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INFECTION AND IMMUNITY,
0019-9567/01/$04.00⫹0 DOI: 10.1128/IAI.69.5.2865–2871.2001
May 2001, p. 2865–2871 Vol. 69, No. 5
Copyright © 2001, American Society for Microbiology. All Rights Reserved.
Gender Is a Major Factor in Determining the Severity of
Mycoplasma Respiratory Disease in Mice
ANTHONY L. YANCEY,
1
HAROLD L. WATSON,
2
SAM C. CARTNER,
3
AND JERRY W. SIMECKA
4
*
Department of Microbiology
1
and Department of Comparative Medicine,
3
University of Alabama, Birmingham,
Alabama; Lilly Research Laboratories, Indianapolis, Indiana
2
; and Department of Molecular Biology
and Immunology, University of North Texas Health Science Center, Fort Worth, Texas
4
Received 6 November 2000/Returned for modification 19 January 2001/Accepted 24 January 2001
Gender is a significant factor in determining the susceptibility to and severity of pulmonary diseases in both
humans and animals. Murine respiratory mycoplasmosis (MRM), due to Mycoplasma pulmonis infection, is an
excellent animal model for evaluation of the role of various host factors on the development of acute or chronic
inflammatory lung diseases. MRM has many similarities to mycoplasma respiratory disease in humans. The
purpose of the present study was to determine whether gender has a significant impact on lung disease due to
M. pulmonis infection in mice. It was demonstrated that male mice consistently developed more severe disease
in the lung parenchyma than did female mice. There was no gender difference in disease severity along the
airways or any difference in mycoplasma numbers in lungs of male and female mice. Furthermore, surgical
removal of reproductive organs reduced the severity of mycoplasma disease and the numbers of mycoplasma
organisms recovered from lungs. Thus, gender plays a significant role in determining the severity of M. pul-
monis disease. In fact, the gender of the host was a major factor in determining whether an acute or chronic
inflammatory lung disease developed after infection with M. pulmonis.
Respiratory disease is a major health problem in the United
States, with males, in general, being more susceptible than
females to several major lung diseases (4, 11, 19, 26, 29).
Chronic obstructive pulmonary disease, which includes chronic
bronchitis, chronic asthma, and emphysema, is the fifth most
common cause of death. Chronic obstructive pulmonary dis-
ease is especially problematic in the elderly, with males being
affected more frequently than females (19). Males are also
more likely to develop community-acquired and nosocomial
bacterial pneumonias than are females (11, 26, 29). Further-
more, the severity of pneumonia appears greater in male pa-
tients, since as males have a higher risk of hospitalization and
mortality due to pneumonia (4, 19). In the adolescent patient
population, the same tendency exists in that males can also be
more susceptible to lung disease than females. This is demon-
strated in Mycoplasma pneumoniae disease, which is one of the
most prevalent respiratory infections in children and young
adults (12, 17, 18). Thus, gender has an effect on susceptibility
to several pulmonary diseases and may be an unappreciated
but significant factor when considering the diagnosis and treat-
ment of respiratory diseases in humans.
Gender also influences the development of infectious dis-
ease in animals. Male mice are either more susceptible to or
develop more severe disease after infection with Candida, cox-
sackievirus, and Leishmania (3, 23, 28). However, there are few
animal models of respiratory disease where gender has been
shown to influence host susceptibility. After infection with
Mycobacteria marinum or Mycobacteria intracellulare, male
mice developed more severe granulomatous lung lesions than
did females (39, 40). The difference in disease severity corre-
sponds to the numbers of M. intracellulare cells in the lungs. In
M. marinum infection, as well as the other models of infectious
diseases (28, 39), it was further demonstrated that testosterone
exacerbated disease severity. Although the results of the stud-
ies with mycobacteria are important, lung disease in humans is
not limited to the characteristic granulomatous lesions de-
scribed in these animal models. Therefore, here is a need to
establish additional animal models to investigate the influence
of gender on respiratory disease.
Murine respiratory mycoplasmosis (MRM) is an excellent
animal model for use in evaluation of the role of various
factors on the development of acute or chronic inflammatory
lung diseases. MRM is a naturally occurring respiratory disease
in rodents and results from infection with Mycoplasma pulmo-
nis (8, 25, 35). Although it is not an exact model of human
disease, there are similarities in the pathology and clinical signs
between the mycoplasma respiratory disease in humans and
M. pulmonis disease in mice. As in many human diseases, host
and environmental factors can affect the progression of M. pul-
monis respiratory disease (13–15, 25, 27, 30, 31). An additional
advantage of MRM is that both acute alveolar and chronic
peribronchial pneumonias are characteristic of M. pulmonis
disease in mice. Because of its similarity to human disease and
the presence of both acute and chronic inflammation, MRM
appears to be an ideal model to examine the effect of gender
on the pathogenesis of lung disease. The purpose of the pres-
ent study was to determine if gender does influence the sever-
ity of lung lesions due to M. pulmonis infection in mice.
MATERIALS AND METHODS
Animals. Six-week old, specific-pathogen-free C3H/HeN mice, reared and
maintained in Trexler-type plastic film isolators, were used in these experiments
(30). All retired breeders from the colony were examined for the presence of
serum immunoglobulin G (IgG) and IgM antibodies to M. pulmonis and Myco-
plasma arthritidis by enzyme-linked immunosorbent assays (ELISA). The ab-
* Corresponding author. Mailing address: Department of Molecular
Biology and Immunology, University of North Texas Health Science
Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107. E-mail:
jsimecka@hsc.unt.edu.
2865
sence of other murine pathogens was confirmed using bacterial fecal cultures,
necropsy, histological examination, and serologic tests for viruses. Sera from
mice were tested by hemagglutination inhibition, complement fixation, or ELISA
by Charles River Biotechnical Services (Wilmington, Mass.) for the following
pathogens: Sendai virus, pneumonia virus of mice, polyomavirus, minute virus of
mice, ectromelia virus, mouse hepatitis virus, reovirus type 3, Theiler’s GD-VII
virus, lymphocytic choriomeningitis virus, and mouse adenovirus. No murine
pathogens have been detected in this animal colony during the past 5 years.
Specific-pathogen-free C57BL/6N and DBA/2N mice were obtained from the
National Cancer Institute, Frederick Cancer Research Facility, Frederick, Md.
Health surveillance was similarly performed on these mice to exclude the pres-
ence of murine mycoplasma, viruses, bacteria, and parasites.
Experimental mice were maintained in microisolators with sterile bedding
(five to six mice per cage), and sterile food and water was provided ad libitum.
Prior to experimental manipulation, mice were anesthetized with a intramuscular
injection of 10 mg of ketamine hydrochloride (Bristol Laboratories, Syracuse,
N.Y.) per 100 g of body weight and 3.0 mg of xylazine (Haver-Lockhart, Shaw-
nee, Kans.) per 100 g of body weight.
Mycoplasma. M. pulmonis strain CT was derived from a naturally infected
mouse (14). A defined mixture of mycoplasma subclones, derived from the
parental M. pulmonis CT strain, was shown to consistently result in both peri-
bronchial and alveolar inflammatory disease (unpublished results). This organ-
ism stock is simply referred to as CTM, and M. pulmonis CTM was used in these
studies unless indicated otherwise. For experimental infection, anesthetized mice
were inoculated intranasally with 50 l of mycoplasma at a total dose of 10
6
CFU, unless otherwise noted. Medium and harvesting techniques were previ-
ously described (5, 6, 14).
Lung homogenates were cultured on Hayflick’s agar plates to determine the
numbers of mycoplasma CFU. Samples were diluted in broth from 10
-1
to 10
-6
dilutions. Portions (20 l) of the diluted broth were pipetted on the agar plates
and then incubated for 7 days at 37°C. Mycoplasma colonies were counted using
a dissecting microscope.
Surgical removal of reproductive organs. Anesthetized mice were prepared
for surgery by shaving the abdomen and swabbing it with Betadine Surgical Scrub
(Purdue Frederick, Norwalk, Conn.). A midline surgical incision was made in the
abdominal wall. For ovahysterectomy, the uterus, oviducts, and ovaries were
removed and ligatures were placed at the uterine-cervical junction. For orchiec-
tomies, the seminal vesicles and testicles were removed. For all surgeries, the
abdominal muscular layer was sutured using surgical chromic gut and the skin
was sutured with silk. For controls (sham neutered), a midline surgical incision
was made on the abdomen and a surgical probe was used by manipulate the
reproductive organs. The probe was removed, and the muscular layer and skin
were sutured as above. The mice were allowed to recover and observed for 2 to
4 h after surgery. Mice were infected with Mycoplasma 2 weeks after surgery.
Histological examination. Lungs and tracheas were removed and inflated with
cold 95% ethanol. The lung lobes were separated and placed in tissue cassettes
for embedding and subsequent hematoxylin and eosin staining. Each lung lobe
was scored subjectively for airway and alveolar disease (6). Airways were scored
as follows: 0, normal tissue; 1, few scattered neutrophils in the airways; 2, some
pooling of neutrophils in the bronchi and bronchioles; 3, major pooling of
neutrophils in the bronchi and bronchioles. Alveolar disease was scored using a
similar scale: 0, normal tissue; 1, inflammatory exudate affecting 1 to 25% of the
lung parenchyma; 2, inflammatory exudate affecting 26 to 50% of the lung
parenchyma; 3, inflammatory exudate affecting more than 50% of the lung
parenchyma. Slides were coded so that subjective scoring of lesions was done
blindly. Alveolar and airway scores for each lobe were summed after adjustment
for their relative contribution to the total lung weight.
Testosterone levels. Serum samples were collected at the time of sacrifice and
pooled. Serum testosterone levels were performed using radioimmunoassay (Tri-
Level Ligand Control; CIBA-Corning Diagnostics Corp., Irvine, Calif.).
Antibody levels. Anti-mycoplasma antibody titers in the sera were determined
using ELISA (6, 34). Serial dilutions of each serum sample were added in
triplicate to microtiter wells coated with M. pulmonis lysate at 10 g/ml. After
overnight incubation, the plates were washed with phosphate-buffered saline–
0.2% Tween 20. A secondary antibody, labeled with alkaline phosphatase, was
then added to each of the wells at a dilution shown to have minimal nonspecific
binding to antigen-coated wells. Next, the microtiter wells were incubated for 30
min at 37°C, and the optical density was read at 405 nm using a model 3550
microplate reader (Bio-Rad Laboratories, Richmond, Calif.). The relative anti-
body activities were determined relative to a standard composed of a pool of
high-titer sera from M. pulmonis-infected mice. The standard was given an
arbitrary activity of 3,000 and used to compare the activity of other sera. Com-
parisons between serum activities were made only with values obtained within a
single ELISA run to eliminate daily variation within the assay.
Statistical analysis. Statistics were performed using the SYSTAT program
(Systat, Inc., Evanston, Ill.). Arcsine transformation was performed on lesion
indices to normalize the data. Data were analyzed by analysis of variance fol-
lowed by post hoc tests for multigroup comparisons, as needed. Survival and
frequency of gross lesions were compared by Yates corrected chi-square analysis.
Testosterone levels were analyzed by Student’s independent ttests. A probability
(P) of less than 0.05 was accepted as significant.
RESULTS
Male mice develop more severe alveolar pneumonia than
female mice do. To determine if gender influences the severity
of M. pulmonis respiratory disease, male and female mice were
experimentally infected with M. pulmonis. Animals were ob-
served daily for clinical signs and mortality. At 14 days after
infection, mice were sacrificed and their lungs were collected
for histologic examination.
Male mice infected with M. pulmonis developed more severe
clinical disease than did female mice. The clinical signs seen
included ruffled fur, weight loss, and a hunched position. Fe-
male mice were consistently more active than male mice, and
those that survived even showed signs of improvement. Over-
all, a larger proportion of male mice than female mice died
after infection (Pⱕ0.001). In three experiments, 60% of male
mice died (n⫽22) compared to only 9% of the female mice
(n⫽33).
There was also a histopathological difference in the lungs of
male and female mice inoculated with M. pulmonis (Fig. 1).
Lung lesions in male mice were associated predominantly with
an alveolar disease characterized by thickened alveolar walls,
edema, hemorrhage, and accumulation of acute inflammatory
cells. In addition, the airways and adjacent air spaces contained
inflammatory exudates. The character of the lesions in the
male mice was the same whether the mice survived or not. In
contrast to male mice, alveolar disease was minimal in female
mice but the severity of airway lesions was similar to that in
male mice.
FIG. 1. Lung disease in male and female mice after infection with
M. pulmonis. The graph shows the mean lesion index scores, along with
standard error bars, from male and female mice infected with M. pul-
monis 14 days previously. No significant difference was observed in the
severity of peribronchial lesions between male and female mice. How-
ever, there was a significant difference (Pⱕ0.05) in the severity of
interstitial lung lesion between the sexes. The asterisk denotes a sig-
nificant difference in lesion indices between male and female mice.
2866 YANCEY ET AL. INFECT.IMMUN.
Neutering of mice reduces the severity of mycoplasma lung
disease. To examine the influence of the reproduction organs
on the development of lesions after infection, male and female
mice were neutered at 6 weeks of age. Sham-neutered mice
were included as controls. The mice were infected with M. pul-
monis after 14 days of recovery and then sacrificed at 14 days
after infection, and their lungs were removed for histological
examination.
Removal of the reproductive organs reduced the severity of
lung lesions in both male and female infected mice. As in
previous experiments, infected male mice developed an acute
interstitial pneumonia while infected female mice developed
a chronic bronchopneumonia (Fig. 2). Sham-neutered male
mice infected with M. pulmonis had more severe interstitial
lung disease than did neutered male mice. In neutered male
mice, the severity of inflammatory cell infiltrates was reduced.
Similarly, there was a reduction in the severity of the peri-
bronchial lesions in female mice after surgical removal of the
reproductive organs. There were no observable histological
changes in the lungs of uninfected male and female mice after
surgery.
Gender differences were also present earlier than 14 days.
For mice infected with M. pulmonis and sacrificed at 7 days
postinfection, male mice had an acute inflammatory disease of
the alveoli while the disease in female mice was localized to the
airways of the lungs. In both sexes, pulmonary disease was less
severe in mice that had undergone gonadectomy (Fig. 3).
Orchiectomies decreased the presurgical levels of testoster-
one in male mice. The mean level of testosterone in males
before surgery was 842 ⫾217 ng/ml (mean ⫾standard error).
Postsurgery, the level of testosterone was significantly reduced
to 67 ⫾43 ng/ml (Pⱕ0.05).
Influence of gender and neutering on mycoplasma numbers
in the lung. To determine if the effects of gender and surgery
were associated with a change in the numbers of mycoplasma
in the lungs, neutered and sham-neutered mice were infected
at 8 weeks old and sacrificed at 7 days postinfection. There was
no significant difference in the numbers of mycoplasma recov-
ered from the lungs of sham-neutered male and female mice
after infection (Table 1). However, surgical removal of repro-
ductive organs affected the numbers of mycoplasmas in lungs.
At 7 days after infection, neutered male mice had significantly
FIG. 2. Effect of neutering on the severity of M. pulmonis disease at 14 days after infection. Neutered male and female mice were infected with
M. pulmonis, and the severity of interstitial and peribronchial lesions was determined 14 days after infection. Sham-neutered mice were included
for comparison. (A) As in earlier studies, no significant difference was observed in the severity of peribronchial lesions between sham-neutered
male (n⫽12) and female (n⫽11) mice. However, there was a significant difference (Pⱕ0.05) in the severity of the interstitial lung lesion between
the sexes. (B and C) Removal of reproductive organs from male (n⫽8) and (B) female (n⫽7) (C) mice significantly decreased (Pⱕ0.05) the
severity of disease. Removal of the reproductive organs of infected male mice resulted in a significant decrease in alveolar inflammation, while
removal of the reproductive organs of female mice led to a decrease in the severity of both interstitial and peribronchial lesions. Gonadectomy
had no significant effect on the peribronchial inflammatory response. The graph shows the mean lesion index scores, along with standard error bars,
from lungs of infected mice. The asterisk denotes a significant difference in lesion indices between male and female mice (A) or reduction in
severity after surgery (B and C).
VOL. 69, 2001 GENDER DIFFERENCES IN MYCOPLASMA RESPIRATORY DISEASE 2867
FIG. 3. Effect of neutering on M. pulmonis disease in mice at 7 days after infection. Neutered male and female mice were infected with
M. pulmonis, and the severity of interstitial and peribronchial lesions was determined 7 days after infection. Sham-neutered mice were included
for comparison. These are representative sections from each of the experimental groups. Sham-neutered male mice (n⫽11) had more severe
inflammatory response in the alveoli than did neutered male mice (n⫽13). Similarly, sham-neutered female mice (n⫽15) had more severe lung
lesions than did female mice with ovohysterectomies (n⫽15).
2868 YANCEY ET AL. INFECT.IMMUN.
smaller numbers of mycoplasmas in lungs than did control
(sham-neutered) male mice. Similarly, smaller numbers of my-
coplasmas were recovered from the lungs of neutered female
mice than of sham-neutered female mice after infection. Last-
ly, there was a significant difference in the mycoplasma num-
bers obtained from infected male mice that were neutered and
from infected female mice that were neutered.
Serum anti-mycoplasma antibody levels in mice. We deter-
mined the serum antibody levels of surgically neutered mice
and sham-neutered mice infected with M. pulmonis at 7 days
postinfection. Only very low levels of M. pulmonis-specific IgA
and IgG were detected, although significant levels of M. pul-
monis-specific IgM were present. Sham-neutered male mice
had an IgM titer of 555 ⫾57, compared 570 ⫾75 for neutered
male mice. The mean IgM titers were 288 ⫾57) and 438 ⫾57
for sham-neutered and neutered female mice, respectively.
Overall, there was no significant difference in the IgM antibody
response between male and female mice in any of the experi-
mental groups.
Gender influences the severity of mycoplasma disease in
other mouse strains. To determine if gender influences the
severity of M. pulmonis respiratory disease in other strains of
mice, C57BL/6N and DBA/2N mice were infected with 2 ⫻10
4
CFU of M. pulmonis CT and mortality and the presence of
gross lung lesions were noted at 21 days after infection. Overall
significantly greater numbers of C57BL/6N male mice had
gross lung lesions than C57BL/6N female mice (Table 2). Also,
there was a higher mortality in DBA/2N male mice than DBA/
2N female mice.
DISCUSSION
Although gender is a significant factor that affects the sus-
ceptibility to and severity of respiratory disease in humans, there
are few animal models of infectious lung disease where gender
is shown to influence the outcome. MRM due to M. pulmonis
infection in mice is an excellent animal model of acute and
chronic inflammatory lung disease (7, 9). The purpose of the
present studies was to determine if M. pulmonis disease in mice
is affected by gender.
Male mice infected with M. pulmonis developed more severe
clinical disease and had higher mortality than did infected
female mice. Female C3H mice displayed a chronic wasting syn-
drome characterized by weight loss, ruffled fur, and hunched
appearance but with few deaths. However, male C3H mice
often exhibited a fatal shock-like syndrome within 4 to 6 days
after infection. Gender differences were also present in DBA/
2N and C57BL/6N mice infected with M. pulmonis. Thus, the
gender differences in disease susceptibility were not unique to
one strain of mice, indicating that the increased susceptibility
of male mice to severe mycoplasma respiratory disease is a
common phenomenon.
Pulmonary histopathological tests demonstrates that gender
affects the type and character of the inflammatory response in
C3H mice. In M. pulmonis-infected male mice, the pulmonary
lesion was an acute inflammatory response in the alveoli, char-
acterized by a predominantly neutrophilic infiltrate, edema,
and hemorrhage. In contrast, infected female mice developed
a chronic peribronchial inflammatory response with an infil-
tration of mononuclear cells and few neutrophils. This differ-
ence in the inflammatory response between the sexes was not
due to the number of organisms, because the mycoplasma
numbers in the lungs of male and female mice were similar.
Thus, the difference due to gender in mycoplasma disease was
independent of the clearance of the organism but was related
to the mechanisms which regulate the type and character of the
inflammatory response.
Sex hormones appear to directly or indirectly influence the
inflammatory process and host resistance to mycoplasma in the
lungs. M. pulmonis-infected male mice which were neutered
developed less severe lung lesions and had correspondingly
smaller numbers of mycoplasma in the lungs than did infected
control mice. A similar decrease in disease and infection was
observed in female mice after neutering. Surgical removal of
male gonads has been reported to increase protection against
other infections (28, 39). For example, gonadectomized BALB/c
male mice infected with M. marium had increased host resis-
tance, smaller numbers of organisms, and less severe lung le-
sions than did infected control males (39). In preliminary stud-
ies, we also found that testosterone treatment of neutered
female mice increased the severity of lung disease due to M.
pulmonis (unpublished results). Although sex hormones are
probably involved in mycoplasma disease, the mechanisms re-
sponsible for the gender differences in inflammatory lesions,
independent of the clearance of the organism, are unknown.
Since the severity of inflammation is regulated by lympho-
cyte and macrophage activities, gender differences may be linked
to one or both of these cell populations. In previous studies, we
demonstrated that lymphocyte activity has both beneficial and
deterimental effects on the pathogenesis of mycoplasma dis-
ease, including the development of pulmonary inflammation
(5). In support of lymphocyte responses contributing to the
gender differences in mycoplasma disease, female mice are
TABLE 2. Gender differences after infection with M. pulmonis
a
Outcome of
infection
% of mice showing outcome
b
C57BL/6 DBA/2N
Female Male Female Male
Gross lung lesions 0 (0/15) 53 (8/15)
c
100 (16/16) 100 (16/16)
Death 0 (0/15) 0 (0/15) 38 (6/16) 100 (16/16)
c
a
C57BL/6N and DBA/2N mice were infected with 2 ⫻10
4
CFU M. pulmonis
CT. Mortality and the presence of gross lung lesions were noted 21 days postin-
fection.
b
Percentage of affected mice (number of affected mice/total number of mice).
c
A significant difference between male and female mice was found (Pⱕ0.05).
Experiments were performed twice.
TABLE 1. Influence of neutering on mycoplasma
numbers in the lungs
Gender Control mice Neutered mice
CFU
a
nCFU
a
n
Male 59 ⫻10
3
(1.4) 11 17 ⫻10
3
(1.7)
b
10
Female 33 ⫻10
3
(1.5) 11 4.4 ⫻10
3
(1.2)
b
12
a
Geometric mean (x/⫼standard error) mycoplasma numbers recovered from
the lungs at 7 days postinfection.
b
Neutered male and female mice had a significantly smaller number of my-
coplasmas in their lungs than did sham-neutered mice (Pⱕ0.05). There was no
significant difference between the mycoplasma numbers recovered from sham-
neutered male and female mice.
VOL. 69, 2001 GENDER DIFFERENCES IN MYCOPLASMA RESPIRATORY DISEASE 2869
known to develop higher antibody responses to various anti-
gens after immunization (1, 33). Also, sex hormones regulate
T-cell-mediated immune function (24, 37, 38). However, we
found no significant difference in the levels of anti-M. pulmonis
antibody in serum in male and female mice at 7 days after
infection. At this time point, the predominant antibody re-
sponse was of the IgM class, with low levels of IgG and IgA.
Differences in disease due to gender were observed within the
first week after infection, further suggesting that adaptive im-
mune responses are not responsible for these phenomena. In
support, preliminary studies demonstrate that these gender
differences are observed in mice with severe combined immu-
nodeficiency (SCID mice), which lack functional T and B cells
(unpublished results). In addition, sex hormones are able to
modulate the activation of macrophages, including the produc-
tion of proinflammatory cytokines (2, 32, 36). Thus, the differ-
ences in the early stage of M. pulmonis disease in male and
female mice may be due to the proinflammatory activity of
macrophages in the lungs (2, 32, 36) rather than to gender
differences in their anti-mycoplasmal activity in the lungs (10,
16, 20–22, 36, 39, 40). However, additional work is needed
before we can further understand the mechanisms through
which gender affects the susceptibility to respiratory diseases.
In summary, this is the first study to demonstrate that gender
does play a significant role in determining the severity of my-
coplasma respiratory disease in mice. In fact, the gender of the
host was a major factor in determining whether an acute or
chronic inflammatory lung disease developed after infection
with M. pulmonis. This is in contrast to the gender differences
described for mycobacterial infection of mice, where only gran-
ulomatous lung lesions are present (39, 40). The results of
these studies also suggest that modulation of innate host de-
fenses and proinflammatory responses by sex hormones is a
major factor in these gender-related differences. Although
gender is a significant factor in lung disease in humans and
animals, the mechanisms for these differences are not clearly
understood; however, mycoplasma disease in mice will serve as
an excellent animal model to further delineate the role of sex
hormones on both acute and chronic inflammatory lung dis-
eases.
ACKNOWLEDGMENTS
The technical support of Heather Baker, Eugene Arms, Chandra E.
Frank, and Yvette Hale is greatly appreciated. We thank J. Russell
Lindsey and Gail H. Cassell for their useful discussion and support
during the performance of these studies.
This work and preparation of the manuscript was supported by
Public Health Service grants HL19741 (to G.H.C.), AI 42075 (to J.W.S.),
and RR11105 (to J. R. Lindsey) from the National Institutes of Health.
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Editor: E. I. Tuomanen
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