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Infection and Immunity, June 2001, p. 3869-3876, Vol. 69, No. 6
Departments of Pediatric Infectious Diseases and Pathology,
University of Texas Southwestern Medical Center, Dallas,
Texas,1 and Diagnostic Mycoplasma
Laboratory, University of Alabama, Birmingham,
Alabama2
Received 5 February 2001/Returned for modification 6 March
2001/Accepted 26 March 2001
Because Mycoplasma pneumoniae is hypothesized to play
an important role in reactive airway disease/asthma, a comprehensive murine model of M. pneumoniae lower respiratory infection
was established. BALB/c mice were intranasally inoculated once with M. pneumoniae and sacrificed at 0 to 42 days
postinoculation. All mice became infected and developed histologic
evidence of acute pulmonary inflammation, which cleared by 28 days
postinoculation. By contrast, M. pneumoniae persisted in
the respiratory tract for the entire 42 days studied. Tumor necrosis
factor alpha, gamma interferon, interleukin-6 (IL-6), KC (functional
IL-8), MIP-1 Mycoplasma pneumoniae is
a known significant cause of acute respiratory illness in humans,
including pharyngitis, tracheobronchitis, and community acquired
pneumonia. More recently it has been associated with reactive airway
disease and asthma. This association with asthma is particularly
intriguing. In some studies, M. pneumoniae has been isolated
from the respiratory tract of up to 20 to 25% of asthmatics
experiencing acute exacerbations (9, 25; S. Esposito, F. Blasi, C. Arosio, et al., Abstr. 39th Intersci. Conf. Antimicrob.
Agents Chemother., p. 700, 1999). Increased bronchoconstriction with
acute infection and impaired pulmonary function, especially of small
airways, for up to 3 years after initial infection has also been
described (5, 14, 17, 23, 30; Esposito et al., 39th
ICAAC). Recent investigations have suggested that timely and effective
treatment of acute M. pneumoniae respiratory infection can
improve the course of reactive airway disease beyond the acute episode
of wheezing and can prevent the development of deleterious changes in
pulmonary function tests (Esposito et al., 39th ICAAC; D. Gendrel, E. Marc, F. Moulin, et al., Abstr. 39th Intersci. Conf. Antimicrob. Agents
Chemother., p. 661, 1999). Pulmonary structural abnormalities
suggestive of small airway obstruction have been detected in children 1 to 2 years after M. pneumoniae pneumonia by high-resolution
computed tomography with significantly increased frequency compared
with controls, even though the children were treated with
macrolides for 14 days. In these children, a greater antimycoplasma
antibody titer was a significant risk factor for the development of
abnormal pulmonary sequelae suggesting that the host immune response
may play a pathogenic role (13).
While the clinical significance of M. pneumoniae infection
is becoming evident, the pathogenic mechanisms of disease and host response are not well defined. In fact, most related in vitro and in
vivo investigations have been conducted with Mycoplasma pulmonis, a murine pathogen, and other mycoplasma species
(7, 21, 26, 28). Previous studies of murine cytokine
expression with M. pneumoniae pneumonia have been
informative but have not quantified cytokines and chemokines over the
entire course of active infection nor correlated these findings with
the microbiologic and histologic stage of disease.
Our laboratory previously described the microbiologic and histologic
findings of experimental murine M. pneumoniae pneumonia up
to 15 days postinoculation, at which time there was still evidence of
acute infection (32). In the present study, we extend this model to 42 days, well past the resolution of pulmonary inflammation. Additionally, we describe the dynamics of the pulmonary tumor necrosis
factor alpha (TNF- This study was undertaken to establish a comprehensive animal model of
M. pneumoniae pulmonary infection. It is anticipated that
this model will provide insight and a baseline for future studies
designed to elucidate the pathogenesis of M. pneumoniae infection and its role in reactive airway disease.
(This work was presented in part at the 39th ICAAC, San Francisco,
Calif., September 1999 [abstr. B803] and at the 40th ICAAC, Toronto,
Canada, September 2000 [abstr. B1021].)
Organism and growth conditions.
M. pneumoniae
(ATCC 29342) was reconstituted in SP4 broth and subcultured after 24 to
48 h in a flask containing 20 ml of SP4 media at 37°C. When the
broth turned an orange hue (approximately 72 h), the supernatant
was decanted, and 2 ml of fresh SP4 broth was added to the flask. A
cell scraper was used to harvest the adherent mycoplasmas from the
bottom of the flask. This achieved an M. pneumoniae
concentration in the range of 108 to 109
CFU/ml. Aliquots were stored at Animals and inoculation.
Methoxyflurane, an inhaled
anesthetic, was used for inoculum sedation. Two-month-old mycoplasma-
and murine virus-free female BALB/c mice were intranasally inoculated
once (day 0) with 1.25 to 3.75 × 107 CFU of M. pneumoniae in 50 µl of SP4 broth. Control mice were inoculated
with sterile SP4 broth. Mice were obtained from commercial vendors
(Charles River and Harlan), who confirmed their mycoplasma- and murine
virus-free status. Mice were housed in filter-top cages and allowed to
acclimate to their new environment for 1 week. Animal guidelines were
followed in accordance with the Institutional Animal Care and Research
Advisory Committee at the University of Texas Southwestern Medical
Center at Dallas.
Sample collection.
Mice were anesthetized with an
intraperitoneal injection of 75 mg of ketamine per kg of body weight
and 5 mg/kg of acepromazine before cardiac puncture. Blood was
centrifuged at 3,500 × g for 10 min, and the plasma
was stored at Culture quantification.
Twenty-five µl of neat and serial
10-fold dilutions in SP4 broth of BAL fluid (50 µl of neat was used
for the initial dilution) were immediately cultured on SP4 agar plates
at 37°C, while the remainder of BAL neat specimens were stored at
BAL PCR.
Selected BAL samples were evaluated by PCR using
open reading frame 6 primers to M. pneumoniae (Abbott
Diagnostics LCX analyzer) (22).
Histopathology.
Histopathologic score (HPS) was determined
by a pathologist who was unaware of the infection status of the animals
from which specimens were taken. HPS was based on grading of
peribronchiolar and bronchial infiltrates, bronchiolar and bronchial
luminal exudates, perivascular infiltrate, and parenchymal pneumonia.
This HPS system assigned values from 0 to 26 (the greater the score the
greater the inflammatory changes in the lung) (2).
UV radiation killing of mycoplasma.
An aliquot of inoculum
material was exposed to UV radiation (UV Crosslinker, Fisher Biotech)
for 16 h to obtain dead M. pneumoniae for intranasal
inoculation of mice. A sample of this aliquot was cultured to confirm
that it was nonviable. Mice, 6 to 10 per time point, were inoculated
with dead M. pneumoniae and sampled in the same manner as
mice with live M. pneumoniae.
BAL cytokines.
BAL specimens up to 28 days postinoculation
were assessed for concentrations of TNF- Plethysmography.
Whole-body, unrestrained plethysmography
(Buxco, Troy, N.Y.) was utilized to monitor the respiratory dynamics of
mice in a quantitative manner. Mice were allowed to acclimate in the
unrestrained chamber, and then recordings were taken for 5 min. The
experimental and control groups (n = 3 to 9 per group)
of mice were monitored serially and in parallel for 28 days. Enhanced
pause (Penh) is a dimensionless value that represents a function of the
ratio of peak expiratory flow to peak inspiratory flow and of the
timing of expiration. Penh correlates with pulmonary airflow resistance or obstruction. Penh as measured by plethysmography has been previously validated in animal models of airway hyperresponsiveness (10, 11,
24, 31).
Serology.
The presence of IgM and IgG antibodies to M. pneumoniae in the sera of infected mice was determined by ELISA. A
sample was considered positive if its optical density (OD) reading was
Statistics.
A t test was used to compare the
different groups of animals at the same time point, as most of the data
were normally distributed. In the few instances where the data was not
normally distributed, the Mann-Whitney rank sum test was used for
comparison. The Spearman rank order test was used for correlations, as
all the data taken together were not normally distributed. As M. pneumoniae culture, cytokine and chemokine, IgM, and IgG data were
all sampled from the same mouse, raw data were used for these
correlations. HPS and Penh data were each from separate mice, so median
values at each time point were used for correlations involving these
indices. A comparison was considered statistically significant if the
P value was <0.05.
These results represent a compilation of data from two to four
separate experiments, depending on the specific parameter.
Clinical results.
The fur of the mice developed a ruffled
appearance 1 to 2 days postinoculation with live and dead M. pneumoniae. This ruffled appearance persisted for approximately 2 days. Otherwise, there was no visible difference between the
experimental mice and the controls.
BAL culture.
BAL cultures were positive in 100% of the mice
up to 14 days postinoculation and in 75% of animals at 42 days (Fig.
1). The mean titers of positive BAL
cultures ranged from 6.7 to 5.4 log10 CFU/ml during the
first 7 days of infection and then from 3.5 to 1.6 log10
CFU/ml at day 28 (Fig. 2). At 35 and 42 days, the mean titers were 1.8 ± 0.2 and 1.8 ± 0.3 log10 CFU/ml ± standard error, respectively. All
control mice had negative BAL cultures, as did all the mice inoculated
with dead M. pneumoniae.
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.6.3869-3876.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Elevated Cytokine and Chemokine Levels and Prolonged Pulmonary
Airflow Resistance in a Murine Mycoplasma pneumoniae
Pneumonia Model: a Microbiologic, Histologic, Immunologic, and
Respiratory Plethysmographic Profile
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
, and MCP-1/JE concentrations were significantly
elevated in bronchoalveolar lavage samples, whereas IL-4 and IL-10
concentrations were not significantly elevated. Pulmonary airflow
resistance, as measured by plethysmography, was detected 1 day
postinoculation and persisted even after pulmonary inflammation had
resolved at day 28. Serum anti-M. pneumoniae immunoglobulin
G titers were positive in all mice by 35 days. This mouse model
provides a means to investigate the immunopathogenesis of M. pneumoniae infection and its possible role in reactive airway
disease/asthma.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
), gamma interferon (IFN-
), interleukin-4 (IL-4), IL-6, KC (functional IL-8), IL-10, MIP-1, and MCP-1/JE host
response over the course of infection. These cytokines and chemokines
were chosen because of their proven significance in pulmonary
antimicrobial host defense (16, 19) and their broad range
of cytokine and chemokine class representation. Indices of respiratory
physiology during infection, as assessed by whole-body unrestrained
plethysmography, are also presented. Plethysmography provides a
functional assessment of illness in animal models of respiratory disease.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
80°C. All SP4 media contained nystatin (50 U/ml) and ampicillin (1.0 mg/ml) to inhibit growth of contaminants.
80°C. Bronchoalveolar lavage (BAL) specimens were
obtained by infusing 0.5 ml of SP4 broth through a 25-gauge needle into
the lungs, via the trachea, followed by aspiration of this fluid into a
syringe. Whole-lung specimens, including the trachea and both lungs,
were collected and fixed with a 10% buffered formalin solution for
histologic evaluation. Samples were obtained at 2 and 16 h and at
1, 2, 4, 7, 14, 21, 28, 35, and 42 days postinoculation. At each time,
different infected mice were utilized for BAL (five to eight mice) and
fixed-lung (five to eight mice) specimens. Six uninfected controls were
utilized at each time point (three for BAL and three for histologic evaluation).
80°C. Quantification was performed by counting colonies on plated
specimens and expressed as log10 CFU/ml. If plated
dilutions were negative for growth but the corresponding
10
1 broth dilution was positive, then the specimen was
assigned a value of 20 CFU/ml, the lower limit of detection.
, IFN-, IL-4, IL-6, KC
(functional IL-8), IL-10, MIP-1, and MCP-1/JE by enzyme-linked
immunosorbent assay (ELISA) (R&D Systems, Minneapolis, Minn.).
2 standard deviations above the mean OD of the control serum samples (1).
RESULTS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
View larger version (70K):
[in a new window]
FIG. 1.
Percentage of mice infected with M. pneumoniae by culture and PCR in BAL fluid at 0 to 42 days
postinoculation.
View larger version (23K):
[in a new window]
FIG. 2.
Mean HPS for mice inoculated with live (n = 5 to 8) versus dead (n = 3 to 5) M. pneumoniae (Mp) and quantitative bronchoalveolar lavage (BAL)
culture (Cx). Time points are at 2 and 16 h and at 1, 2, 4, 7, 14, 21, and 28 days. Values are expressed as means ± standard errors.
, P < 0.05
between the HPS of mice inoculated with live M. pneumoniae
and the HPS of mice inoculated with dead M. pneumoniae.
BAL PCR. M. pneumoniae PCR was performed on culture-negative BAL specimens (BAL specimens from mice inoculated with dead M. pneumoniae were not included). This increased the percentage of mice positive for M. pneumoniae detection to 75 to 100% at all time points, as shown in Fig. 1. Additionally, PCR was positive in 10 of 10 culture-positive specimens and was negative in specimens from uninfected control mice.
Histopathology.
Inflammation in the lungs after inoculation
with live M. pneumoniae was most severe during the initial 7 days postinoculation, with a mean HPS of 7 for each group of animals
during this interval (Fig. 2). Thereafter, inflammation declined and
the lungs appeared normal at 28, 35, and 42 days postinfection. Figure
3 demonstrates the appearance of a
control mouse lung compared with a lung demonstrating peribronchial and
parenchymal inflammation at the height of disease during the first week
postinoculation with live M. pneumoniae. All control mice
had an HPS of 0 or 1.
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BAL cytokines.
BAL concentrations of TNF-, IFN-, IL-6,
KC (functional IL-8), MIP-1, and MCP-1/JE were significantly greater
(P < 0.05) in the mice infected with live M. pneumoniae compared with controls, in the mice inoculated with
dead M. pneumoniae compared with controls, and with the
exception of IFN- (P = 0.064), in the groups
inoculated with live compared with those inoculated with dead M. pneumoniae. IL-4 and IL-10 concentrations were not statistically
different between these three groups (Fig.
4).
|
,
P < 0.05 between mice given dead M. pneumoniae and control mice.
,
P < 0.05 between mice given live M. pneumoniae and mice given dead M. pneumoniae.
Plethysmography.
Penh peaked at day 2 in the mice infected
with live M. pneumoniae and was significantly (P < 0.05) elevated compared with the control group through day 28, the last day of observation (Fig. 5).
Penh peaked at day 1 for the mice inoculated with dead M. pneumoniae and was significantly (P < 0.05)
elevated from controls only at day 3 (Fig. 5, inset).
|
Serology.
M. pneumoniae IgM was present in serum in
44% of the infected mice (Fig. 6A). The
IgG titers increased from the time of detection to day 42, at which
time all the mice tested demonstrated positive titers (Fig. 6B).
|
Correlations.
M. pneumoniae quantitative culture
demonstrated a positive correlation with Penh (r = 0.89, P < 0.001, n = 9). HPS also
demonstrated a positive correlation with Penh (r = 0.92, P < 0.001, n = 9). M. pneumoniae IgG demonstrated a negative correlation with both quantitative culture (r = 0.68, P < 0.001, n = 40) and Penh (r = 0.81, P = 0.01, n = 8). Numerous
significant correlations were also found among the cytokine and
chemokine, HPS, Penh, and M. pneumoniae culture and antibody
data from the mice inoculated with live M. pneumoniae (Table
1).
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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These results describe a murine model of M. pneumoniae pulmonary infection that can be consistently achieved with a single intranasal inoculation containing a high concentration of M. pneumoniae. Acute pulmonary infection occurred in all mice after a single inoculation, in contrast to previous work in our laboratory that utilized three consecutive daily inoculations. Titers of M. pneumoniae in BAL decreased from an initial high of 106 CFU/ml to approximately 101 to 102 CFU/ml during the first 28 days of infection and remained at this low titer to the last day of observation (day 42). Acute pulmonary inflammation was uniformly present for 21 days postinoculation, with the peak inflammatory changes occurring at 2 to 4 days after infection. In this model, M. pneumoniae infection induced an acute inflammatory phase lasting approximately 3 weeks, followed by a state in which low titers of the organism persisted in the respiratory tract in the absence of pulmonary inflammation by histologic examination.
In humans, M. pneumoniae is reported to persist in the respiratory tract for up to several months after recovery from illness (4). Even after therapy with effective antibiotics, M. pneumoniae has been shown to persist by culture for as long as 2 months (8, 27). To our knowledge, the duration for which M. pneumoniae can be detected in the human respiratory tract after acute pneumonia as determined by PCR has not been investigated. It is known that chronic carriage may occur among people with humoral immunodeficiency (29). In a recent study that detected M. pneumoniae in the lower airways of chronic, stable asthmatics by PCR, all M. pneumoniae cultures were negative (15). It will be important to investigate the chronicity of M. pneumoniae in our model, especially since chronic infection has been postulated to lead to pathologic as well as functional changes in the respiratory tract.
We demonstrated that inoculation with dead M. pneumoniae generated in the lungs of mice a histologic inflammatory response that was significantly greater than that in controls. However, this inflammatory response was less intense and of shorter duration than that induced by viable organisms. Additionally, while dead organisms were able to induce mild peribronchiolar and bronchial infiltrates, perivascular infiltrates, and pneumonia, they did not induce the bronchiolar and bronchial luminal exudates found after inoculation with viable organisms.
Correspondingly, a wide range of cytokines and chemokines were
generated in the respiratory tracts by both live and dead M. pneumoniae, including proinflammatory (TNF-), TH1 (IFN-),
TH2 (IL-6), -chemokine (KC/IL-8), and 
-chemokine (MIP-1,
MCP-1/JE). The TH2 cytokines IL-4 and IL-10 were detected, but their
concentrations were not significantly elevated. Similar to the
differences shown by histopathology, live organisms induced
significantly greater concentrations of cytokines and chemokines for a
longer duration than did dead organisms, except in the case of IFN-.
Additionally, strong correlations were identified between the cytokines
and chemokines
especially the -chemokines (MIP-1, MCP-1/JE)and M. pneumoniae culture, HPS, Penh, and the antibody response.
These correlations are particularly interesting given the link between asthma and -chemokines.
The plethysmography results paralleled the histopathologic and cytokine and chemokine findings, with the live organisms triggering significantly greater pulmonary airflow resistance or obstruction for a longer duration than what was observed with animals given dead organisms or SP4 broth alone (controls). The persistence for the entire 28 days of observation of significant airflow resistance in mice with live M. pneumoniae infection, even when histology was normalized, lends plausibility to chronic pulmonary M. pneumoniae infection having clinical significance.
The parallel findings in histopathology, cytokines and chemokines, and plethysmography support two important points. First, M. pneumoniae antigen (dead organism) can be a significant pulmonary stimulus producing immunologic and physiologic alterations upon exposure. Many mycoplasma species have been shown to possess bacterial modulins (bacterially derived molecules that generate an inflammatory reaction) capable of inducing cytokines and chemokines (3, 6, 12, 18, 20). Evidence that M. pneumoniae may also contain bacterial modulins that affect immunologic and physiologic pulmonary function is intriguing, given its link with reactive airway disease. Second, these findings suggest that live M. pneumoniae are causing an active infection in this model and not merely an antigenic reaction. The lesser inflammatory reaction observed with nonviable organisms may be due to the absence of specific pathogenic mechanisms that are present only with viable organisms or possibly to the process of killing M. pneumoniae, which may have altered the organism's antigens. The elucidation of these mechanisms is important in understanding the immunopathology of M. pneumoniae infection.
The mice developed a specific immunologic response to M. pneumoniae. Although almost one-half of the mice developed positive IgM titers, there was no clear pattern of IgM antibody during the 6 weeks. It should be noted that this IgM murine antibody assay is not as specific as the IgG assay and is prone to nonspecific color development. In contrast, the specific IgG response was delayed, with all animals demonstrating IgG antibody by the end of the experiment. The pattern of the M. pneumoniae serology after this point will be investigated in future studies. The importance of the specific antibody response is suggested by the significant negative correlations between IgG and M. pneumoniae culture titer and between IgG and Penh.
This mouse model provides a means to investigate M. pneumoniae pulmonary infection, especially as it relates to the immunopathogenesis of reactive airway disease. The possible advantages of a mouse model over other existing M. pneumoniae animal models include the ease of working with mice, the availability of murine immunologic assays and transgenic knockouts, and the vast amount of existing immunologic data on mice. The significant correlations between cytokines and chemokines and markers of disease severity (M. pneumoniae culture, HPS, and Penh) in this study give fodder for future inquiries involving immunologic manipulation. This model can also be utilized to assess the effects of novel antibiotics and immunomodulators on microbiologic, histologic, immunologic, and respiratory indices during M. pneumoniae infection. Further investigations are planned to explore chronic infection in a manner similar to that described for this study, particularly to look for the presence of an altered pulmonary immunoenvironment and physiology after M. pneumoniae pneumonia, as has been suggested by studies of reactive airway disease in children and adults.
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ACKNOWLEDGMENTS |
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R. D. H. is the recipient of a Pediatric Infectious Diseases Society Fellowship award sponsored by Roche Laboratories. Additional support was provided by Abbott Laboratories and The American Lung Association.
R.D.H. and H.S.J. contributed equally to this work.
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FOOTNOTES |
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* Corresponding author. Mailing address: Dept. of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9063. Phone: (214) 648-3720. Fax: (214) 648-2961. E-mail: Robert.Hardy{at}UTSouthwestern.edu.
Editor: E. I. Tuomanen
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References
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Infection and Immunity, June 2001, p. 3869-3876, Vol. 69, No. 6
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.6.3869-3876.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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