scholarly journals Chlamydia-Specific IgA Secretion in the Female Reproductive Tract Induced via Per-Oral Immunization Confers Protection against Primary Chlamydia Challenge

2020 ◽  
Vol 89 (1) ◽  
pp. e00413-20
Author(s):  
Nita Shillova ◽  
Savannah E. Howe ◽  
Besmir Hyseni ◽  
Deahneece Ridgell ◽  
Derek J. Fisher ◽  
...  
Keyword(s):  
Reproductive Tract ◽  
Transmitted Disease ◽  
Oral Immunization ◽  
Female Reproductive Tract ◽  
Infection Model ◽  
Content Type ◽  
Sexually Transmitted ◽  
Mouse Infection Model ◽  
Per Oral

ABSTRACTChlamydia trachomatis is an obligate intracellular pathogen that causes sexually transmitted disease. In women, chlamydial infections may cause pelvic inflammatory disease (PID), ectopic pregnancy, and infertility. The role of antibodies in protection against a primary Chlamydia infection is unclear and was a focus of this work. Using the C. muridarum mouse infection model, we show that intestinal mucosa is infected via intranasal (i.n.) or per-oral (p.o.) Chlamydia inoculation and that unlike the female reproductive tract (FRT) mucosa, it halts systemic Chlamydia dissemination. Moreover, p.o. immunization or infection with Chlamydia confers protection against per-vaginal (p.v.) challenge, resulting in significantly decreased bacterial burden in the FRT, accelerated Chlamydia clearance, and reduced hydrosalpinx pathology. In contrast, subcutaneous (s.c.) immunization conferred no protection against the p.v. challenge. Both p.o. and s.c. immunizations induced Chlamydia-specific serum IgA. However, IgA was found only in the vaginal washes and fecal extracts of p.o.-immunized animals. Following a p.v. challenge, unimmunized control and s.c.-s.c.-immunized animals developed Chlamydia-specific intestinal IgA yet failed to develop IgA in the FRT, indicating that IgA response in the FRT relies on the FRT to gastrointestinal tract (GIT) antigen transport. Vaginal secretions of p.o.-immunized animals neutralize Chlamydia in vivo, resulting in significantly lower Chlamydia burden in the FRT and Chlamydia transport to the GIT. We also show that infection of the GIT is not necessary for induction of protective immunity in the FRT, a finding that is important for the development of p.o. subunit vaccines to target Chlamydia and possibly other sexually transmitted pathogens.

scholarly journals Simultaneous Administration of 2-Aminoethyl Diphenylborinate and Chloroquine Reverses Chloroquine Resistance in Malaria Parasites

2015 ◽  
Vol 59 (5) ◽  
pp. 2890-2892 ◽  
Author(s):  
Ehab Mossaad ◽  
Wakako Furuyama ◽  
Masahiro Enomoto ◽  
Satoru Kawai ◽  
Katsuhiko Mikoshiba ◽  
...  
Keyword(s):  
Chloroquine Resistance ◽  
Infection Model ◽  
Simultaneous Administration ◽  
Plasmodium Chabaudi ◽  
Content Type ◽  
Mouse Infection Model ◽  
Complete Reversal ◽  
The Mean

ABSTRACTA nearly complete reversal of chloroquine (CQ) resistance in the CQ-resistantPlasmodium falciparumK-1 strain, with a significant decrease in the mean ± standard deviation (SD) 50% inhibitory concentration (IC50) from 1,050 ± 95 nM to 14 ± 2 nM, was achievedin vitroby the simultaneous administration of 2-aminoethyl diphenylborinate (2-APB). The CQ resistance-reversing activity of 2-APB, which showed the same efficacy as verapamil, was also observed in anin vivomouse infection model with the CQ-resistantPlasmodium chabaudiAS(30CQ) strain.

scholarly journals Genome-Wide Mutagenesis Identifies Factors Involved in Enterococcus faecalis Vaginal Adherence and Persistence

2020 ◽  
Vol 88 (10) ◽  
Author(s):  
Norhan Alhajjar ◽  
Anushila Chatterjee ◽  
Brady L. Spencer ◽  
Lindsey R. Burcham ◽  
Julia L. E. Willett ◽  
...  
Keyword(s):  
Enterococcus Faecalis ◽  
Reproductive Tract ◽  
Female Reproductive Tract ◽  
Complex Nature ◽  
Aerobic Vaginitis ◽  
Content Type ◽  
Vaginal Colonization ◽  
Vaginal Tract

ABSTRACT Enterococcus faecalis is a Gram-positive commensal bacterium native to the gastrointestinal tract and an opportunistic pathogen of increasing clinical concern. E. faecalis also colonizes the female reproductive tract, and reports suggest vaginal colonization increases following antibiotic treatment or in patients with aerobic vaginitis. Currently, little is known about specific factors that promote E. faecalis vaginal colonization and subsequent infection. We modified an established mouse vaginal colonization model to explore E. faecalis vaginal carriage and demonstrate that both vancomycin-resistant and -sensitive strains colonize the murine vaginal tract. Following vaginal colonization, we observed E. faecalis in vaginal, cervical, and uterine tissue. A mutant lacking endocarditis- and biofilm-associated pili (Ebp) exhibited a decreased ability to associate with human vaginal and cervical cells in vitro but did not contribute to colonization in vivo. Thus, we screened a low-complexity transposon (Tn) mutant library to identify novel genes important for E. faecalis colonization and persistence in the vaginal tract. This screen revealed 383 mutants that were underrepresented during vaginal colonization at 1, 5, and 8 days postinoculation compared to growth in culture medium. We confirmed that mutants deficient in ethanolamine catabolism or in the type VII secretion system were attenuated in persisting during vaginal colonization. These results reveal the complex nature of vaginal colonization and suggest that multiple factors contribute to E. faecalis persistence in the reproductive tract.

scholarly journals Pharmacodynamics of Isavuconazole in an Aspergillus fumigatus Mouse Infection Model

2015 ◽  
Vol 59 (5) ◽  
pp. 2855-2866 ◽  
Author(s):  
Seyedmojtaba Seyedmousavi ◽  
Roger J. M. Brüggemann ◽  
Jacques F. Meis ◽  
Willem J. G. Melchers ◽  
Paul E. Verweij ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Drug Exposure ◽  
Quantitative Relationship ◽  
Maximum Effect ◽  
Infection Model ◽  
Wild Type ◽  
Content Type ◽  
Type Isolate ◽  
Mouse Infection Model

ABSTRACTAzole resistance is an emerging problem inAspergillus fumigatuswhich translates into treatment failure. Alternative treatments with new azoles may improve therapeutic outcome in invasive aspergillosis (IA) even for strains with decreased susceptibility to current azoles. Thein vivoefficacy of 0.25, 1, 4, 16, 64, 128, 256, and 512 mg/kg of body weight/day prodrug isavuconazonium sulfate (BAL8557) (isavuconazole [ISA]-equivalent doses of 0.12, 0.48, 1.92, 7.68, 30.7, 61.4, 122.9, and 245.8 mg/kg/day, respectively) administered by oral gavage was assessed in an immunocompetent murine model of IA against four clinicalA. fumigatusisolates: a wild-type isolate (ISA MICEUCAST, 0.5 mg/liter) and three azole-resistant isolates harboring substitutions in thecyp51Agene: G54W (ISA MICEUCAST, 0.5 mg/liter), M220I (ISA MICEUCAST, 4 mg/liter), and TR34/L98H (ISA MICEUCAST, 8 mg/liter). The maximum effect (100% survival) was reached at a prodrug isavuconazonium sulfate dose of 64 mg/kg for the wild-type isolate, 128 mg/kg for the G54W mutant, and 256 mg/kg two times per day (q12) for the M220I mutant. A maximum response was not achieved with the TR34/L98H isolates with the highest dose of prodrug isavuconazonium sulfate (256 mg/kg q12). For a survival rate of 50%, the effective AUC0–24/MICEUCASTratio for ISA total drug was 24.73 (95% confidence interval, 22.50 to 27.18). The efficacy of isavuconazole depended on both the drug exposure and the isavuconazole MIC of the isolates. The quantitative relationship between exposure and effect (AUC0–24/MIC) can be used to optimize the treatment of human infections byA. fumigatus, including strains with decreased susceptibility.

Sexually transmitted disease in birds: occurrence and evolutionary significance

1993 ◽  
Vol 339 (1290) ◽  
pp. 491-497 ◽  
Keyword(s):  
Mate Choice ◽  
Reproductive Tract ◽  
Transmitted Disease ◽  
Female Reproductive Tract ◽  
Reproductive Physiology ◽  
Evolutionary Significance ◽  
Sexually Transmitted ◽  
Secondary Sexual Characteristics ◽  
Sexual Characteristics ◽  
Sexual Selection Theory

Sexually transmitted diseases (STDS) span two current areas of sexual selection theory, namely the roles of multiple mating in determining individual reproductive success, and of parasites in mate choice, yet have been relatively neglected in the ecological literature. I reviewed the occurrence of STDS in populations of commercially kept birds and found widespread evidence for the existence of pathogenic STDS in such populations. STDs may have important consequences for the evolution of behaviour, reproductive physiology and some secondary sexual characteristics. Where STDS are costly they are hypothesized to affect the evolution of mating systems, and, via selection for hostility in the female reproductive tract, to explain high levels of sperm mortality after insemination. The potential for coevolutionary cycling is large, as some STDS may coevolve with female and male reproductive physiology, which may themselves coevolve. Although little information currently exists concerning the occurrence of STDS in wild birds, techniques for their identification are well established. This study raises a number of testable predictions about the consequences of STDS for avian reproductive biology, and I suggest that stds should be considered as a potentially powerful factor in future studies of mate choice and sperm competition.

scholarly journals Linker Editing of Pneumococcal Lysin ClyJ Conveys Improved Bactericidal Activity

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
Hang Yang ◽  
Dehua Luo ◽  
Irina Etobayeva ◽  
Xiaohong Li ◽  
Yujing Gong ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Protective Efficacy ◽  
Infection Model ◽  
Content Type ◽  
Bacterial Surface ◽  
Linker Sequence ◽  
Cell Wall Binding ◽  
Mouse Infection Model ◽  
Intraperitoneal Dose

ABSTRACT Streptococcus pneumoniae is a leading human pathogen uniquely characterized by choline moieties on the bacterial surface. Our previous work reported a pneumococcus-specific chimeric lysin, ClyJ, which combines the CHAP (cysteine, histidine-dependent amidohydrolase/peptidase) enzymatically active domain (EAD) from the PlyC lysin and the cell wall binding domain (CBD) from the phage SPSL1 lysin, which imparts choline binding specificity. Here, we demonstrate that the lytic activity of ClyJ can be further improved by editing the linker sequence adjoining the EAD and CBD. Keeping the net charge of the linker constant, we constructed three ClyJ variants containing different lengths of linker sequence. Circular dichroism showed that linker editing has only minor effects on the folding of the EAD and CBD. However, thermodynamic examination combined with biochemical analysis demonstrated that one variant, ClyJ-3, with the shortest linker, displayed improved thermal stability and bactericidal activity, as well as reduced cytotoxicity. In a pneumococcal mouse infection model, ClyJ-3 showed significant protective efficacy compared to that of the ClyJ parental lysin or the Cpl-1 lysin, with 100% survival at a single ClyJ-3 intraperitoneal dose of 100 μg/mouse. Moreover, a ClyJ-3 dose of 2 μg/mouse had the same efficacy as a ClyJ dose of 40 μg/mouse, suggesting a 20-fold improvement in vivo. Taking these results together, the present study not only describes a promising pneumococcal lysin with improved potency, i.e., ClyJ-3, but also implies for the first time that the linker sequence plays an important role in determining the activity of a chimeric lysin, providing insight for future lysin engineering studies.

scholarly journals Effect of Macrolide and Rifampin Resistance on Fitness of Rhodococcus equi during Intramacrophage Replication and In Vivo

2019 ◽  
Vol 87 (10) ◽  
Author(s):  
Jennifer M. Willingham-Lane ◽  
Londa J. Berghaus ◽  
Roy D. Berghaus ◽  
Kelsey A. Hart ◽  
Steeve Giguère
Keyword(s):  
Resistant Strain ◽  
Clinical Signs ◽  
Rhodococcus Equi ◽  
Infection Model ◽  
Content Type ◽  
Mouse Infection Model ◽  
Pulmonary Macrophages ◽  
Rifampin Resistance

ABSTRACT The soil-dwelling, saprophytic actinomycete Rhodococcus equi is a facultative intracellular pathogen of macrophages and causes severe bronchopneumonia when inhaled by susceptible foals. Standard treatment for R. equi disease is dual-antimicrobial therapy with a macrolide and rifampin. Thoracic ultrasonography and early treatment with antimicrobials prior to the development of clinical signs are used as means of controlling endemic R. equi infection on many farms. Concurrently with the increased use of macrolides and rifampin for chemoprophylaxis and the treatment of subclinically affected foals, a significant increase in the incidence of macrolide- and rifampin-resistant R. equi isolates has been documented. Previously, our laboratory demonstrated decreased fitness of R. equi strains that were resistant to macrolides, rifampin, or both, resulting in impaired in vitro growth in iron-restricted media and in soil. The objective of this study was to examine the effect of macrolide and/or rifampin resistance on intracellular replication of R. equi in equine pulmonary macrophages and in an in vivo mouse infection model in the presence and absence of antibiotics. In equine macrophages, the macrolide-resistant strain did not increase in bacterial numbers over time and the dual macrolide- and rifampin-resistant strain exhibited decreased proliferation compared to the susceptible isolate. In the mouse model, in the absence of antibiotics, the susceptible R. equi isolate outcompeted the macrolide- or rifampin-resistant strains.

scholarly journals In VivoGrowth Rates Are Poorly Correlated with Phage Therapy Success in a Mouse Infection Model

2011 ◽  
Vol 56 (2) ◽  
pp. 949-954 ◽  
Author(s):  
J. J. Bull ◽  
G. Otto ◽  
I. J. Molineux
Keyword(s):  
Phage Therapy ◽  
Growth Dynamics ◽  
Infection Model ◽  
Content Type ◽  
Phage Types ◽  
Mouse Infection Model ◽  
Slight Growth ◽  
Therapy Success ◽  
K1 Capsule

ABSTRACTTwo classes of phages yield profoundly different levels of recovery in mice experimentally infected with anEscherichia coliO18:K1:H7 strain. Phages requiring the K1 capsule for infection (K1-dep) rescue virtually all infected mice, whereas phages not requiring the capsule (K1-ind) rescue modest numbers (∼30%). To rescue infected mice, K1-ind phages require at least a 106-fold-higher inoculum than K1-dep phages. Yet theirin vivogrowth dynamics are only modestly inferior to those of K1-dep phages, and competition between the two phage types in the same mouse reveals only a slight growth advantage for the K1-dep phage. Thein vivogrowth rate seems unlikely to be the primary determinant of phage therapy success. An alternative explanation is that the success of K1-dep phages is due substantially to their proteomic composition. They encode an enzyme that degrades the K1 capsule, which has been shown in other work to be sufficient to cure infection in the complete absence of phages.

scholarly journals Orientia tsutsugamushiIs Highly Susceptible to the RNA Polymerase Switch Region Inhibitor Corallopyronin AIn VitroandIn Vivo

2018 ◽  
Vol 62 (4) ◽  
pp. e01732-17 ◽  
Author(s):  
Fredericke Kock ◽  
Matthias Hauptmann ◽  
Anke Osterloh ◽  
Till F. Schäberle ◽  
Sven Poppert ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Scrub Typhus ◽  
Adaptive Immune Response ◽  
Antimicrobial Treatment ◽  
Infection Model ◽  
Switch Region ◽  
Content Type ◽  
Mouse Infection Model

ABSTRACTScrub typhus is a potentially lethal infection caused by the obligate intracellular bacteriumOrientia tsutsugamushi. Reports on the emergence of doxycycline-resistant strains highlight the urgent need to develop novel antiinfectives against scrub typhus. Corallopyronin A (CorA) is a novel α-pyrone compound synthesized by the myxobacteriumCorallococcus coralloidesthat was characterized as a noncompetitive inhibitor of the switch region of the bacterial RNA polymerase (RNAP). We investigated the antimicrobial action of CorA against the human-pathogenic Karp strain ofO. tsutsugamushiin vitroandin vivo. The MIC of CorA againstO. tsutsugamushiwas remarkably low (0.0078 μg/ml), 16-fold lower than that againstRickettsia typhi. In the lethal intraperitonealO. tsutsugamushimouse infection model, a minimum daily dose of 100 μg CorA protected 100% of infected mice. Two days of treatment were sufficient to confer protection. In contrast to BALB/c mice, SCID mice succumbed to the infection despite treatment with CorA or tetracycline, suggesting that antimicrobial treatment required synergistic action of the adaptive immune response. Similar to tetracycline, CorA did not prevent latent infection ofO. tsutsugamushiin vivo. However, latency was not caused by acquisition of antimicrobial resistance, sinceO. tsutsugamushireisolated from latently infected BALB/c mice remained fully susceptible to CorA. No mutations were found in the CorA-binding regions of the β and β′ RNAP subunit genesrpoBandrpoC. Inhibition of the RNAP switch region ofO. tsutsugamushiby CorA is therefore a novel and highly potent target for antimicrobial therapy for scrub typhus.

scholarly journals In VivoEfficacy of Anuran Trypsin Inhibitory Peptides against Staphylococcal Skin Infection and the Impact of Peptide Cyclization

2015 ◽  
Vol 59 (4) ◽  
pp. 2113-2121 ◽  
Author(s):  
U. Malik ◽  
O. N. Silva ◽  
I. C. M. Fensterseifer ◽  
L. Y. Chan ◽  
R. J. Clark ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Cyclic Peptide ◽  
Sequence Similarity ◽  
Infection Model ◽  
Content Type ◽  
Wide Range ◽  
Inhibitory Activities ◽  
The Impact

ABSTRACTStaphylococcus aureusis a virulent pathogen that is responsible for a wide range of superficial and invasive infections. Its resistance to existing antimicrobial drugs is a global problem, and the development of novel antimicrobial agents is crucial. Antimicrobial peptides from natural resources offer potential as new treatments against staphylococcal infections. In the current study, we have examined the antimicrobial properties of peptides isolated from anuran skin secretions and cyclized synthetic analogues of these peptides. The structures of the peptides were elucidated by nuclear magnetic resonance (NMR) spectroscopy, revealing high structural and sequence similarity with each other and with sunflower trypsin inhibitor 1 (SFTI-1). SFTI-1 is an ultrastable cyclic peptide isolated from sunflower seeds that has subnanomolar trypsin inhibitory activity, and this scaffold offers pharmaceutically relevant characteristics. The five anuran peptides were nonhemolytic and noncytotoxic and had trypsin inhibitory activities similar to that of SFTI-1. They demonstrated weakin vitroinhibitory activities againstS. aureus, but several had strong antibacterial activities againstS. aureusin anin vivomurine wound infection model. pYR, an immunomodulatory peptide fromRana sevosa, was the most potent, with complete bacterial clearance at 3 mg · kg−1. Cyclization of the peptides improved their stability but was associated with a concomitant decrease in antimicrobial activity. In summary, these anuran peptides are promising as novel therapeutic agents for treating infections from a clinically resistant pathogen.

scholarly journals Efficacy of Humanized Cefiderocol Exposures over 72 Hours against a Diverse Group of Gram-Negative Isolates in the Neutropenic Murine Thigh Infection Model

2018 ◽  
Vol 63 (2) ◽  
pp. e01040-18 ◽  
Author(s):  
Sean M. Stainton ◽  
Marguerite L. Monogue ◽  
Masakatsu Tsuji ◽  
Yoshinori Yamano ◽  
Roger Echols ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acinetobacter Baumannii ◽  
Infection Model ◽  
Diverse Group ◽  
Gram Negative ◽  
Content Type ◽  
Adaptive Resistance

ABSTRACT Herein, we evaluated sustainability of humanized exposures of cefiderocol in vivo over 72 h against pathogens with cefiderocol MICs of 0.5 to 16 μg/ml in the neutropenic murine thigh model. In Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae displaying MICs of 0.5 to 8 μg/ml (n = 11), sustained kill was observed at 72 h among 9 isolates. Postexposure MICs revealed a single 2-dilution increase in one animal compared with controls (1/54 samples, 1.8%) at 72 h. Adaptive resistance during therapy was not observed.

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