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Department of Pathology, Colorado State University College of Veterinary Medicine and Biomedical Sciences, Fort Collins, CO 80523
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-12, and
inducible nitric oxide synthase), but with enhancement of the Th2
cytokine IL-4, whereas no changes in the levels of IL-10 and TGF-ß
were noted. Importantly, salivary gland lysate directly up-regulated
expression of IL-4 mRNA in mice in the absence of infection with
L. major. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The response that mice mount to infection with L. major by
syringe (i.e., in the absence of any sand fly salivary material) has
been extensively characterized and represents one of the best studied
models in which selective activation of Th1 or Th2 cells occurs
(reviewed in Refs. 7–11). In resistant mice (e.g., CBA), IFN- is
the principal mediator of resistance to L. major due to its
ability to activate macrophages
(M
)4 to destroy the
parasite (12, 13, 14, 15), and treating mice with a neutralizing
anti-IFN- Ab exacerbates the course of infection by promoting
the outgrowth of Th2 cells (16, 17). In susceptible mice (BALB/c), IL-4
can block the ability of IFN- to activate M to destroy
Leishmania (18, 19), and treating mice with a neutralizing
anti-IL-4 Ab allows the animals to cure their infection by
promoting the outgrowth of Th1 cells (20, 21). In addition, other cells
of the immune system, such as M, can produce cytokines and factors
(e.g., IL-10, IL-12, nitric oxide (NO), and TGF-ß) that can modulate
an immune response and influence the outcome of infection with L.
major in mice (7, 8, 9, 10, 11).
In contrast to our extensive work with New World L. longipalpis salivary gland lysate (1, 2, 3, 4, 5, 6), relatively little is known about the effects of Phlebotomus papatasi salivary gland lysate on infection with L. major. Yet, importantly, while P. papatasi transmits L. major in nature, L. longipalpis does not (22, 23). Preliminary studies showed that P. papatasi salivary gland lysate enhanced lesion size in C57BL/6 mice infected with L. major (4). Here, we extend these studies to show that P. papatasi salivary gland lysate not only significantly enhances lesion size but also enhances parasite burden in the lesion. In addition, as a result of this effect, P. papatasi salivary gland lysate markedly alters the immune response to L. major.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Young adult female CBA/CaH-T6J mice were obtained from The Jackson Laboratory (Bar Harbor, ME) or were bred in the animal facilities at Colorado State University (Fort Collins, CO). Stationary phase promastigotes of L. major (LV39 (MRHO/Sv/59/P) isolate) (1) were used. Parasites were maintained as previously described (1). Salivary glands of P. papatasi (Israel isolate) were collected and lysed as previously described (1).
Infecting mice and determining parasite numbers in cutaneous lesions
Mice were injected with 105 L. major with or without salivary gland lysate (the equivalent of 0.5 gland) in one hind footpad, and lesion development was followed by measuring the thickness of the infected footpad compared with that of the contralateral uninfected footpad. Parasite numbers were determined in infected footpads using a published limiting dilution assay for determining parasite burdens in infected mouse tissues (24).
Competitive PCR analysis of cytokine production
RNA isolation. Groups of three mice each were infected with L. major with or without salivary gland lysate as described above. At the times indicated, total RNA from the draining inguinal and popliteal lymph nodes was isolated by an acid guanidinium isothiocyanate-phenol-chloroform-isoamyl alcohol procedure (25). Briefly, lymph nodes were homogenized in 1 ml of denaturing solution (4 M guanidinium thiocyanate, 25 mM sodium citrate (pH 7), 0.5% sarcosyl, and 0.1 M 2-ME). Then, 0.1 ml of 2 M sodium acetate, 1 ml of water-saturated phenol (Amresco, Solon, OH), and 0.2 ml of a chloroform-isoamyl alcohol mixture (49/1; Fluka, Ronkonkoma, NY) were sequentially added to the lysates with thorough mixing after each addition. The mixture was chilled on ice for 15 min and centrifuged for phase separation at 4°C. The aqueous phase was recovered, and the RNA was precipitated with 1 ml of isopropanol (Sigma, St. Louis, MO) at -20°C for at least 1 h. The pellet was redissolved in denaturing solution and precipitated again in isopropanol. Precipitates were pelleted, washed twice in 75% ethanol, air-dried, and resuspended in diethylpyrocarbonate (Sigma)-treated water. The RNA concentration was determined by absorbance at 260 nm.
cDNA synthesis. One microgram of total RNA was brought to a volume of 11.5 µl with diethylpyrocarbonate-treated H2O. The solution was heated to 65°C for 5 min, centrifuged, and chilled on ice for 1 min. The sample was brought to room temperature, and 1 µl of oligo(dT) (0.5 mg/ml; 15 mer; Promega, Madison, WI) was added and incubated for 10 min at room temperature. The mixture was then incubated with 4 µl of 5x reverse transcription buffer (Boehringer Mannheim, Indianapolis, IN), 1 µl of 0.2 M DTT (Boehringer), 0.5 µl of RNase inhibitor (40 U/µl; Boehringer), 1 µl of mixed dNTP (10 mM each of dATP, dGTP, dCTP, and dTTP; Sigma), and 20 U of Moloney murine leukemia virus reverse transcriptase (20 U/µl; Boehringer) for 110 min at 40°C. The reaction mixture was then heated to 95°C for 5 min, cooled to room temperature, and brought to 100 µl with ddH2O. The cDNA was stored at -20°C until use.
Competitive PCR. The sequence of cytokine primers used for the
competitive PCR is described in Table I
.
Primers and competitors specific for murine IL-4, TGF-ß, inducible
nitric oxide synthase (iNOS), IFN-, and ß-actin were purchased
from Clontech (Palo Alto, CA). Primers and mimics specific for murine
IL-10 and IL-12 (p40 subunit) were gifts from Dr. M. B. Tompkins
(North Carolina State University; methods of production in 26 .
The first-strand cDNA was used as a template in the presence of serial
dilutions of the competitor. cDNA was normalized against the level of
expression of the ß-actin gene. The conditions of the PCR were as
follows: 10 mM Tris-HCl (pH 8.3); 50 mM KCl; 1.5 mM MgCl2
(Sigma); 0.2 mM each of dATP, dGTP, dCTP, and dTTP (Sigma); 0.4 µM of
each 5' and 3' primer; 4 µM DTT; 5 µl cDNA; 2 µl competitor; and
40 U/ml Taq polymerase (Perkin-Elmer, Branchburg, NJ) in a 50-µl
reaction volume. This mixture was incubated for 3 min at 94°C in a
Hybaid Omn-E thermal cycler (Hybaid, Middlesex, U.K.) followed by
37–43 cycles of 1-min annealing at 56°C, 2-min elongation at 72°C,
and 45-s denaturation at 94°C. The last elongation reaction was
conducted for 8 min at 72°C. The PCR reaction was analyzed with a
1.6% agarose-ethidium bromide gel. Results (except for iNOS) are
expressed as the fold increase in mRNA expression in mice infected with
L. major with or without saliva compared with expression in
uninfected mice.
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Lesion progression data were analyzed for statistical
significance using analysis of variance for repeated measures. After
analysis, a result was considered significant when p 
0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To test whether salivary gland lysate of P. papatasi enhanced infection with L. major in mice, we patterned our experiments after those originally performed with New World L. longipalpis salivary gland lysates (1). The lysate of one-half of a P. papatasi gland was coinjected with 105 L. major into one hind footpad of CBA mice, and lesion progression was monitored. The CBA mouse was used because it is very sensitive to the disease-exacerbating effects of salivary gland lysate (4).
As can be seen in Fig. 1, the salivary
gland lysate markedly enhanced the development of lesions in the
animals. Throughout the course of infection, lesions on salivary gland
lysate-treated mice were 3–4 times the size of lesions on mice not
treated with salivary gland lysate. Moreover, while untreated mice
healed their lesions within 42 days, salivary gland lysate-treated mice
still bore substantial cutaneous lesions at this time (0.62 ±
0.21 mm swelling; Fig. 1). However, since CBA mice are resistant to
infection with L. major, the lesions on salivary gland
lysate-treated mice ultimately healed (Fig. 1). It should be noted that
this is also the case in the same mice treated with L.
longipalpis salivary gland lysate (1).
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Since lesion size and parasite burden in the lesion do not always
correlate (24), we tested whether parasite numbers in the lesions were
also markedly elevated in salivary gland lysate-treated mice. We found
a dramatic increase in parasite burden at 4 wk of infection (152-fold;
Table II), a time when the maximal
effects of salivary gland lysate on lesion development were observed
(Fig. 1
). Moreover, by 42 days of infection, lesions on salivary
gland lysate-treated mice still contained parasites, while no parasites
were detected in lesions of mice not treated with salivary gland
lysate. Thus, the effects of salivary gland lysate on lesion
development and parasite burden directly correlated (compare Fig. 1
with Table II).
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IL-4 is produced by susceptible mice following infection with
L. major (7, 8, 9, 10, 11). Since sand fly salivary gland lysate
enhanced both the development of lesions of L. major and the
burden of parasites present in the lesions, we hypothesized that IL-4
mRNA expression might be enhanced by salivary gland lysate. CBA mice
were infected with L. major with or without salivary gland
lysate, and at varying times of infection (days 1, 3, 5, 7, 14, 21, 28,
and 42), the lymph nodes draining the cutaneous lesion (popliteal plus
inguinal) were analyzed for the expression of IL-4 mRNA. IL-4 mRNA was
detected earlier in L. major- plus salivary gland
lysate-treated mice than in mice infected with L. major
alone (day 3 as opposed to day 14), and the level of expression was
approximately fourfold higher in the lysate-treated mice (Figs. 2 and 5). However, by late in the course
of infection (day 42; Fig. 2) there was no difference in the expression
of IL-4 mRNA. This was also the time when lesions were resolving in
salivary gland lysate-treated mice (Fig. 1 and Table II).
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and IL-12 mRNA
expression in the lymph nodes draining lesions of L.
major
Resistance to L. major infection is associated with the
production of IFN- and IL-12 (7, 8, 9, 10, 11). Therefore, we next tested
whether salivary gland lysate inhibited the production of these
cytokines. Salivary gland lysate markedly inhibited the production of
both IFN- and IL-12 (Figs. 3 and 5).
Beyond day 7 of infection the expression of IFN- mRNA was inhibited
approximately 4- to 10-fold, but by day 28 of infection the expression
of IFN- mRNA was equivalent in salivary gland lysate-treated and
untreated mice (Fig. 3). The effects of salivary gland lysate on IL-12
mRNA expression were similar to the effects on IFN- mRNA expression
(Figs. 3 and 5). Between days 7 and 28 of infection, IL-12 mRNA
expression was inhibited approximately 4- to 16-fold by salivary gland
lysate. Therefore, the maximum degree of inhibition of IFN- and
IL-12 mRNA expression correlated with those times of infection when
lesion size and lesion parasite burden were maximally enhanced by
salivary gland lysate (compare Fig. 3 with Fig. 1 and Table II).
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In addition to IL-12, accessory cells such as M can produce
IL-10 and TGF-ß. These factors can modulate an immune response and
can affect the outcome of infection with L. major (7, 8, 9, 10, 11).
Therefore, we measured the expression of IL-10 and TGF-ß mRNA and
found little or no difference in the expression of these cytokines by
salivary gland lysate-treated and untreated mice (Fig. 4).
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to kill L. major in vitro
and for mice to clear an infection with L. major (7, 8, 9, 10, 11).
Therefore, we hypothesized that since sand fly salivary gland lysate
exacerbates infection with L. major, it should inhibit the
expression of iNOS in lymph nodes draining cutaneous lesions of
L. major. Unlike the cytokines analyzed to date, we were
unable to detect any iNOS mRNA in normal lymph node tissue. Thus, we
were not able to express results with iNOS mRNA expression as a fold
increase in mRNA expression. Instead, results are given as iNOS mRNA
expression (femtograms per microliter of cDNA) in Table III. Salivary gland lysate delayed the
expression of iNOS mRNA and reduced the level of its expression
eightfold (Table III and Fig. 5).
However, identical with the results obtained with IFN- and IL-12
mRNA expression (Fig. 3), iNOS mRNA expression was not inhibited by
salivary gland lysate beyond 28 days of infection (Table III).
Importantly, salivary gland lysate-treated mice began to resolve their
lesions (Fig. 1) and to destroy their parasite burden (Table II) beyond
28 days of infection.
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Finally, since P. papatasi salivary gland lysate
up-regulated IL-4 mRNA expression in mice infected with L.
major (Fig. 2), we determined whether the lysate was able to
up-regulate IL-4 expression in the absence of infection with L.
major. To test this hypothesis, we injected the lysate of 0.5
salivary gland of P. papatasi and measured the level of
expression of IL-4 mRNA 7 days later. We chose 7 days, since this was
the time by which IL-4 expression was up-regulated in mice coinjected
with lysate and L. major (Fig. 2). Injecting salivary gland
lysate alone up-regulated IL-4 mRNA expression to the same extent as it
did in mice coinjected with lysate and L. major (compare
Figs. 2, 5, and 6).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), and
that this increased lesion size is accompanied by a marked increase in
parasite burden within the lesions (Table II). Indeed, the degree of
exacerbation is equivalent to that caused by New World L.
longipalpis salivary gland lysate (1, 2, 3, 4, 5, 6).
CBA mice resist infection with L. major; therefore, the mice
mount a Th1-type response to the parasite. This response is
characterized by low levels of expression of IL-4 mRNA (Fig. 2) and
high levels of expression of IFN-, IL-12 (Fig. 3), and iNOS mRNA
(Table III). Because P. papatasi salivary gland lysate
exacerbated infection with L. major, the immune response to
the parasite was markedly altered. These mice expressed higher levels
of IL-4 mRNA, and this IL-4 mRNA was detected at earlier time points of
infection than in mice infected with L. major alone. In
salivary gland lysate-treated mice, IL-4 mRNA was detected between days
3–7 of infection at levels from 4- to 16-fold above background levels
(Fig. 2).
The production of IL-4 is associated with susceptibility to L.
major infection in BALB/c mice (7, 8, 9, 10, 11, 27, 28), and neutralizing
this IL-4 with an anti-IL-4 Ab allows the mice to cure an infection
with the parasite (20, 21). Therefore, early production of IL-4 in
P. papatasi salivary gland lysate-treated mice may interfere
with the development of a protective Th1 response. Indeed, it has been
shown that IL-4 produced early in BALB/c mice infected with L.
major inhibits the elaboration of IFN- and renders T cells
unresponsive to IL-12 (28). In addition, the disease-exacerbative
effects of New World L. longipalpis salivary gland lysate
after infection with Leishmania braziliensis in BALB/c mice
are blocked by treating the mice with anti-IL-4 Ab (29). To test
the hypothesis that P. papatasi salivary gland lysate blocks
the development of a Th1 response to L. major, we analyzed
the effect of the lysate on the expression of IFN- mRNA. Between
days 7 and 21 of infection, the expression of IFN- mRNA was
inhibited by 4- to 10-fold in salivary gland lysate-treated mice
compared with that in untreated mice (Figs. 3 and 5).
These observations demonstrate that P. papatasi salivary
gland lysate inhibits the development of a Th1 response in mice
infected with L. major. However, the exact mechanism
underlying the effects of salivary gland lysate are unknown. As
discussed above, salivary gland lysate enhances IL-4 production in
treated mice; however, this is probably an indirect and downstream
effect of the lysate. Previous studies have shown that salivary gland
material acted at the level of APCs rather than exerted a direct effect
on T cells (5). Therefore, P. papatasi saliva may affect
interactions that occur between T cells and APCs. For example, salivary
gland lysate may affect the expression of costimulatory molecules such
as B7 or CD40 on APCs. Alternatively, the lysate may inhibit IL-12
while it augments IL-6 secretion by APCs. In support of this latter
hypothesis is our observation here that P. papatasi salivary
gland lysate inhibited IL-12 mRNA expression in treated mice (Fig. 3).
In addition, we have recently shown that the vasodilator, termed
maxadilan (MAX) (30), present in L. longipalpis salivary
glands augments IL-6 production by M in vitro (31), and it has been
proposed by others (32) that IL-6 promotes the development of a Th2
response. Finally, we have recently begun to analyze the effect that
P. papatasi salivary gland lysate has on murine epidermal
cells (which contain primarily keratinocytes as well as potent APCs
known as Langerhans cells). We reasoned that since sand flies inject
their saliva into host skin, the effects of saliva should be most
pronounced on epidermal cells. Ongoing experiments are revealing that
saliva down-regulates B7-2 (CD86) expression on epidermal cells.
However, we anticipate that Old World P. papatasi salivary
gland lysate will have multiple and complex effects on multiple cell
targets, since the effects of New World L. longipalpis
salivary gland lysate and MAX from the salivary gland are complex. For
example, New World saliva inhibits the production of TNF-
(31), NO
(R.G.T. unpublished observations), and antigen presentation (5)
by APCs, while it augments the production of IL-6, PGE2,
and intracellular cAMP (31).
NO is critical for the killing of L. major in vitro (33, 34, 35)
and in vivo (36, 37). iNOS represents the cytokine-inducible form of
NOS. iNOS activity is up-regulated by a variety of factors, including
IFN-, TNF-, and LPS (38). In addition, macrophages from IFN-
or IFN-R knockout mice show impaired production of NO (39, 40). It
has been previously shown that P. papatasi saliva was able
to inhibit in vitro the production of NO by L.
major-infected macrophages and as a result to also inhibit
destruction of the parasite (41). We show here in vivo evidence that
the disease-exacerbative effect of P. papatasi saliva also
correlates with an inhibition of the expression of the iNOS gene in
situ (Table III). This inhibition of iNOS mRNA expression appeared as
early as day 7 postinfection and was observed through day 28 (Table III). It is tempting to speculate that the inhibition of iNOS mRNA
expression resulted at least in part from the down-regulation of
IFN- mRNA expression seen in salivary gland lysate-treated mice
(Fig. 3). Alternatively, deactivators of M functions (e.g., TGF-ß
and IL-10) could have been responsible for the inhibition of iNOS mRNA
expression. For example, TGF-ß has been shown to be involved in the
down-regulation of the expression of iNOS mRNA in
Leishmania-infected mice (42). However, salivary gland
material had little or no effect on either TGF-ß or IL-10 mRNA
expression (Fig. 4).
Finally, it is important to note that although Old and New World sand
fly salivary gland lysates both exacerbate infection with
Leishmania in mice, they have differing pharmacologic
effects in experimental animals. Notable among these differences is
that while L. longipalpis salivary gland lysate contains a
powerful vasodilator, a similar molecule has not been detected in the
salivary gland of P. papatasi (43, 44, 45). We have recently
reported that MAX, the L. longipalpis vasodilator, has
several immunomodulatory effects on M (31). In addition, ongoing
experiments are revealing that synthetic MAX is able to substitute for
whole L. longipalpis salivary gland lysate and to induce the
same degree of exacerbation of L. major infection in mice
(unpublished results). This suggests that MAX is an important mediator
of disease exacerbation in New World L. longipalpis salivary
glands. Therefore, since P. papatasi salivary glands do not
contain a vasodilator (43, 44, 45), this suggests that the ability of
P. papatasi salivary gland lysates to exacerbate infection
with L. major is mediated by either 1) a greatly modified
MAX-like molecule that lost its ability to mediate vasodilation but not
immunomodulation, or 2) a molecule(s) unrelated to MAX.
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Acknowledgments |
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Footnotes |
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2 Current address: Division of Geographic Medicine, Case Western Reserve University, 2109 Adelbert Rd., Cleveland, OH 44106-4984.
3 Address correspondence and reprint requests to Dr. Richard G. Titus, Department of Pathology, Colorado State University College of Veterinary Medicine and Biomedical Sciences, Fort Collins, CO 80523-1671.
4 Abbreviations used in this paper: M, macrophage; NO, nitric oxide; iNOS, inducible nitric oxide synthase; MAX, maxadilan.
Received for publication March 20, 1998. Accepted for publication July 13, 1998.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R. V. Morris, C. B. Shoemaker, J. R. David, G. C. Lanzaro, and R. G. Titus Sandfly Maxadilan Exacerbates Infection with Leishmania major and Vaccinating Against It Protects Against L. major Infection J. Immunol., November 1, 2001; 167(9): 5226 - 5230. [Abstract] [Full Text] [PDF]
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