The Expression of Mannose Receptors in Skin Fibroblast and Their Involvement in Leishmania (L.) amazonensis Invasion
Lab. Ultra-estrutura Celular (RCH,MdNSLM,SC-R) and Lab. Biologia Celular (MdNCS,MBM), Departamento de Ultra-estrutura e Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brasil
Correspondence to: Dr. Maria de Nazaré Correia Soeiro, Lab. Biologia Celular, Departamento de Ultra-estrutura e Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil 4365, Manguinhos, Rio de Janeiro, RJ, 21045-900, Brasil. E-mail: soeiro{at}ioc.fiocruz.br
![]() |
Summary |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key Words: skin fibroblasts mannose receptors Leishmania (L.) amazonensis transmission electron microscopy
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
It is known that the parasites invade phagocytic cells of the vertebrate host with the involvement of different ligand-receptor systems, including the mannose receptors (MR) (Blackwell et al. 1985; Palatnik-de-Sousa et al. 1993
; de Almeida et al. 2003
). Inside the phagolysosomal compartment, the promastigotes differentiate to amastigotes and multiply until the lyses of infected cell, releasing large amounts of amastigotes, which can be taken up by other host cells. The life cycle is completed by the bite of the female phlebotomine sand fly when it takes the infecting blood meal containing amastigotes that again differentiate into promastigotes in the insect midgut (Grimaldi Jr. et al. 1983
; Mauël 1990
; Peters et al. 1995
; Sacks and Kamhawi 2001
).
The macrophage mannose receptors are C-type lectin, transmembrane glycoproteins (175 kD), which belong to a multilectin receptor protein family displaying eight carbohydrate recognition domains (CRDs) (Wileman et al. 1986; Taylor et al. 1990
; East and Isacke 2002
). The receptor is expressed on the surface of several cellular types and mediates the binding and internalization of mannosylated glycoproteins (Stahl et al. 1976
; Lane et al. 1998
; Leteux et al. 2000
; Linehan et al. 2000
; Lee et al. 2002
) as well as participates in the endocytosis of different pathogens enriched with mannose residues at their surface such as Trypanosoma cruzi (Soeiro et al. 1999
), Mycobacterium tuberculosis (Noorman et al. 1997
), Candida albicans (Stahl 1990
) and Leishmania donovani (Wilson and Pearson 1988
).
Although most analysis concerning Leishmania invasion has been done using macrophages as host cells due to their high in vivo infection rates, some studies clearly show the infection of other cellular types by the parasites of the Leishmania genus in both in vivo (Zuckerman 1953) as well as in vitro assays (Belle 1958
; Lewis 1974
), including the infection of cultured human skin fibroblasts (Chang 1978
; Schwartzman and Pearson 1985
). Since fibroblasts are localized in close proximity to the parasite inoculation area, they can represent a potential cell target for Leishmania early infection and spreading as already observed by others in hamster (Zuckerman 1953
) and canine infections (Hervas Rodriguez 1996
). Our present aim is to characterize the mannose-receptor expression in primary cultures of skin fibroblasts, examining its possible role in Leishmania (L.) amazonensis infection.
![]() |
Materials and Methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Parasites
Leishmania (L.) amazonensis (MHOM/BR/77/LTB0016) isolated from a human case of cutaneous leishmaniasis was used in all experiments and was kindly supplied by Dr. Gabriel Grimaldi, Jr. (Department of Immunology, Fundação Oswaldo Cruz, RJ, Brasil). Amastigote forms were isolated from the lesions of heavily infected animals and maintained in NNN blood agar medium (Novy, McNeal and Nicolle) with an overlay of modified LIT medium (liver infusion-Trypticase) at 25C (Jaffe et al. 1984). The promastigotes obtained on the 7th day of cultivation were harvested by centrifugation at 1500 x g for 10 min at 4C and washed twice in 0.1 M phosphate-buffered saline (PBS) immediately before the experiments.
Primary Cultures of Skin Fibroblasts
Primary cultures of skin fibroblasts (SF) were obtained by the dissociation of mouse skin embryos. The tissues were dissected, minced and incubated for 30 min at 37C in a dissociation solution containing 0.03% collagenase diluted in Dulbecco's modified Eagle medium (DMEM). After three dissociation steps, the enzyme digestion was interrupted by adding 10% fetal bovine serum, the suspension was centrifuged and resuspended in DMEM supplemented with 5% fetal bovine serum, 1 mM L-glutamine plus 1000 U ml1 penicillin and 50 g ml1 streptomycin. Skin fibroblast cells (105 cells/well and 106 cells/plate) were seeded in 0.02% gelatin-treated 24-well culture plates (for light microscopy assays) or in 35-mm culture plates (for electron microscopy studies), respectively. The cultures were incubated at 37C in a 5% CO2 atmosphere and the medium replaced every 2 days. All procedures were carried out in accordance with the guidelines established by the FIOCRUZ Committee of Ethics for the Use of Animals, resolution 242/99.
ParasiteHost Cell Infection Assays
Promastigote forms of Leishmania (L.) amazonensis were resuspended in PBS to achieve a ratio of 10:1 parasite/host cell. After 2 hr of interaction at 34C, the SF were rinsed with PBS to remove extracellular parasites, fixed or maintained for 24 hr/34C. In some assays, the infection was followed for 7 days. For light microscopy assays, the SF were fixed with Bouin's solution (75 ml 1.2% aqueous picric acid solution, 25 ml formalin (40% formaldehyde) and 5 ml glacial acetic acid) and stained with Giemsa. The percentage of skin fibroblasts containing associated parasites (parasite association rates) was determined by examining at least 400 randomly selected cells at x63 magnification under a Zeiss Axioplan microscope (Carl Zeiss Inc., Thornwood, NJ). The randomization permits the evaluation of the whole coverslips avoiding non-representative analysis of the cell culture infection. All the assays described here were run three to five times at least in duplicate, as described (Soeiro et al. 1999).
Transmission Electron Microscopy Analysis of Mannose Receptors in SF
The expression of mannose receptors in skin fibroblasts was analyzed by two different ultrastructural approaches using the HRP as mannosylated probe (Soeiro et al. 1999). HRP was coupled to 15 or 10 nm colloidal gold particles (HRP-Au) according to Goodman et al. (1979)
. In the first approach, SF were incubated for 30 min/4C with HRP-Au in the presence of 5 mM calcium chloride, washed to remove unbound ligands and then chased for 24 h/37C. After the incubations, the cultures were fixed for 1 hr/4C with 2.5% glutaraldehyde (GA) in 0.1 M sodium cacodylate buffer and postfixed with 1% osmium tetroxide diluted in the same buffer. The monolayer was then peeled off from the plastic dish in the washing buffer, harvested and centrifuged. The pellet was dehydrated in a graded series of acetone and embedded in Poly/bed 812. In the second approach, the samples were fixed for 30 min/4C with 4% PFA 0.01% GA diluted in 0.1 M sodium cacodylate buffer containing 3.5% sucrose. The monolayer was then peeled off from the plastic dish in the washing buffer, harvested and centrifuged. The pellet was dehydrated in a graded series of methanol and embedded in Lowicryl resin. Sections were hydrated in PBS buffer and incubated for 30 min in 50 mM ammonium chloride. After washing with 0.1 M PBS 3% BSA, the sections were incubated for 10 min in a blocking solution containing 0.1 M PBS 3% BSA 0.2% Tween 20 and then incubated for 1 hr at room temperature with 50 µg/ml HRP-Au. In both protocols, the grids were stained with uranyl acetate and lead citrate and finally observed at Zeiss EM 10C Transmission Electron Microscope. We performed competition assays by incubating the samples with HRP-Au in the presence of 250 mM D-mannose.
The Endocytotic Activity of Mannose Receptors in SF
The ability of skin fibroblasts to incorporate large mannosylated particles was further investigated by using zymosan A particles (Zy) as probe. For light microscopy studies, uninfected cultures were formerly incubated for 10 min24 hr at 37C with 106 Zy particles, washed and fixed with Bouin's solution followed by staining with Giemsa. The analysis of skin fibroblasts with internalized Zy particles was performed using a Zeiss photomicroscope (Zeiss Inc., Thornwood, NY). Fluorescent studies were conducted by staining Zy for 30 min/37C with low doses of Concanavalin-A-TRITC (5 µg/ml), exhaustively washed and then incubated for 10 min and 24 hr/37C with the skin fibroblasts. After the incubations, the SF were washed to remove unbound Con-A-treated Zy and fixed for 20 min/4C with 2% PFA diluted in 0.1 M PBS. The DNA was stained with 10 µg/ml 4,6-diamidino-2-phenylindole (DAPI) to enable the visualization of SF nuclei, the coverslips were mounted over the sections with 2.5% 1.4-diazabicyclo-(2.2.2)-octane (DABCO) and examined immediately using a Zeiss photomicroscope equipped with epifluorescence. All the assays described here were run two to four times at least in duplicate.
D-Mannose Competition Assays
To ascertain the participation of mannose receptors during the Leishmania invasion, SF were incubated for 30 min with increasing doses of D-mannose (0500 mM) and then allowed to interact for 2 h/34C with the promastigotes (parasite:host cell ratio of 10:1) diluted in serum-free medium. After interaction, the SF were washed with PBS, fixed with Bouin's solution, stained with Giemsa and the parasite association rates measured as described above.
Statistical Analysis
Student's t-test was used to determine whether differences between means in the D-mannose competition assays were significant. A p value <0.05 was considered significant. The data are representative of three to five experiments run in duplicate.
Analysis of Mannose Receptors by Neoglycoprotein Binding
To analyze the expression of mannose receptors through fluorescent approaches, skin fibroblasts were allowed to interact for 2, 24, 48 and 72 hr/34C with L. (L.) amazonensis promastigote forms (parasite:host cell ratio of 10:1). After washing, both uninfected and Leishmania-infected SF were immediately fixed for 20 min/4C in 2% PFA. The cultures were then incubated for 1 hr/37C with 50 µg/ml -L-fucopyranosyl-albumin-FITC (fuc-BSA-FITC), a tracer for mannose receptors (Stahl et al. 1976
; Avrameas et al. 1996
; Lane et al. 1998
). After washing with PBS, the uninfected and Leishmania-infected cultures were further incubated with DAPI for visualization of SF and parasites nuclei and kinetoplast of the parasites, mounted with DABCO and examined as described above. In all experiments, optimal lectin or neoglycoprotein concentrations were determined by preliminary titration assays. To assure labeling specificity, some assays were performed with the addition of 250 mM D-mannose.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Although macrophages are considered the major host cells for Leishmania infection in vivo, the infection of other phagocytes has been reported both in vivo as well as in vitro, including neutrophils (Laskay et al. 2003) and dendritic cells (Colmenares et al. 2004
; Prina et al. 2004
). Regarding the infection of non-professional phagocytic cells, Belle (1958)
described the infection of epithelial cells by L. (L.) donovani in vitro and later Lewis (1974)
demonstrated the ability of L. (L.) mexicana parasites to invade MDCK epithelial cells. Likewise, the infection of fibroblasts by Leishmania species has been reported both in in vivo (Zuckerman 1953
; Hervas Rodriguez 1996
; Tarantino et al. 2001
) and in vitro studies (Chang 1978
; Schwartzman and Pearson 1985
; Côrte-Real et al. 1995
).
The MR are expressed on the surface of several cellular types, including mononuclear phagocytes, especially tissue macrophages (Shepherd et al. 1982; Basu et al. 1991
), retina epithelial cells (Lane et al. 1998
), dendritic and Langerhans cells (Noorman et al. 1997
), tracheal smooth muscle cells, kidney mesangial cells and Kaposi sarcoma cells (reviewed in Leteux et al. 2000
), fibroblasts (Straus 1983
) and cardiomyocytes (Soeiro et al. 1999
). It has been implicated in clearing glycoconjugates ending in mannose, L-fucose, glucose or N-acetyl-O-glucosamine residues (Lane et al. 1998
; Linehan et al. 2000
). MR also plays a role in host defense due to its ability to recognize the patterns of sugars usually present at the plasma membrane and cell walls of a wide range of infectious agents, such as bacteria, fungi, yeast, and protozoa, mediating their internalization and providing a possible link between innate and adaptive immunity (Linehan et al. 2000
; Gordon 2002
). Alternatively, the MR could also cooperate in inflammation processes by removing potential harmful enzymes found at the extracellular space and limiting tissue injury (Lane et al. 1998
). A similar soluble receptor, the mannose-binding protein (MBP) (also named mannose-binding lectin) was isolated from the plasma of rabbits, rodents and human sera (reviewed in Ezekowitz and Stahl 1988
). The soluble receptor can contribute to the clearance of lysosomal enzymes, which have escaped into the blood (Sastry and Ezekowitz 1993
). It also neutralizes the invading microorganisms by binding to their cell-surface carbohydrates (mannose and N-acetyl-glucosamine residues) and activating MBP-associated serine proteases-1, -2 and -3 (Ezekowitz and Stahl 1988
; Sastry and Ezekowitz 1993
; Chen and Wallis 2004
). Regarding the MR and Leishmania, it is known that promastigotes of L. (L.) donovani utilize mannose receptors during their invasion into macrophages (Blackwell 1985
; Palatnik-de-Sousa et al. 1993
; Chakraborty et al. 1998
), down-regulating after infection (Basu et al. 1991
). Furthermore, MBP binds to the surface of L. (L.) major and L. (L.) mexicana promastigotes possibly through the surface molecule lipophosphoglycan (LPG) (Green et al. 1994
). The authors suggested that MBP could have the potential to opsonize the major developmental stages of Leishmania parasites, and provide a possible mechanism for the antibody-independent activation of complement on the parasite surface.
In the present work, we characterized the expression of MR in primary cultures of skin fibroblasts evaluating its role during the invasion by L. (L.) amazonensis promastigotes. Our data revealed that uninfected skin fibroblasts express mannosyl binding sites because 1. they bound a neoglycoprotein that specifically bind to mannose receptors (Avrameas et al. 1996); 2. they are able to internalize zymosan A, which are mannosylated particles frequently used in phagocytic assays (Speert and Silverstein 1985
; Lombard et al. 1994
); and 3. ultrastructural assays evidenced the association of HRP-Au to the SF surface, another mannosylated ligand commonly used for MR analysis (Shepherd et al. 1994
; Marzolo et al. 1999
; Soeiro et al. 2002
). The addition of D-mannose efficiently blocked the binding of both HRP-Au and
-L-fucopyranosyl-albumin-FITC demonstrating that the ligands specifically bound to the MR. Our results corroborated previous cytochemical assays that demonstrated the presence of mannosyl binding sites in fibroblasts localized in liver (Straus 1981
) and uterus (Straus 1983
). The competence of live SF to internalized zymosan A and horseradish peroxidase, in addition to validating the MR activity, also revealed the phagocytic capacity of the SF as previously reported for other non-professional phagocytes (Soeiro et al. 2002
). Actually, fibroblasts are denominated facultative phagocytes being able to internalize a variety of particles and pathogens both in vitro and in vivo (Rabinovitch 1970
; Chang 1978
; Dedet et al. 1983
; Schwartzman and Pearson 1985
; Côrte-Real et al. 1995
), although without the high phagocytic capacity of cells from the mononuclear phagocytic system (Van Furth 1970
). Zymosan A is mainly composed of mannan and ß-(1-3)-glucan (Di Carlo and Fiore 1957
). Since data reported in the literature showed that it can be ingested by mannose receptors (Speert and Silverstein 1985
) via CR3 leading to O2- production (Le Cabec et al. 2000
) and by ß-glucan receptors (Reis e Sousa et al. 1993
), we cannot discard the possibility that zymosan A internalization by fibroblasts may also involve ß-glucan receptors, which have already been reported in murine macrophages and in other white blood cells (Goldman 1988
; Brown and Gordon 2001
). These receptors may be expressed in the fibroblasts and also contribute with the mannose receptors for zymosan A uptake in a similar manner to what was found for Langerhans cells (Reis e Sousa et al. 1993
).
After characterizing the MR in skin fibroblasts, we next evaluated its role during the invasion of L. (L.) amazonensis promastigotes. Competition experiments conducted by the addition of increasing concentrations of D-mannose impaired the parasite association, showing a clear dose- dependent inhibition. These data suggest the participation of MR in the interaction of promastigotes and SF, in a similar way to the described data employing macrophages as host cells (Wilson and Pearson 1986, 1988
; Chakraborty et al. 1998
). However, as the interaction medium was depleted from serum sources, we cannot discard the possibility that other receptor-ligand systems cooperated as well during the invasion of SF by promastigotes, mostly in the presence of serum opsonins in analogy to the well-known invasion of promastigotes into macrophages.
Finally, as 1. the modulation of MR has been described in host cells infected with various microorganisms, including Bacillus Calmette-Guérin (Ezekowitz and Gordon 1982), L. (L.) donovani (Basu et al. 1991
), Candida albicans (Shepherd et al. 1997
; Gelderman et al. 1998
), Pneumocystis carinii (Ezekowitz et al. 1991
), Trypanosoma cruzi (Soeiro et al. 1999
), and 2. our present data pointed to the participation of MR during the parasite invasion, and our next aim was to analyze the expression of MR in Leishmania-infected SF. Our results showed a gradual increase in the expression of MR in infected SF, reaching maximal expression after 48 hr of infection, with the labeling localized mostly at the cellular surface as well as intracellularly. The reversion of the up-regulation was evidenced after 72 hr of infection concomitantly to the presence of non-viable parasites and cellular debris visualized and confirmed by transmission electron microscopy, which was suggestive of abortive infection of L. (L.) amazonensis in SF. The mechanisms that govern the MR modulation in Leishmania-infected skin fibroblasts were not presently characterized, but some possibilities can be envisaged including alterations in the receptor degradation levels and/or transportation of recycled receptors (and/or newly synthesized) for the cellular surface and/or reduced MR synthesis mediated by the parasite and/or hostinfected-cell factors. Our results demonstrated that the modulation in the expression of host mannose receptors induced by Leishmania invasion was reverted concomitantly to the loss of parasite viability, suggesting that the presence of viable parasites is required for the alteration maintenance noted in the MR.
The modulation of MR has been reported during other parasitic infections (Ezekowitz and Gordon 1982; Basu et al. 1991
; Shepherd et al. 1997
; Gelderman et al. 1998
; Soeiro et al. 1999
). Then the modulation of MR during the invasion of SF by Leishmania promastigotes could be expected by analogy with MR modulation by Bacillus Calmette-Guérin (Ezekowitz and Gordon, 1982
), L. (L.) donovani (Basu et al. 1991
), Candida albicans (Shepherd et al. 1997
; Gelderman et al. 1998
) and T. cruzi (Soeiro et al. 1999
). At the present time, assays are underway to better investigate the factors involved in this up-regulation.
In summary, our present results pointed to the role of mannose receptor during the interaction of L. (L.) amazonensis promastigotes and skin fibroblasts in a similar way to the already reported system occurring during the invasion of macrophages by Leishmania promastigotes.
![]() |
Acknowledgments |
---|
![]() |
Footnotes |
---|
Received for publication May 13, 2004; accepted August 13, 2004
![]() |
Literature Cited |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Avrameas A, McIlroy D, Hosmalin A, Autran B, Debre P, Monsigny Roche AC, Midoux P (1996) Expression of a mannose-fucose membrane lectin on human dendritic cells. Eur J Immunol 26(2):394400[Medline]
Bañuls AL, Hide M, Tibayrenc M (1999) Molecular epidemiology and evolutionary genetics of Leishmania parasites. Int J Parasitol 29(8):11371147[CrossRef][Medline]
Basu N, Sett R, Das PK (1991) Down regulation of mannose receptors on macrophages after infection with Leishmania donovani. Biochem J 277:451456[Medline]
Belle EA (1958) Cultivation of Leishmania donovani in human amnion epithelial cell tissue cultures: a preliminary report. Canad M A J 79:726728
Blackwell JM, Ezekowitz RA, Roberts MB, Channon JY, Seed RB, Gordon S (1985) Macrophage complement and lectin-like receptors bind Leishmania in the absence of serum. J Exp Med 162:324331[Abstract]
Blackwell JM (1985) Role of macrophage complement and lectin-like receptors in binding Leishmania parasites to host macrophages. Immunology Letters 11:227232[CrossRef][Medline]
Brown GD, Gordon S (2001) Immune recognition. A new receptor for beta-glucans. Nature 413:3637[CrossRef][Medline]
Butcher BA, Sklar LA, Seamer LC, Glew RH (1992) Heparin enhances the interaction of infective Leishmania donovani promastigotes with mouse peritoneal macrophages. A fluorescence flow cytometric analysis. J Immunol 148(9):28792886
Chakraborty RS, Chakraborty P, Basu MK (1998) Macrophage mannosyl fucosyl receptor: its role in invasion of virulent and avirulent L. donovani promastigotes. Biosci Rep 18:129142[CrossRef][Medline]
Chang KP (1978) Leishmania infection of human skin fibroblasts in vitro: absence of phagolysosomal fusion after induced phagocytosis of promastigotes, and their intracellular transformation. Am J Trop Med Hyg 27(6):10841096[Medline]
Chen CB, Wallis R (2004) Two mechanisms for mannose-binding protein modulation of the activity of its associated serine proteases. J Biol Chem [Epub ahead of print]
Colmenares M, Corbi AL, Turco SJ, Rivas L (2004) The dendritic cell receptor DC-SIGN discriminates among species and life cycle forms of Leishmania. J Immunol 172(2):11861190
Côrte-Real S, Santos CB, Meirelles MNL (1995) Differential expression of the plasma membrane Mg2+ ATPase and Ca2+ ATPase activity during adhesion and interiorization of Leishmania amazonensis in fibroblasts in vitro. J Submicrosc Cytol Pathol 27(3):359366[Medline]
Cunningham AC (2002) Parasitic adaptative mechanisms in infection by Leishmania. Exp Mol Pathol 72:132141[CrossRef][Medline]
Da Silva RP, Hall BF, Joiner KA, Sacks DL (1989) CR1, the C3b receptor, mediates binding of infective Leishmania major metacyclic promastigotes to human macrophages. J Immunol 143(2):617622
de Almeida MC, Vilhena V, Barral A, Barral-Netto M (2003) Leishmanial infection: analysis of its first steps. A review. Mem Inst Oswaldo Cruz 98(7):861870[Medline]
Dedet JP, Ryter A, Vogt E, Hosli P, Da Silva LP (1983) Uptake and killing of Leishmania mexicana amazonensis amastigotes by human skin fibroblasts. Ann Trop Med Parasit 77(1):3544[Medline]
Di Carlo FJ, Fiore JV (1957) On the composition of zymosan. Science 127:756757
East L, Isacke CM (2002) The mannose receptor family. Biochim Biophys Acta 1572:364386[Medline]
Ezekowitz RA, Gordon S (1982) Down-regulation of mannosyl receptor-mediated endocytosis and antigen F4/80 in Bacillus Calmette-Guérin-activated mouse macrophages. J Exp Med 155:16231637
Ezekowitz RA, Stahl PD (1988) The structure and function of vertebrate mannose lectin-like proteins. J Cell Sci 9:121133
Ezekowitz RA, Williams DJ, Koziel H, Armstrong MY, Warner A, Richards FF, Rose RM (1991) Uptake of Pneumocytis carinii mediated by the macrophage mannose receptor. Nature 351:155158[CrossRef][Medline]
Gelderman MP, Leikowitz DL, Leikowitz SS, Bollen A, Moouilevsky N (1998) Exposure of macrophages to an enzimatically inactive macrophage mannose receptor ligand augments killing of Candida albicans. Proc Soc Exp Biol Med 217:8188[Abstract]
Goldman R (1988) Characteristics of the beta-glucan receptor of murine macrophages. Exp Cell Res 174:481490[CrossRef][Medline]
Goodman SL, Hodges GM, Trejdosiewicz LK, Livingston DC (1979) Colloidal gold probesa further evaluation. Scan Electron Microsc 3:619628[Medline]
Gordon S (2002) Pattern recognition receptors: doubling up for the innate immune response. Cell 111(7):927930[Medline]
Green PJ, Feize T, Stoll MS, Thiel S, Prescott A, McConville MJ (1994) Recognition of the major cell surface glycoconjugates of Leishmania parasites by the human serum mannan-binding protein. Mol Biochem Parasitol 66:319328[CrossRef][Medline]
Grimaldi G Jr, Côrte-Real S, Pinho RT, Moriearty PL (1983) Interactions between Leishmania mexicana mexicana promastigotes and amastigotes and murine peritoneal macrophages in vitro. Mem Inst Oswaldo Cruz 78(2):135146[Medline]
Guy RA, Belosevic M (1993) Comparison of receptors required for entry of Leishmania major amastigotes into macrophages. Infect Immun 61(4):15531558[Abstract]
Handman E, Bullen DVR (2002) Interaction of Leishmania with the host macrophage. Trends in Parasitol 18(8):332334[CrossRef]
Hervas Rodriguez J (1996) Leishmania infection of canine skin fibroblasts in vivo. Vet Pathol 33(4):469473[Abstract]
Jaffe CL, Grimaldi G Jr, McMahon-Pratt, D (1984) The cultivation and cloning of Leishmania. In: Morel CM, ed. Genes and Antigens of Parasites. A Laboratory Manual, Rio de Janeiro, Fundação Oswaldo Cruz, 121135
Kedzierski L, Montgomery J, Bullen D, Curtis J, Gardiner E, Jimenez-Ruiz A, Handman E (2004) A leucine-rich repeat motif of Leishmania parasite surface antigen 2 binds to macrophages through the complement receptor 3. J Immunol 172(8):49024906
Kelleher M, Moody SF, Mirabile P, Osborn AH, Bacic A, Handman E (1995) Lipophosphoglycan blocks attachment of Leishmania major amastigotes to macrophages. Infect Immun 63(1):4350[Abstract]
Lane KB, Ega B, Vick S, Abdolrasulnia R, Shepherd VL (1998) Characterization of rat alveolar macrophage cell line that expresses a functional mannose receptor. J Leukoc Biol 64:345350[Abstract]
Laskay T, Van Zandbergen G, Solbach W (2003) Neutrophil granulocytes Trojan horses for Leishmania major and other intracellular microbes? Trends Microbiol 11(5):210214[Medline]
Le Cabec V, Cols C, Maridonneau-Parini I (2000) Nonopsonic phagocytosis of zymosan and Mycobacterium kansasii by CR3 (CD11b/CD18) involves distinct molecular determinants and is or is not coupled with NADPH oxidase activation. Infect Immun 68:47364745
Lee SJ, Evers S, Roeder D, Parlow AF, Risteli J, Risteli L, Lee YC, Feizi T, Langen H, Nussenzweig MC (2002) Mannose receptor-mediated regulation of serum glycoprotein homeostasis. Science 295:18981901
Leteux C, Chai W, Loveless RW, Yuen CT, Uhlin-Hansen L, Combarnous Y, Jankovic M, Maric SC, Misulovin Z, Nussenzweig MC, Feizi T (2000) The cysteine-rich domain of the macrophage mannose receptor is a multispecific lectin that recognizes chondroitin sulfates A and B and sulfated oligosaccharides of blood group Lewisa and Lewisx types in addition to the sulfated N-glycans of lutropin. J Exp Med 191(7):11171126
Lewis DH (1974) Infection of tissue culture of low phagocytic ability by Leishmania mexicana mexicana. Ann Trop Med Parasit 68(3):327336[Medline]
Linehan SA, Martínez-Pomares L, Gordon S (2000) Macrophages lectins in host defense. Microb Infect 2:279288[CrossRef][Medline]
Lombard Y, Giaimis J, Makaya-Kumba M, Fomteneau P, Poindron P (1994) A new method for studying the binding and ingestion of zymosan particles by macrophages. J Immunol Methods 174(12):155165[CrossRef][Medline]
Marzolo MP, von Bernhsrdi R, Inestrosa NC (1999) Mannose receptor is present in a functional state in rat microglial cells. J Neurosci Res 58(3):387395[CrossRef][Medline]
Mauël J (1990) Macrophage-parasite interactions in Leishmania infections. J Leukoc Biol 47:187193[Abstract]
Mosser DM, Vlassara H, Edelson PJ, Cerami A (1987) Leishmania promastigotes are recognized by the macrophage receptor for advanced glycosylation endproducts. J Exp Med 165:140145[Abstract]
Noorman F, Barrett-Bergshoeff MM, Bekkers JJ, Emeis DC, Rijken DC (1997) Inhibition of mannose receptor-mediated clearance of tissue-type plasminogen(t-PA) by dextran: a new explanation for its antithrombotic effect. Thromb Haemost 78:12491254[Medline]
Palatnik-de-Sousa CB, Dutra HS, Borojevic R (1993) Leishmania donovani surface glycoconjugate GP36 is the major immunogen component of the Fucose-Mannose Ligand (FML). Acta Tropica 53:5972[CrossRef][Medline]
Peters C, Aebischer T, Stierhof YD, Fuchs M, Overath P (1995) The role of macrophages receptors in adhesion and uptake of Leishmania mexicana amastigotes. J Cell Scien 108:37153724
Prina E, Abdi SZ, Lebastard M, Perret E, Winter N, Antoine JC (2004) Dendritic cells as host cells for the promastigote and amastigote stages of Leishmania amazonensis: the role of opsonins in parasite uptake and dendritic cell maturation. J Cell Sci 117(Pt 2):315325
Rabinovitch M (1970) Phagocytic recognition. In Van Furth R, ed. Mononuclear phagocytes. Oxford, Blackwell Scientific, 299313
Reis e Sousa C, Stahl PD, Austyn JM (1993) Phagocytosis of antigens by Langerhans cells in vitro. J Exp Med 178:509519[Abstract]
Rizvi FS, Ouaissi MA, Marty B, Santoro F, Capron A (1988) The major surface protein of Leishmania promastigotes is a fibronectin-like molecule. Eur J Immunol 18:473476[Medline]
Russell DG, Talamas-Rohana P (1989) Leishmania and the macrophage: a marriage of inconvenience. Immun Today 10(10):328333[CrossRef][Medline]
Sacks D, Kamhawi S (2001) Molecular aspects of parasite-vector and vector-host interactions in leishmaniasis. Annu Rev Microbiol 55:453483[CrossRef][Medline]
Sastry K, Ezekowitz RA (1993) Collectins: pattern recognition molecules involved in first line host defense. Curr Opin Immunol 5:5966[Medline]
Schwartzman JD, Pearson RD (1985) The interaction of Leishmania donovani promastigotes and human fibroblasts in vitro. Am J Trop Med. Hyg. 34(5):850855[Medline]
Shepherd VL, Campbell EJ, Senior RM, Stahl PD (1982) Characterization of the mannose/fucose receptor on human mononuclear phagocytes. J Reticuloendot Soc 32:423431
Shepherd VL, Cowan HB, Abdolrasulnia R, Vick S (1994) Dexamethasone blocks the interferon--mediated down regulation of the macrophage mannose receptor. Arch Biochem Bioph 312(2):367374[CrossRef][Medline]
Shepherd VL, Lane KB, Abdolrasulnia R (1997) Ingestion of Candida albicans down-regulates mannose receptor expression on rat macrophages. Arch Biochem Biophys 344(2):350356[CrossRef][Medline]
Soeiro MNC, Paiva MM, Barbosa HS, Meirelles MNSL, Araújo-Jorge TC (1999) A cardiomyocyte mannose receptor system is involved in Trypanosoma cruzi invasion and is down-modulated after infection. Cell Struct Funct 24:139149[CrossRef][Medline]
Soeiro MNC, Mota RA, Batista DGJ, Meirelles MNL (2002) Endocytic pathway in mouse cardiac cells. Cell Struct Funct 27:469478[CrossRef][Medline]
Speert DP, Silverstein SC (1985) Phagocytosis of unopsonized zymosan by human monocyte-derived macrophages: maturation and inhibition by mannan. J Leuk Biol 38:655658[Abstract]
Stahl P, Schlesinger PH, Rodman JS, Doebber T (1976) Recognition of lysosomal glycosidases in vivo inhibited by modified glycoproteins. Nature 264:8688[Medline]
Stahl PD (1990) The macrophage mannose receptor: current status. Am J Respir Cell Mol Biol 2(4):317318[Medline]
Straus W (1981) Cytochemical detection of mannose-specific receptors for glycoprotein with horseradish peroxidase as a ligand. Histochem 73:3947[CrossRef]
Straus W (1983) Competition between glycoprotein hormones and horseradish peroxidase for mannose-specific binding in cells of endocrine organs. Histochem 78:289302[CrossRef]
Taylor ME, Conary JT, Lennartz MR, Stahl PD, Drickamer K (1990) Primary structure of the mannose receptor contains multiple motifs resembling carbohydrate-recognition domains. J Biol Chem 265:1215612162
Tarantino C, Rossi G, Kramer LH, Perrucci S, Cringoli G, Macchioni G (2001) Leishmania infantum and Neospora caninum simultaneous skin infection in a young dog in Italy. Vet Parasitol 102(12):7783[CrossRef][Medline]
TDR (2002) http://www.who.int/tdr/diseases/leish/diseaseinfo.htm
Van Furth R (1970) Origin and kinetics of monocytes and macrophages. Semin Hematol 7:125141[Medline]
Vannier-Santos MA, Martiny A, De Souza W (2002) Cell biology of Leishmania spp.: invading and evading. Curr Pharm Des 8:297318[Medline]
Wileman TE, Lennartz MR, Stahl PD (1986) Identification of the macrophage mannose receptor as a 175-kDa membrane protein. PNAS 83:25012505[Abstract]
Wilson ME, Pearson RD (1986) Evidence that Leishmania donovani utilizes a mannose receptor on human mononuclear phagocytes to establish intracellular parasitism. J Immunol 136(12):46814688
Wilson ME, Pearson RD (1988) Roles of CR3 and mannose receptor in the attachment and ingestion of Leishmania donovani by human mononuclear phagocytes. Am Soc Microb 56(2):363369
Zuckerman A (1953) Initial reaction to the subcutaneous inoculation of cultures of Leishmania tropica in the hamster. Acta Med Orient 12:238240[Medline]