Experimental transmission of Neisseria gonorrhoeae from pregnant rat to fetus.
ABSTRACT Sprague-Dawley rats were infected on day 20 of pregnancy by intraperitoneal inoculation with Neisseria gonorrhoeae. Disseminated gonococcal infection (DGI) and pelvic inflammatory disease (PID) strains in the presence of C1q but not in the presence of bovine serum albumin (BSA) were able to spread from the pregnant rat to the fetus and resulted in fetal mortality. Transmission of DGI and PID strains that are serum resistant (ser(r)) and sac-4 positive but not of a local infection strain that is ser(s) and sac-4 negative was facilitated by the C1q-dependent mechanism. This study provides the first experimental model that may mimic the transmission of gonococcal infection from mother to the fetus during pregnancy.
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ABSTRACT: The mammalian uterus faces unique immunological challenges. It must nurture and protect the semiallogenic fetus from attack by the maternal immune system while guarding against infection by pathogens that compromise fetal and maternal health. Complement has recently been implicated in the etiology of pregnancy loss, but its regulation by steroid hormones and its role in host defense in the uterus are not clearly defined. Here we use biochemical, functional, and physiological assays to elucidate the regulation of complement proteins in the rat uterus. We demonstrate that estrogens (17 beta-estradiol) and glucocorticoids (dexamethasone) have major, but opposing, effects on the amount and latent activity of complement effectors in the uterus. Treatment with 17 beta-estradiol induced vasodilation and an increase in vascular permeability, which resulted in extravasation of plasma and complement into the uterus, rather than de novo complement biosynthesis. In vitro assays revealed that 17 beta-estradiol induced a potent bactericidal activity in uterine luminal fluid and that the antibacterial component was complement. These proinflammatory and immunomodulatory effects were evident within 4 h of treatment and were blocked by coadministration of dexamethasone. We also found that estrogen effects on the vasculature were mediated in part by activation of the contact system and bradykinin B1 receptors. These results indicate that complement plays a central role in innate immunity in the female reproductive tract and suggest that estrogens or glucocorticoids might be used therapeutically to enhance or inhibit complement-dependent processes in the uterus.Biology of Reproduction 03/2006; 74(2):265-74. · 4.03 Impact Factor
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ABSTRACT: A high index of suspicion is critical in the prevention of serious complications of gonorrheal infection. This article reviews published information regarding the pathophysiology, epidemiology, clinical characteristics, diagnosis, and treatment of gonorrhea. MEDLINE was used to search the literature for articles and studies that have a bearing on these issues. Keywords used were disseminated gonococcal infection; septic arthritis; gonorrhea and pregnancy; and gonorrhea and pathophysiology. We conclude that disseminated gonococcal infection (DGI) should be in the differential diagnosis of any sexually active patient who presents with arthritis, dermatitis, and/or tenosynovitis. Although the incidence of DGI has declined in recent years, it still is the most common cause of newly diagnosed arthritis requiring hospitalization. Careful culturing of every site that could be infected is imperative to aid in diagnosis and treatment. Prompt therapy with appropriate antibiotics such as ceftriaxone will prevent the more serious complications of DGI.Primary Care Update for OB/GYNS 01/2003;
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ABSTRACT: Problem Intrauterine inflammation is a frequent and significant factor associated with the pathogenesis of preterm labor/birth (PTL/PTB). However, it remains unclear whether the intrauterine inflammatory responses activate the maternal peripheral circulation. We explored the association between PTL/PTB and the ‘activation’ of the peripheral circulatory system by determining whether CD55 mRNA expression within peripheral WBCs differed between PTL and control patients not in labor.Method of Study RNA was purified from white blood cells collected from pregnant women with preterm labor (n = 45), and from pregnant (n = 30) control women. CD55 gene expression was evaluated by quantitative PCR.Results The mean CD55 mRNA level within the PTL group (0.77 ± 0.03) was 1.48-fold higher than that observed (0.52 ± 0.02) within the control group (P < 0.0001); 71% of PTL patients and only 6.7% of control subjects expressed elevated CD55 mRNA. The receiver operating characteristics (with 95% CI) of CD55 as a marker for PTL were as follows: Sensitivity, 69% (53–82%); Specificity, 93% (78–99%); Positive Predictive Value, 94% (80–99%); and Negative Predictive Value, 67% (51–80%). In the patient population that delivered prematurely (before 37 weeks), 81% expressed elevated CD55 mRNA levels with a mean of 0.78 ± 0.03 and 95% CI of 0.71–0.84. The receiver operating characteristics were as follows: Sensitivity, 73% (54–88%); Specificity, 86% (71–95%); Positive Predictive Value, 81.5% (62–94%); and Negative Predictive Value, 80% (64–91%).Conclusion Here we report for the first time that CD55 mRNA expression was elevated in the peripheral WBCs of subjects with preterm labor compared with control gestationally-matched pregnant woman and that elevated leukocyte CD55 may be a useful predictor of subsequent PTB.American Journal Of Reproductive Immunology 04/2009; 61(5):360 - 367. · 3.32 Impact Factor
INFECTION AND IMMUNITY,
Copyright © 1999, American Society for Microbiology. All Rights Reserved.
Sept. 1999, p. 4974–4976Vol. 67, No. 9
Experimental Transmission of Neisseria gonorrhoeae from
Pregnant Rat to Fetus
STELLA NOWICKI,1,2* RANGARAJ SELVARANGAN,1,2AND GARLAND ANDERSON1
Division of Infectious Diseases, Department of Obstetrics & Gynecology,1and Department of Microbiology and
Immunology,2The University of Texas Medical Branch at Galveston, Galveston, Texas 77555-1062
Received 16 February 1999/Returned for modification 16 April 1999/Accepted 15 June 1999
Sprague-Dawley rats were infected on day 20 of pregnancy by intraperitoneal inoculation with Neisseria
gonorrhoeae. Disseminated gonococcal infection (DGI) and pelvic inflammatory disease (PID) strains in the
presence of C1q but not in the presence of bovine serum albumin (BSA) were able to spread from the pregnant
rat to the fetus and resulted in fetal mortality. Transmission of DGI and PID strains that are serum resistant
(serr) and sac-4 positive but not of a local infection strain that is sersand sac-4 negative was facilitated by the
C1q-dependent mechanism. This study provides the first experimental model that may mimic the transmission
of gonococcal infection from mother to the fetus during pregnancy.
Gonorrhea affects 150 million people worldwide annually.
One of the most serious clinical forms of gonococcal infections
is disseminated gonococcal infection (DGI) (36). DGI affects 1
to 3% of patients with gonorrhea (2, 7, 12, 18, 25, 31). Further,
women infected with human immunodeficiency virus (HIV)
are at increased risk of contracting DGI (3, 5, 17, 23, 32).
Gonorrhea during pregnancy increases the risk of DGI (9, 33).
Gestational DGI increases the risk of perinatal infant morbid-
ity and mortality (6, 24, 27). Infected mothers may transmit
Neisseria gonorrhoeae to their newborns during pregnancy or
delivery or in the postpartum period (1, 11, 13, 27). The prev-
alence of prenatal gonococcal infection has been estimated at
about 7.5% among high-risk populations in the United States
(1). Newborns exposed to gonorrhea may develop systemic
illnesses, including septicemia and arthritis. Neonatal sepsis is
a life-threatening disease (1). The factors involved in the trans-
mission of N. gonorrhoeae from the mother to the fetus during
pregnancy are not characterized. The absence of an adequate
experimental model hampers understanding of the mecha-
nisms of transmission of N. gonorrhoeae to the fetus during
pregnancy. Identification of the host and bacterial factors that
increase risk for neonatal gonococcal sepsis would be impor-
tant to understand the mechanism of gestational infection and
to develop novel preventive approaches.
A nonprimate animal model of gonococcal bacteremia in rat
pups was recently developed (28). In this model, intraperito-
neal (i.p.) inoculation of serum-resistant (serr) N. gonorrhoeae
JC1, preincubated with human complement C1q, resulted in
bacteremia that lasted 6 to 7 days (28). Preincubation of strain
JC1 with C1q, instead of the initiation of killing via activation
of the classical complement pathway, protected N. gonorrhoeae
from the bactericidal effect of rat pup serum both in vitro and
in vivo (28).
The purpose of this investigation was to evaluate (i) whether
serrstrains of N. gonorrhoeae that express C1q-mediated viru-
lence may be transmitted from a pregnant mother to the fetus
and (ii) whether human complement C1q may enhance trans-
In the first set of experiments, we investigated whether preg-
nant rats are susceptible to N. gonorrhoeae infection. Three
strains of N. gonorrhoeae, JC1 from DGI, 2005 from pelvic
inflammatory disease (PID), and 1658 from local infection
(LI), were used to infect pregnant rats. Selection of these three
strains was based on significantly different clinical virulence to
humans, which has been shown to correlate with C1q-mediated
peritonitis to rat pups (Table 1). Eighty-six Sprague-Dawley
rats were infected on day 20 of their pregnancy by i.p. inocu-
lation with three different N. gonorrhoeae strains originating
from patients with PID, DGI, and LI. Each group was divided
into two subgroups consisting of those inoculated with 5 ? 108
CFU of N. gonorrhoeae preincubated for 15 min at 37°C with
80 ?g of C1q/ml or bovine serum albumin (BSA) (control).
Human C1q isolated from human serum was shown to be pure
by sodium dodecyl sulfate–5.6% polyacrylamide gel electro-
phoresis and by double immunodiffusion against a goat anti-
C1q monospecific antiserum (Cytotech, San Diego, Calif.)
(20). The C1q was shown to be active by standard hemolytic
assay. BSA (catalog no. A3156) and nonimmune goat serum
(catalog no. S2007) were purchased from Sigma (St. Louis,
Bacterial suspension in buffered saline was prepared from
piliated (P?) and opaque (OP?) colonies (75% P?, OP?).
Twenty-four hours postinoculation, blood samples were col-
lected from pregnant rats and cultured. Pregnant rats were
sacrificed 24 h postinoculation, the uterus was opened imme-
diately, and the number of live and/or infected fetuses was
evaluated. Ten-microliter blood samples were collected from
fetuses by heart puncture without anticoagulant, and dilutions
were made immediately and subcultured on modified Thayer-
Martin agar plates in triplicate and incubated for 48 h in 5%
CO2. Bacterial infection was evaluated by counting CFU per
milliliter of blood. Five pregnant control rats received 200 ?l of
buffer with C1q (80 ?g/ml) i.p. to determine whether C1q
alone influenced pregnancy outcome. Results showed that
none of the three N. gonorrhoeae strains JC1, 2005, or 1658,
pretreated with BSA, were recovered from the blood of the
pregnant rats. Pretreatment of tested strains of N. gonorrhoeae
with C1q did not result in infection of the pregnant rats them-
selves (Table 2); however, the fetuses of these pregnant rats
were infected. It is not clear why adult rats are resistant to
infection, but one possible explanation is that they have bac-
tericidal antibody to N. gonorrhoeae, while pups do not.
Table 2 shows that 100% of live fetuses of pregnant rats
* Corresponding author. Mailing address: Department of Obstetrics
& Gynecology, The University of Texas Medical Branch at Galveston,
301 University Blvd., Galveston, TX 77555-1062. Phone: (409) 772-
7598. Fax: (409) 747-0475. E-mail: email@example.com.
inoculated with N. gonorrhoeae JC1 and 2005 pretreated with
C1q had positive blood cultures, while none inoculated with
strain 1658 pretreated with C1q had positive blood cultures.
Blood cultures of dead fetuses were negative. Furthermore,
the fetuses of pregnant rats inoculated with BSA-pretreated
strain JC1, 2005, or 1658 showed negative blood cultures.
Figure 1 shows quantitative blood cultures of fetuses ob-
tained from one litter. The mean values, expressed as CFU/ml,
of fetal blood for strains JC1 (DGI), 2005 (PID), and 1658 (LI)
were 106, 104, and 0, respectively.
These results demonstrate that N. gonorrhoeae strains asso-
ciated with DGI or PID were able to spread from the pregnant
rats to the fetuses. These two strains possess a 344-bp DNA
fragment of sac-4, conferring resistance to N. gonorrhoeae to
human and rat pup sera and virulence to rat pups in the
presence of C1q (29). The fetuses were not infected in utero
when the pregnant rat was challenged with sersLI strain miss-
ing the 344-bp DNA fragment of sac-4 or with BSA-pretreated
N. gonorrhoeae (DGI, PID, and LI).
The next set of experiments was designed to investigate the
effects of C1q concentration on bacteremia and fetal death.
There was an 18-fold increase in CFU/ml in the blood of
fetuses infected with JC1 and a 7.6-fold increase in the blood
of fetuses infected with strain 2005 treated with a higher con-
centration of C1q (120 ?g/ml) and reached statistical signifi-
cance for both strains. For statistical evaluation of the associ-
ations between two factors, the Fisher exact test was utilized to
determine the significance level. P values less than 0.05 implied
the existence of a statistically significant association between
the tested factors. When pregnant rats were inoculated with
C1q (80 ?g/ml)-pretreated DGI and PID strains, 38.4 and
33.3% of the fetuses, respectively, died (P ? 0.75). With an
increase in the C1q concentration (120 ?g/ml), the death rate
among the fetuses increased to 45.3% (DGI) and 33.7% (PID),
respectively, but did not reach statistical significance (P ?
0.75). Incidentally, human gonococcal infection during preg-
nancy is also associated with 35% infant mortality (27). It is
important that blood cultures from the dead fetuses were neg-
ative. Although the reason for this result is not clear at this
time, it is possible that N. gonorrhoeae cannot survive in dead
animals. Alternatively, fetal death may have been caused by
complement and/or proinflammatory cytokines that could be
induced by lipooligosaccharide released from killed N. gonor-
rhoeae in the maternal bloodstream. This hypothesis is sup-
ported by previous findings that systemic administration of
bacterial lipopolysaccharide to pregnant rats induced fetal re-
sorption or fetal death (4, 10, 37).
The rate of fetal bacteremia correlated with C1q concentra-
tion. The results suggest that C1q not only supported the
spread of N. gonorrhoeae strains carrying the 344-bp DNA
region from the peritoneal cavity of the pregnant rat to the
fetus but also increased morbidity and mortality.
Human C1q is known to activate rat complement (28) and
also protected serrN. gonorrhoeae from the killing effect of rat
pup complement (28). It is, therefore, conceivable that serr
strains inoculated with human C1q activate complement on the
surface of bacteria in vivo without bacterial death. Further
activation of complement in infected fetuses (15) may contrib-
ute to the proinflammatory responses via cytokines, activation
of neutrophils, and the enhancement of vasopermeability and,
therefore, increase virulence to the fetus (9, 12, 22).
Although the precise role of the complement in the patho-
genesis of gonococcal sepsis is not clear (8, 21, 27, 34, 35, 40),
in human bacteremia, complement played an essential role in
septic shock (14, 16, 20, 26, 30, 34, 38, 39). It is also known that
FIG. 1. Recovery of N. gonorrhoeae from fetuses’ blood 24 h after i.p. inoc-
ulation of rats on day 20 of pregnancy with the following three types of N.
gonorrhoeae strains: DGI (JC1), PID (2005), and LI (1658).
TABLE 1. Relevant phenotype and genotype of strains used for experimental infection
aR, serum resistant; S, serum sensitive.
b?, detection of 344-bp DNA fragment of sac-4 region by PCR; ?, negative by PCR.
TABLE 2. Transmission of N. gonorrhoeae from pregnant rats
% Dead fetuses
% Rat fetuses
bThese data represent nine litters from three independent experiments.
c?, N. gonorrhoeae pretreated with C1q (80 ?g/ml); ?, N. gonorrhoeae pre-
treated with BSA (80 ?g/ml).
dBlood culture negative.
eThree litters of rats, including three pregnant rats and 34 ? 5 (mean ?
standard deviation) number of fetuses in each group, were sacrificed and bled
24 h postinoculation. The percentage of pregnant rats with positive blood cul-
tures was 0.
VOL. 67, 1999 NOTES 4975
inhibition of the biologic effects of complement in baboons
with sepsis attenuates the lethal complications (38). It remains
to be investigated whether inhibition of the biologic effects of
complement C1q in pregnant rats may successfully prevent
Overall, we propose that the model showing C1q-dependent
transmission of serrN. gonorrhoeae from mother to fetus may
be relevant for the evaluation of pathogenesis of gestational
gonococcal infection and fetal morbidity. Future studies are
planned to evaluate the molecular mechanisms responsible for
the C1q-dependent mother-fetus transmission of N. gonor-
rhoeae and the inhibition of this process before the onset of
neonatal sepsis and stillbirth.
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Editor: V. A. Fischetti