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From the Department of Biochemistry and Immunology,* Cell Biology, Pathology, and Internal Medicine, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; the Department of Microbiology, Immunology and Parasitology,¶ Federal University of São Paulo, São Paulo, Brazil; Department of Microbiology and Parasitology,|| Federal University of Rio Grande do Norte, Natal, RN, Brazil; and the Immunobiology Section,** Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
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Abstract |
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in the course of Paracoccidioides brasiliensis (Pb) infection in mice. We found an association between KC and MIP-1
(CCL3) production and neutrophil infiltration in the lungs of Pb-infected mice during the early acute phase of infection. High levels of RANTES/CCL5, MCP-1/CCL2, IP-10/CXCL10, and Mig/CXCL9 simultaneously with mononuclear cell infiltration in the lungs was found. In the absence of IFN- (GKO mice) we observed increased production of KC and MIP-1 and chronic neutrophilia. Moreover, we found a change in the chemokine receptor profiles expressed by wild-type (WT) versus GKO animals. Increased expression of CXCR3 and CCR5, and low levels of CCR3 and CCR4 were observed in the lungs of Pb-infected WT mice, whereas the opposite effect was observed in the lungs of GKO mice. Consistent with these results, infected cells from WT mice preferentially migrated in response to IP-10 (CXCR3 ligand), while those from GKO mice migrated in response to eotaxin/CCL11 (CCR3 ligand). These results suggest that IFN- modulates the expression of chemokines and chemokine receptors as well as the kind of cells that infiltrate the lungs of Pb-infected mice.
The human defense against P. brasiliensis infection depends on effective cellular immune response at the initial infection site, the lungs.4,5
Macrophage activation and granuloma formation, which are thought to protect the host against extrapulmonary dissemination of the infection, characterize the inflammatory response induced by the fungus.3
Activated macrophages, neutrophils, and natural killer (NK) cells are able to kill or inhibit the growth of P. brasiliensis in vitro.6-8
In vivo, macrophages and lymphocytes are generally believed to be the major effector cells involved in controlling the disease4,5,9
through TNF and IFN- production.10-12
The absence of IFN- leads to development of incipient granulomas, which are unable to control dissemination of the fungus.11,13
Although IFN- and TNF play important roles in Pb-infection resistance, the sequence of events responsible for the granuloma formation, including the specific factors involved in the initial recruitment of inflammatory cells to the site of infection, are unknown. TNF may play a role in the pathogenicity of the inflammatory response induced by the fungus,12,14
but the full sequence of events ultimately responsible for the granuloma formation has yet to be elucidated. Recently, there has been much interest in chemokines, inflammation mediators that appear to play a major role in mediating the extravasation and accumulation of specific leukocyte subsets in both acute and chronic inflammatory processes in several diseases.15
Chemokines are small peptides that possess potent chemotactic activity for leukocytes and are produced, following stimulation by cytokines or microbial products, by a variety of cells, including leukocytes, fibroblasts, epithelial, endothelial, and other cell types.15
Chemokine sequences usually have four conserved cystein residues. Based on the position of the first two cystein residues, they can be divided into four subfamilies: CXC (), CC (ß), C (), and CX3C (
). CXC chemokines with a glutamic acid-leucine-arginine (ELR) sequence preceding the CXC sequence are chemoattractant for neutrophils (eg, murine MIP-2 and KC), whereas those lacking this sequence (such as Mig and IP-10) act predominantly on lymphocytes.15-17
The CC chemokines, including MCP-1, MIP-1, MIP-1ß and RANTES, attract monocytes, eosinophils, and lymphocytes with variable selectivity.15,16
The selective attraction of leukocytes in response to chemokines may be determined by the expression of specific chemokine receptors on the cell surface. Some receptors are associated with subsets of T cells.18,19
One receptor for IP-10 and Mig, CXCR3, is highly expressed in Th1, but not Th2 cells. On the other hand, CCR3, a receptor for eotaxin and RANTES, is preferentially expressed in Th2, but not Th1 cells.20
Whereas IFN- can induce Mig and IP-10 and up-regulate RANTES expression,15,19
it can also down-regulate the expression of the neutrophil chemoattractants KC and MIP-2.21
The aims of this study were to analyze the chemokines produced in the lungs of P. brasiliensis-infected WT and GKO mice and the role of IFN- in the control of chemokines, chemokine receptor expression, and cell recruitment in the lungs of P. brasiliensis-infected mice.
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Materials and Methods |
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Breeding pairs of mice with targeted disruption of IFN- (GKO mice) were obtained from Jackson Laboratories (Bar Harbor, ME). The breeding stock backcrossed on C57Bl/6 was obtained and the genotype of GKO mice determined by PCR as previously described.22
Male C57Bl/6 WT and GKO mice, 6 to 8 weeks old, were bred and maintained in microisolator cages in the SPF animal housing facility of the Department of Biochemistry and Immunology, University of São Paulo.
Fungus and Mice Infection
Yeast cells of virulent Pb 18 strain of P. brasiliensis were cultured at 37°C in Fava-Netto’s medium for 7 days and washed three times in phosphate-buffered saline (PBS), pH 7.2. Viability of yeast cells was determined as previously described.22 The animals were infected intravenously with 1 x 106 viable yeast cells in 100 µl of PBS.
Preparation of Lung Leukocytes
Lungs of mice were excised, minced, and enzymatically digested for 30 minutes. using 15 ml/lung mass of digestion buffer (RPMI, 5% fetal calf serum, antibiotics, 1 mg/ml collagenase, and 30 µg/ml DNase). The cell suspension and undigested fragments were further dispersed by use of 10-ml syringe and nytex screen (Sigma Co., St. Louis, MO). Total cell suspension was then pelleted, resuspended in RPMI-1640 with 5% of fetal bovine serum (Sigma) and counted in a hemacytometer chamber in the presence of trypan blue. For differential counting of Rosenfeld stained samples, the suspensions were cytospun onto slides for determination of subsets of isolated leukocytes (neutrophils, macrophages and lymphocytes). At the time point studied no mortality was observed in the WT mice, while 50% and 75% of GKO mice had succumbed on days 7 and 14 after infection, respectively.
Flow Cytometry
Leukocytes obtained from lung digestion were incubated in the presence of fluorescein isothiocyanate-conjugated anti-Mac-1 and anti-CD4 antibodies and phycoerythrin-conjugated anti-GR-1, anti-CD8, and anti-CD19 antibodies (BD Biosciences PharMingen, San Diego, CA) for 30 minutes at 4°C in the dark. The cells were then washed and resuspended in PBS, 1% formaldehyde. Data acquisition was performed using a FACSorter (BD Biosciences, San Jose, CA).
Organ Homogenates and Chemokine Quantification
Lungs harvested at designated time points were homogenized in 1 ml of complete protease inhibitor cocktail buffer (Boeringher, Mannheim, Germany) using a tissue homogenizer (Omni International, Gainesville, VA). The samples were centrifuged at 5000 x g for 10 minutes. Supernatants were collected and stocked at -20°C for ELISA. The levels of MCP-1, MIP-1, RANTES, and KC were measured using commercial kits (Quantikine, R&D Systems, Minneapolis, MN), in accordance with manufacturer’s instructions.
Total RNA Extraction and cDNA Preparation by Reverse Transcription
For reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, lungs were harvested on different days after Pb18 infection and total RNA extracted using 1 ml of Trizol reagent according to manufacturer’s recommendation (Life Technologies, Inc., Gaithersburg, MD). Each RNA sample was resuspended in water at 0.5 µg/µl. The cDNA was synthesized from 2 µl of sample using Superscript II reverse transcriptase according to the supplier’s specifications (Life Technologies, Inc.).
Detection of mRNA for the Chemokine Receptors
For the chemokine receptors CCR2, CCR3, CCR4, CCR5, and CXCR3, for the chemokines MCP-1, MIP-1, RANTES, MDC, Mig, IP-10, KC, and for ß-actin, mRNAs were analyzed by RT-PCR. PCRs were performed using Taq polymerase (Life Technologies, Inc.) in a PTC-100 thermocycler (MJ Research, Watertown, MA). The pairs of primer sequences used were as follows: For CCR2, 5'-CTA-CGA-TGA-TGG-TGA-GCC-TTG-T-3' (sense) and 5'-ACC-AAT-GTG-ATA-GAG-CCC-TGT-G-3' (antisense). For CCR3, 5'-CAA-CTT-GGC-AAT-TTC-TGA-CCT-G-3' (sense) and 5'-TTT-CCA-GCT-GTC-TTC-TTC-ACC-T-3' (antisense). For CCR4, 5'-CTT-GCA-CCA-AGG-AAG-GTA-TCA-A-3' (sense) and 5'-TGG-CCA-GGT-ATC-TGT-CTA-TGC-T-3 (antisense). For CCR5, 5'-CTC-TTC-CTG-CTC-ACA-CTA-CCA-T-3' (sense) and 5'-TGT-GTA-GAA-AAT-GAG-GAC-TGC-A-3' (antisense). For CXCR3, 5'-ATC-TAC-CTA-TCA-GCC-AAC-TAC-G-3' (sense) and 5'-ACA-TCC-ACA-TTT-TCT-CTC-TGA-A-3' (antisense). For MCP-1, 5'-CTA AGG ACC ACT TGC CAT GGA-3' (sense) and 5'-CTG GTA GCT CTC TGC CCT GTT T-3' (antisense). For MIP-1, C CGG AAG ATT CCA CGC CAA TT-3' (sense) and 5'-T GAG GAA CGT GTC CTG AAG-3' (antisense). For RANTES, 5'-C CCA CGT CAA GCA GTA TTT C-3' (sense) and 5'-CTG GTT TCT TGG GTT TGC TGT G-3' (antisense). For MDC, 5'GTG GCT CTC GTC CTT CTT GC-3' (sense) and 5'-GGA CAG TTT ATG GAG TAG CTT-3' (antisense). For IP-10, 5'-TCG CAC CTC CAC ATA GCT TAC AG-3' (sense) and 5'-TCA GCA GAG ATG TCT GAA TC-3' (antisense). For Mig, 5'-GAT CAA ACC TGC CTA GAT CC-3' (sense) and 5'-GGC TGT GTA GAA CAC AGA GT-3' (antisense). For KC, 5'-CC TTG ACC CTG AAG CTC CCT TGG TTC-3' (sense) and 5'-CGT GCG TGT TGA CCA TAC AAT ATG-3' (antisense). For ß-actin, 5'-TGG-AAT-CCT-GTG-GCA-TCC-ATG-AAA-C-3' (sense) and 5'-TAA-AAG-GCA-GCT-CAG-TAA-CAG-TCC-G-3' (antisense). Reaction conditions were 27 cycles of 1 minute at 94°C, 1 minute at 54°C, and 2 minutes at 72°C, with a final extension step of 7 minutes at 72°C. For each set of primers, a negative sample (water) was run in parallel. PCR products were separated by acrylamide gel electrophoresis and stained with silver nitrate.
Immunofluorescence
Cryostat sections (10 µm) of lung tissues harvested at day 14 of Pb18 infection were air-dried for 1 hour and fixed with acetone before immunostaining with rabbit anti-mouse IP-10, Mig, CCR3, CCR5, or normal rabbit IgG (control). Sections were then incubated with goat anti-rabbit IgG and labeled with a 1:100 dilution of Alexa Fluor 488 (green fluorescence; Molecular Probes, Eugene, OR) for 20 minutes at room temperature (RT). For anti-Thy1.2 detection, the slides were incubated with biotin-conjugated anti-mouse CD90.2, followed by incubation with Alexa Fluor 546-conjugated streptavidin (red fluorescence; Molecular Probes). The slides were counterstained with 4', 6-diamidine-2-phenylindole dihydrochloride (DAPI, blue fluorescence; Molecular Probes) and analyzed under a fluorescent microscope (Leica, Wetzlar, Germany). The images were processed using SlideBook software (Intelligent Imaging Innovations, Inc., Denver, CO).
Chemotaxis Assay
Chemotaxis assays were performed using the Transwell system (Costar, Cambridge, MA). Lung leukocytes (1 x 107 cells/ml) from WT and GKO mice with 14 days of infection were resuspended in assay medium (RPMI-1640 plus 0.5% bovine serum albumin). Either IP-10 (100 ng/ml), eotaxin (100 ng/ml), and fMLP (10-8M) diluted in serum-free RPMI-1640 medium, or assay medium alone, was added to the lower chamber to a final volume of 600 µl. The filter inserts were placed in the wells and 100 µl of either infected, naïve, or GKO lung leukocytes were added to the top chamber. The plates were incubated for 3 hours in a 5% CO2 incubator at 37°C and cells that transmigrated to the lower chamber were harvested and counted in a hemacytometer chamber.
Statistical Analysis
The results are expressed as the mean ± SE (SD). Statistical analysis was performed using analysis of variance followed by the parametric Tukey-Kramer test (INSTAT software; GraphPad, San Diego, CA). P values of 
0.05 indicated statistical significance.
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Results |
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. We have previously shown that absence of IFN- results in a disorganized granulomatous reaction, dissemination of the fungus throughout the lung and high susceptibility to P. brasiliensis infection.11
To understand the mechanisms involved in the granulomatous inflammatory reaction, we first characterized the cell infiltrate in the lungs of WT and GKO mice on different days after Pb18 infection. We found that the absence of IFN- did not result in decreased cell infiltration, suggesting normal leukocyte migration to the lungs of infected mice (Figure 1A)
. However, cytological analysis revealed that the leukocyte subsets recruited to the lungs differed significantly. Over the first 3 days of infection, the number of pulmonary macrophages increased dramatically in WT mice, whereas the lungs of GKO mice presented no such increase (Figure 1B)
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. The high frequency of neutrophils in the lungs of infected GKO mice was also observed using fluorescence-activated cell sorting analysis of bronchoalveolar lavage (BAL) cells. On day 14 after infection, approximately 40% of leukocytes from lungs of GKO mice were neutrophils (GR-1+Mac-1+), while neutrophils accounted for less than 5% of lung cells in infected WT mice (Figure 2)
. The frequency of eosinophils did not exceed 0.1% in WT and 0.2% in GKO mice on day 14 of infection. The number of lymphocytes increased similarly in both WT and GKO mice until day 7 following Pb18 infection, but on day 14 it was higher in the lungs of WT than in GKO mice (Figure 1D)
. However, in the lungs of infected WT and GKO mice alike, we observed no differences in the populations of the lymphocytes T CD4+ and T CD8+, or in B (CD19+) cells (Table 1)
. Therefore, in pulmonary P. brasiliensis infection, lack of IFN- resulted in defective macrophage recruitment and chronic neutrophilia development.
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Modulates CC and CXC Chemokine Production in the Lungs of P. brasiliensis-Infected Mice
Since the composition of the inflammatory-reaction cell infiltrate occurring in P. brasiliensis was very different in infected WT mice than in GKO mice, we investigated the pattern of chemokine expression in the lungs. We found a similar expression of RANTES mRNA in the lungs of both infected WT and GKO mice. Moreover, the expression of transcripts for MCP-1 and MIP-1 increased on days 3 and 7 of infection in WT mice, while their expression in GKO mice was higher only at the end of infection (days 7 and 14). We also concluded that the expression of KC, a neutrophil chemoattractant, was regulated by IFN-, since KC expression was more intense in the lungs of infected GKO mice (Figure 3)
. We quantified the CC chemokine production in the lung homogenates after 7 and 14 days of infection. We found that MCP-1, MIP-1, RANTES and KC were produced in the lungs of both infected WT and GKO mice (Figure 4)
. It is significant that on day 7 after infection the levels of RANTES (Figure 4A)
and MCP-1 (Figure 4B)
, but not MIP-1 (Figure 4C)
, were higher in the lungs of WT mice than in GKO mice. On day 14, levels of MCP-1 remained unchanged, but were higher than those found in uninfected animals. Finally, the concentration of MIP-1 in the lungs was similar in both WT and GKO mice on day 7 of infection, but was higher in GKO mice than in WT mice on day 14 (Figure 4C)
. On days 7 and 14 after infection, in accordance with RT-PCR, the levels of KC in the lungs were significantly higher in GKO mice than in WT mice (Figure 4D)
.
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We addressed the question of whether IFN- modulates the profile of chemokine receptor expression in the lungs of WT and GKO mice after Pb18 infection. To answer this question, we examined the expression of mRNA for CCR2, CCR3, CCR4, CCR5, and CXCR3 following P. brasiliensis infection. We found that while the expression of CCR2 increased in infected WT mice, it was reduced in the lungs of infected GKO mice. Increased expression of CCR5 and CXCR3, with concomitant lower expression of CCR3 and CCR4, was observed in the lungs of WT compared with GKO mice over the course of infection. Conversely, we observed lower expression of CCR5 and CXCR3 and higher expression of CCR3 and CCR4 in the lungs of infected GKO mice (Figure 5)
. In accordance with this data, we observed higher expression of IP-10 and Mig in the lungs of WT than in GKO mice. Conversely, expression of MDC was detected only in the lungs of infected GKO mice (Figure 5)
. By immunofluorescent staining, we found that production of Mig and IP-10 in the lungs was higher in infected WT than in GKO mice, and the expression of CCR3 in the lungs was higher in infected GKO than in WT mice. Dissimilarly, the expression of CCR5 was comparable in all infected mice (Figure 6)
. Similar results were observed in the spleens of infected mice.
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To determine whether CXCR3 and CCR3 found in the leukocytes from Pb18-infected mice were biologically functional, we performed chemotaxis assay in vitro using IP-10 (CXCR3 ligand) and eotaxin (CCR3 ligand) as chemoattractants. We found that leukocytes from lungs of infected WT mice migrate in response to IP-10 in the chemotaxis assay. On the other hand, cells from infected GKO mice preferentially migrated in response to eotaxin (Figure 7)
. In contrast, leukocytes from non-infected mice failed to migrate to either chemokine. There was significant migration of leukocytes from WT and GKO mice, infected or not, when fMLP was used as chemoattractant stimulus. Together, these data show that there is an IFN--dependent regulation of the leukocytes that infiltrate the lungs of P. brasiliensis-infected mice.
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Discussion |
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, RANTES, Mig, and IP-10 as well as increased expression of CCR5 and CXCR3 in the lungs of infected mice. In contrast to Pb-infected wild-type mice, infected GKO mice do not develop organized granulomas,11
produce lower levels of the mononuclear cell chemoattractants RANTES, Mig, and IP-10, and produce higher levels of the neutrophil chemoattractants KC and MIP-1. We hypothesize that release of chemokines and expression of their receptors participate in the cascade of inflammatory events that result in the accumulation of leukocytes, formation of granuloma, and control of fungal dissemination.
The heavy infiltration of neutrophils in the lung in the early acute phase (day 3) of infection with P. brasiliensis in WT mice (Figure 1C)
correlated with the release of KC and MIP-1 (Figure 3, C and D)
, known to be neutrophil chemoattractants.23,24
Consistent with this finding is the impaired recruitment of neutrophils to the lungs of Aspergillus fumigatus-infected mice that do not express CXCR2 (KC receptor).25
Similarly, the blockage of MIP-1 with monoclonal antibody resulted in decreased influx of neutrophils to the lungs of mice infected with Cryptococcus neoformans.26
Therefore, we suggest that KC and MIP-1 detected in the lungs of P. brasiliensis-infected mice are involved in the mechanisms that lead to accumulation of neutrophils.
It is possible that soon after infection with P. brasiliensis, the fungus interacts with alveolar macrophages inducing the release of chemokines, which attract neutrophils, the first cells to arrive at the inflammatory site.27
In fact, low molecular weight peptides in the supernatants of peritoneal macrophages incubated with live P. brasiliensis are able to attract neutrophils to the peritoneal cavity of mice.28
Neutrophil chemoattractants are also produced by macrophages infected with Candida albicans,29
Listeria monocytogenes,30
and Trypanosoma cruzi.21
The mechanism by which the antigens of P. brasiliensis lead to expression of chemokines and chemokine receptors in the lungs of infected mice or in cultured splenocytes (data not shown) is unknown. One possibility is that it may involve activation of transcription factor NF-
B, since it is well established that NF-B plays a central role in the regulation of a variety of genes involved in host innate immunity, including the genes for various chemokines.31,32
Moreover, although NK-kB had not been analyzed in the infection with P. brasiliensis, it is an important regulator of cytokine production in infections by Mycobacterium tuberculosis,33
Listeria monocytogenes,34
and by the fungus Aspergillus fumigatus.35
As the disease progresses, production of IFN- may modulate expression of chemokine, leading to secretion of chemoattractants for mononuclear cells, which migrate to the site of infection soon after the neutrophils. In fact, high levels of IFN-, a cytokine known to be a regulator of KC,21,30
were detected in the lungs of mice on day 14 of infection with P. brasiliensis.13
Therefore, it is possible that in the absence of IFN- the production of KC is not inhibited, resulting in the neutrophilia observed in the chronic phase of Pb infection, in the absence of granuloma formation and of fungicidal activity, resulting in dissemination of fungus and lower resistance to the infection. On the contrary, in the lungs of WT mice, following the early migration of neutrophil (3 days), there is a change in the profile of chemokine production that may lead to the mononuclear leukocyte infiltration (Figure 1)
, efficient granuloma formation, T cell activation, and nitric oxide (NO) production.11
The increase of macrophages and lymphocytes on day 7 of infection with P. brasiliensis in WT mice may be due to the increased levels of MCP-1 and RANTES, which play important roles in the granulomatous diseases that lead to mononuclear cell attraction.36,37
The roles of these chemokines as monocyte and lymphocyte chemoattractants have been confirmed in models of sarcoidosis,38
delay-type hypersensitivity reactions,39
and C. neoformans-infected mice.40
The resistance to P. brasiliensis infection is dependent on the Th1 cytokines, including IFN-11
and IL-12.41
After interaction with the fungus or its antigens, macrophages and dendritic cells produce IL-12 (data not shown) that can act on NK cells and that are always present in the lungs of infected animals,42
resulting in the production of IFN- seen in the infected mice.13
The IL-12 knockout mice, in which this pathway of IFN- production is defective, are very susceptible to the infections and there is no organized granuloma formation, similar to what is observed in GKO mice. In the lungs of infected WT mice, IFN- appears to enhance the production of Mig and IP-10 (Figure 6)
, resulting in preferential migration of CXCR3+ lymphocytes (Th1) to the inflammatory focus. The Th1 lymphocytes in the tissue could amplify the production of IFN-, activation of macrophages, production of NO and fungicidal capacity, thereby limiting fungal growth and dissemination, while stimulating the formation of compact granulomas. Conversely, in the absence of IFN-, a decreased expression of RANTES, Mig, and IP-10, and increased expression of eotaxin (data not shown) and MDC (Figure 3)
can lead to CCR3+ and CCR4+ cell migration, preferentially expressed by Th2 lymphocytes.19,20,43
Although the absence of IFN- does not alter the recruitment of CD4+ or CD8+ T cells (Table 1)
, the change of chemokine production in GKO mice results in a different pattern of leukocyte infiltration in the lungs after infection with P. brasiliensis. In fact, the lung leukocytes harvested from GKO and WT mice migrated preferentially in response to eotaxin and IP-10, respectively. In support of our data, it has been shown that in the absence of IFN- there is decreased expression of IP-10 during infection with Cryptosporidium parvum,44
in acute lung inflammation,45
and in experimental autoimmune encephalomyelitis.46
Another possible hypothesis to explain the reasons for a distinct pattern of chemokines observed in the lungs of infected GKO mice could be a quantitative or qualitative difference in the antigens produced by P. brasiliensis. However, a different pattern of expression of chemokines (Mig and MDC) and chemokine receptors (CCR3 and CCR4) was observed (Figures 3 and 5)
as soon as 6 and 12 hours after the infection, when the numbers of fungi are similar in WT and GKO mice, suggesting that the differences observed are due to the absence of IFN-. However, after 4 days of infection, when the fungal burden is higher in GKO mice than in WT mice,11
we cannot definitively exclude that the differential expression of chemokine and chemokine receptors is due to the high levels of antigen. Also, although we do not know if the same phenomenon indeed occurs with P. brasiliensis, it is possible that the antigens produced by the fungus in the absence of a Th1 response in GKO mice are qualitatively different, as suggested to occur in infection with Mycobacterium tuberculosis.47
Together, these results contribute to the understanding of the genesis and regulation of inflammatory reactions in P. brasiliensis-infected mice. Understanding the migration of cell populations associated with resistance to infection may constitute a new strategy for manipulation of immune responses and therefore contribute to the search for a cure for P. brasiliensis infection.
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Footnotes |
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Supported by a grant from Fundação de Ampara à Pesquisa do Estado de São Paulo (FAPESP) and by fellowships from Coordenação de Pessoal de Nível Superior (to J.T.S.), FAPESP (to A.P.C.) and Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (to J.S.S., L.R.T., and M.A.R).
Accepted for publication April 23, 2003.
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for enhanced killing of Paracoccidioides brasiliensis or Blastomyces dermatidis. J Immunol 1988, 140:2786-2789[Abstract]
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 A. Rial, D. Lens, L. Betancor, H. Benkiel, J. S. Silva, and J. A. Chabalgoity Intranasal Immunization with a Colloid-Formulated Bacterial Extract Induces an Acute Inflammatory Response in the Lungs and Elicits Specific Immune Responses Infect. Immun., May 1, 2004; 72(5): 2679 - 2688. [Abstract] [Full Text] [PDF]
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