Most notable and best described among the three TREM family members is TREM-1 (15), considering the major deleterious role that this receptor plays in innate immune responses during experimental sepsis syndrome (7) and its increased expression during human endotoxemia (17, 21), bacterial or fungal pneumonia (16, 34), and acute pancreatitis (37). Pertinent to the present study, TREM-1 expression has been observed in tissue infected by A. fumigatus (7, 15), and a fungal stimulus induces TREM-1 expression on neutrophils and monocytes but not dendritic cells (6). Although TREM-1 engagement increased the production of inflammatory cytokines and chemokines from neutrophils and promoted the differentiation of primary monocytes into immature dendritic cells (DCs), its activation does not appear to enhance antimicrobial (i.e., Mycobacterium tuberculosis) activity or phagocytosis (5). KARAP/DAP12 and molecules associated with DAP12 are differentially regulated during host responses to mycobacterial infection (3), and both KARAP/DAP12 and TREM-1 appear to be involved in the development of granulomatous responses by the liver to zymosan A (30).

Because of the major role of KARAP/DAP12 in innate immune activation of a variety of immune cells involved in the antifungal response and the association of TREM-1 with Aspergillus, we examined the roles of both effector molecules in a well-described model of invasive aspergillosis (27). We hypothesized that the increased expression of KARAP/DAP12 would protect mice from the ravages of invasive aspergillosis, whereas the blockade of TREM-1 with TREM-1 Ig would render mice more susceptible to this fungal pathogen. To address this hypothesis, we employed a well-described model of invasive pulmonary aspergillosis (27). This model was initiated via the intraperitoneal injection of 100 µg of RBG-8C5 (a rat monoclonal antibody that targets Ly-6G or Gr-1). Using this antibody approach, circulating neutrophil counts were reduced to <50 cells/µl at day 1 after antibody administration (27). Immediately following the RGB-8C5 monoclonal antibody injection, groups of 15 mice received 4.0 x 108 PFU of a control adenovirus vector (Ad70), an adenovirus encoding a fusion molecule containing the extracellular domain of mouse TREM-1 and the Fc portion of human IgG1 (AdTREM-1 Ig), or an adenovirus containing FLAG-KARAP/DAP12 (AdDAP12) by intranasal inoculation. The construction of these two viral vectors is described in detail elsewhere (30), and both constructs have been used in vivo to explore TREM-1 function through the elaboration of TREM-1 Ig (AdTREM-1 Ig) or enhance KARAP/DAP12 (AdDAP12) expression, respectively (30). Twenty-four hours later, all groups of mice were appropriately anesthetized with ketamine and xylazine. The trachea was exposed in each anesthetized mouse using aseptic surgical techniques and 30 µl of sterile 0.1% Tween 80 (i.e., vehicle) containing 0 or 1.0 x 107 A. fumigatus conidia (ATCC 13073). In the present study, we focused on day 2 after the intratracheal conidial challenge because maximal fungal growth is typically present at this time and mouse mortality follows shortly thereafter in this invasive aspergillosis model (27). Semiquantitative reverse transcriptase PCR analysis was used to confirm that the AdDAP12 vector increased whole-lung KARAP/DAP12 gene expression, whereas the AdTREM-1 Ig vector increased whole-lung TREM-1 gene expression (data not shown).

The consequences of KARAP/DAP12 and TREM-1 Ig transgene delivery during invasive pulmonary aspergillosis were first examined in the bronchoalveolar lavage (BAL) samples, and key differences were noted among these groups (Fig. 1). Specifically, in contrast to BAL samples from saline-challenged mice (Fig. 1A), markedly greater numbers of epithelial cells (denoted by purple staining) were detected in BAL samples from the Ad70-treated group at day 2 after conidial challenge (Fig. 1B). Interestingly, hyphae and conidiophores were readily detected in BAL washings from the Ad70-treated group (Fig. 1B). In contrast, far fewer activated mononuclear cells were apparent in the BAL samples obtained from the AdTREM-1 Ig (Fig. 1C) group than with the Ad70 and AdDAP12 (Fig. 1D) groups at day 2 after conidial challenge. Further, hyphal elements (but no conidiophores) were prominent in BAL washings from the AdTREM-1 Ig group (Fig. 1C). Hyphae were rarely detected in BAL washings from the AdDAP12-treated group, and the cellularity of the BAL samples from this group was greater than that observed in the AdTREM-1 Ig group (Fig. 1D versus 1C). Together these data showed that the adenovirus-mediated delivery of KARAP/DAP12 to neutropenic mice dramatically lowered the presence of sloughed epithelial cells and fungal elements (i.e., hyphae) in the BAL. Further, AdTREM-1 Ig transgene delivery reduced the presence of sloughed epithelial cells, but greater amounts of fungal material were present in the BAL of this group relative to the AdDAP12 group.



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  		FIG. 1. BAL samples from control (i.e., saline challenge alone) (A), Ad70-, AdTREM-1 Ig-, and AdDAP12-treated groups in neutropenic CBA/J mice. The adenovirus-treated groups received 1 x 107 conidia 2 days previously. Hyphae and conidiophores (large arrow) were observed in BAL samples from the Ad70 group (B). Hyphae (arrowheads) were also prominent in BAL samples from the AdTREM-1 Ig-treated group (C), while very few hyphae were detected in BAL samples from the AdDAP12-treated group (D).

The consequences of KARAP/DAP12 and TREM-1 Ig transgene delivery were next examined in the whole-lung environment. Histological examination of whole-lung samples from the adenovirus-treated groups revealed less evidence of inflammation in the Ad70- and AdTREM-1 Ig-treated groups (Fig. 2A and B, respectively). In contrast, evidence of greater inflammation was apparent for the AdDAP12-treated mice relative to the other adenovirus groups (Fig. 2C). As shown in Fig. 2, fungal hyphae were prominent in pulmonary tissues from the Ad70- and AdTREM-1 Ig-treated groups (panels D and E, respectively). Conversely, conidia were present in whole-lung sections from the AdDAP-12 group, but no evidence of fungal growth was apparent (Fig. 2F). Another histological feature observed in the lungs of AdDAP-12-treated mice was evidence of lung hemorrhage, which did not encompass the entire lung, nor was it present in areas devoid of fungal material (Fig. 2F). In confirmation of this histological finding, the chitin levels for AdDAP12-treated mice were significantly lower than chitin levels detected in mice that received the Ad70 vector (Fig. 2, bottom panel). Surprisingly, whole-lung chitin levels were also significantly lower in the AdTREM-1 Ig group than in the Ad70 group but approximately twofold higher than chitin levels in the AdDAP12 group (Fig. 2, bottom panel). The significantly decreased chitin levels in the AdTREM-1 Ig group relative to those in the Ad70 group may reflect the induction of endogenous TREM-1 in the lungs of this group. Thus, these data showed that the overexpression of KARAP/DAP12 dramatically prevented the growth of Aspergillus fumigatus in the lungs of neutropenic CBA/J mice.



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  		FIG. 2. Top: representative photomicrographs of hematoxylin and eosin-stained (panels A to C) and Gomori methenamine silver-stained whole-lung sections from groups treated with Ad70 (A and D), AdTREM-1 Ig (B and E), or AdDAP12 (panels C and F) at day 2 after conidial challenge in neutropenic CBA/J mice. Marked interstitial inflammation was observed in all three groups of mice. However, A. fumigatus conidia and hyphae (stained black) were prominent in whole-lung sections from the Ad70 and AdTREM-1 Ig groups, but only intact conidia were apparent in the AdDAP12 group. Original magnification, x200. Bottom: whole-lung chitin levels in Ad70-, AdTREM-1 Ig-, and AdDAP12-treated groups at day 2 after conidial challenge in neutropenic CBA/J mice. Analysis of variance and a Student-Newman-Keuls multiple comparisons test was used to detect statistical differences between the adenovirus groups. ***, P ≤ 0.001 compared with results for the Ad70-treated group.

Alterations in pulmonary cytokine and/or chemokine levels may be one explanation for the increased fungal clearance from the lungs of neutropenic mice given the AdDAP12 or AdTREM-1 Ig vector. To explore this possibility, enzyme-linked immunosorbent assay (ELISA) analysis of interleukin 12 (IL-12) and tumor necrosis factor alpha (TNF-{alpha}), two major cytokine effectors in the antifungal response (23), was performed on whole-lung homogenates and bronchoalveolar lavage (BAL) samples. ELISA analysis of whole-lung samples for the presence of IL-12 and TNF-{alpha} revealed that these cytokines were significantly lower in whole samples from the AdTREM-1 Ig-treated group than with those from the Ad70-treated group (Fig. 3). In BAL samples, all three adenovirus-treated groups challenged with conidia exhibited similar BAL levels of IL-12 and TNF-{alpha}. Together these data suggested that alterations in IL-12 and TNF-{alpha} did not appear to contribute to the altered antifungal responses observed in the AdDAP12 and AdTREM-1 Ig groups.



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  		FIG. 3. ELISA analysis of whole-lung and BAL IL-12, TNF-{alpha}, CCL17, and CCL22 levels in Ad70-, AdTREM-1 Ig-, and AdDAP12-treated groups at day 2 after conidial challenge in neutropenic CBA/J mice. Groups of mice that received saline alone or conidia alone are also shown. Analysis of variance and a Student-Newman-Keuls multiple comparisons test were used to detect statistical differences between the adenovirus groups. *, P ≤ 0.05; **, P ≤ 0.01, compared with results for the indicated groups of whole-lung or BAL samples.

A number of CC and CXC chemokines relevant to pulmonary antifungal responses were also examined by ELISA, including CCL1, CCL2, CCL3, CCL5, CCL17, CCL22, and CXCL2. Only CCL17 and CCL22 levels were significantly altered in the context of the adenovirus treatments employed in this study. Marked and significant differences in CCL17 and CCL22 levels were apparent in BAL but not whole-lung samples among the adenovirus groups (Fig. 3). Specifically, CCL17 levels in BAL samples were significantly greater in the AdTREM-1 Ig group than in the other adenovirus-treated groups. CCL17 has been shown previously to contribute to the alternative activation of macrophages (20), and recently we showed that this CC chemokine inhibits pulmonary IL-12 and TNF-{alpha} generation in the lung (19). The increased CCL17 levels detected in the AdTREM-1 Ig group may have accounted for the significantly decreased levels of IL-12 and TNF-{alpha} observed in this group. BAL CCL22 levels were significantly greater in the AdTREM-1 Ig- and AdDAP12-treated groups than in the Ad70-treated group (Fig. 3). Accordingly, the increased BAL levels of CCL22 in the AdTREM-1 Ig and AdDAP12 groups may have accounted for the decreased fungal burden observed in these groups compared with the Ad70 group. CCL22 is a macrophage-derived chemokine, and this CC chemokine has been shown to be a potent activator of mononuclear cells during innate immune responses against bacteria (18, 26). Thus, alterations in CCL17 and CCL22 may have exerted a prominent effect on the antifungal response during invasive aspergillosis. Further studies are certainly warranted to elucidate more precisely the interaction between KARAP/DAP-12, TREM-1, CCL17, and CCL22 during invasive pulmonary aspergillosis.

Concluding remarks. The immunocompromised patient is very susceptible to intrapulmonary and/or systemic infection with A. fumigatus. Several strategies have been devised or suggested that may prove effective in combating this fungus in these patients (35). These strategies involve altering innate immune responses by macrophages, NK cells, or dendritic cells through specific immunotherapies and/or vaccines (35). The results from the present study suggest that the innate pulmonary immune response can be enhanced via transient adenovirus-mediated KARAP/DAP12 transgene expression in neutropenic mice, which are normally susceptible to A. fumigatus. While we hypothesized that the blockade of TREM-1 with the AdTREM-1 Ig transgene would impair the antifungal response, the data from the present study suggest we did not achieve this goal, presumably due to the increased induction of TREM-1 in this group. Further studies are necessary in order to elucidate the precise role of TREM-1 in the context of antifungal responses and whether TREM-1 and KARAP/DAP12 work in concert to achieve the clearance of Aspergillus from the immunocompromised host.

While the prolonged augmentation of KARAP/DAP12 in the context of immune therapy may have negative consequences given the findings from the KARAP/DAP12 transgenic mouse (24), the transient increase in KARAP/DAP12 (ideally employing a nonviral delivery system) may promote appropriate increases in immune activation that facilitate the clearance of A. fumigatus from the lungs of susceptible patients. Further mechanistic studies are required in order to determine the direct effects of KARAP/DAP12 on effector immune cells, such as macrophages and dendritic cells, during antifungal responses.


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FOOTNOTES
 
* Corresponding author. Mailing address: Department of Pathology, University of Michigan Medical School, Rm. 5216B, Med. Sci. I, 1301 Catherine Road, Ann Arbor, MI 48109-0602. Phone: (734) 936-7854. Fax: (734) 936-7996. E-mail: hogaboam{at}med.umich.edu. Back

Editor: T. R. Kozel


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Infection and Immunity, December 2005, p. 8402-8406, Vol. 73, No. 12
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.12.8402-8406.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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