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Infection and Immunity, December 2000, p. 7209-7211, Vol. 68, No. 12
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LETTERS TO THE EDITOR
Murine Models of Chlamydia trachomatis Genital
Tract Infection: Use of Mouse Pneumonitis Strain versus Human
Strains
 |
LETTER |
Morrison and Morrison (11) analyzed by in situ
immunohistochemistry the progression of the inflammatory and cytokine
responses in the genital tracts of mice. They provided an important
foundation from which we can study the effects of experimentally
induced perturbations in the systemic immune response on the
development of local genital tract immunity. The observed cytokine
responses were obtained using the Chlamydia trachomatis
strain mouse pneumonitis (MoPn).
The MoPn agent, the mouse biovar of C. trachomatis, is much
more virulent in mice than human strains (14), causing acute pathology throughout the genital tract and characteristically resulting
in systemic infection (12). In addition, the developmental cycle of MoPn is more rapid, its duration being approximately half that
of human strains, and the strain is more prolific. However, in humans
the urogenital C. trachomatis serovars cause no systemic infections and upper genital tract progression, followed by pathology, usually resulting from multiple infections, is only seen in a small
percentage of women (3, 13).
We have shown an important role for gamma interferon (IFN-
) in the
early clearance of chlamydia from the genital tract (4). When we infected IFN-
/ mice with MoPn we observed no
significant differences in the clearance of chlamydiae between infected
and control mice. However, when we infected animals with the human
genital isolate (5, 6, 9) serovar D, we saw striking
differences in infection kinetics between IFN-/ and
control animals beginning as early as day 4 and continuing throughout
the observation period (70 days). Thus, the MoPn strain and the human
C. trachomatis strains differ in response to at least one
important cytokine and most likely will be found to differ in response
to other cytokines.
Recently, a novel high-resolution technique has been introduced for
whole-genome analysis: amplified fragment-length polymorphism (AFLP).
This technique has proven its usefulness as a tool in bacterial
taxonomy and epidemiology. It was shown that human isolates were
clearly different from the MoPn strain of C. trachomatis (10). Both the AFLP and DNA-DNA hybridization demonstrate
that the MoPn strain should be considered a separate
Chlamydia species. Indeed, Everett et al. (2)
proposed a reclassification of the order Chlamydiales and
its current taxa based on phylogenetic analyses of the 16S and 23S rRNA
genes with corroborating genetic and phenotypic information. This
interesting proposal was the first topic on the program of the 4th
European Chlamydia Congress in August this year (Helsinki, Finland).
One of the proposed new species in this reclassification is
Chlamydia muridarum sp. nov. Thus, it is the considered
opinion of bacterial taxonomists that the MoPn strain differs
considerably from human C. trachomatis strains.
Finally, although both in animal models and in humans specific major
histocompatibility complex class I alleles and HLA types were found to
be independently associated with pelvic inflammatory disease and tubal
infertility (1, 7, 8), repeated pelvic inflammatory disease
periods and repeated C. trachomatis infections increase the
risk for tubal infertility significantly (3, 13). This is
most likely based on enhanced autoimmune reactivities, including heat
shock protein 60 autoimmunity. This demonstrates that proteins
expressed by the microorganism are the determinants for the immunologic
response of the host, emphasizing the importance of the choice of the
chlamydial strain to be used as a model for genital tract infection.
Thus, it seems to be worthwhile and potentially clinically more
relevant to investigate the cytokine profiles in the murine genital
tract during the course of infection using human C. trachomatis strains and to compare those cytokine responses to the
results obtained with the MoPn agent. Through this comparison, a basis for the selection of the most appropriate strain for use in murine models of human genital tract infection can be made.
| |
FOOTNOTES |
*
Phone: (626) 359-8111
Fax: (626) 301-8954
E-mail: jlyons{at}coh.org
| |
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| | | | |
Servaas A. Morré
Section of Molecular Pathology
Department of Pathology
University Hospital Vrije Universiteit
Amsterdam, The Netherlands
|
| | | | |
Joseph M. Lyons*
James I. Ito Jr.
Department of Infectious Diseases
City of Hope National Medical Center
1500 E. Duarte Rd.
Duarte, California 91010
|
| |
AUTHOR'S REPLY |
Morré, Lyons, and Ito, Jr., raise several issues that relate to
the legitimacy of the Chlamydia trachomatis mouse
pneumonitis (MoPn) murine model of genital tract infection
(7). The MoPn model is far more comparable to human
chlamydial genital tract infection than alluded to by Morré et
al. Vaginal inoculation of MoPn results in an infection that naturally
ascends from the lower genital tract (vagina and cervix) to infect
upper genital tract tissues (uterine horns and oviducts) (1,
6). The inflammatory response and postinfection sequelae that
develop following MoPn infection, such as tubal occlusion,
hydrosalpinx, and infertility, are characteristic of chlamydial genital
tract infection in women (16). Conversely, vaginal
inoculation of mice with human biovars of C. trachomatis
produces a mild infection of the lower genital tract, which is
characterized by the shedding of fewer chlamydiae for a shorter
duration (9). Human biovars cause postinfection sequelae in
mice only when high doses are inoculated directly into the uterine
horns or ovarian bursa (14, 15). Systemic MoPn infection per
se does not develop following vaginal inoculation. Occasionally, low
numbers of MoPn are isolated from systemic sites (2;
R. P. Morrison, unpublished data), but pathological changes are
only observed in genital tract tissues. Perhaps vaginal infection of
mice with human biovars also results in low levels of systemic chlamydiae, but such information is not presently available.
Comparing the incidence of upper genital tract pathology in the
MoPn model to that of natural infection of women is potentially problematic. A plethora of confounding variables, such as host genetic
influences, antibiotic treatment early during the course of infection,
etc., profoundly influence the progression of chlamydial disease in
experimental models (3, 12, 13) and perhaps similarly affect
disease progression in humans. Nevertheless, the pathology of the
upper genital tract of MoPn infected mice is comparable to that of
women with post-chlamydial infection sequelae (6, 7, 16).
The assertion that tubal infertility or other postinfection sequelae
result from "enhanced autoimmune reactivities, including heat shock
protein 60 autoimmunity," is scientifically unsubstantiated. There
exists no direct evidence that autoimmune responses contribute to the
pathogenesis of chlamydial genital tract disease.
Amplified fragment-length polymorphism provides only a glimpse of the
relative genetic relatedness among chlamydial isolates (5).
On the other hand, the genomic sequence analyses of MoPn and serovar D
conclusively reveal striking similarities in gene content and the order
of genes within the chromosomes (10, 11). MoPn and human
biovars clearly display differences in host range, but that does not a
priori dismiss the MoPn infection model as an inappropriate correlate
of human infection. In fact, the authors of the above-mentioned genomic
study state that "the extraordinary conservation offers encouragement
for investigators using the MoPn biovar to model disease caused by
human biovars of C. trachomatis."
Differences in the response of MoPn and human biovars of C. trachomatis to gamma interferon is an important consideration, and
perhaps a possible shortcoming of the MoPn model of genital tract
infection. The role of gamma interferon in both MoPn and human biovar
models of infection has been extensively evaluated by several research
groups not cited by Morré et al. (2, 4, 8, 9).
Particularly applicable is the study by Perry et al.
(9), who quite eloquently address in their discussion
how differences in sensitivity to gamma interferon may influence
the pathogenesis of murine and human chlamydial infection.
Although not flawless, MoPn genital tract infection of mice is a
reasonable model for the study of Chlamydia-host
interactions. It is important to recognize, however, that regardless of
the model, the pathogenesis of human chlamydial infections will only be
understood through a more thorough investigation of chlamydial infection in its natural human host.
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| | | | |
Richard P. Morrison
Department of Microbiology
Lewis Hall, Room 109
Montana State University
Bozeman, Montana 59717
|
Infection and Immunity, December 2000, p. 7209-7211, Vol. 68, No. 12
0019-9567/00/$04.00+0
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