Influence of Progesterone on Orthopox Viruses in vitro and in vivo

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The influence of progesterone on virus-host-interactions was investigated for orthopox viruses in vitro and in vivo. Virus induced cytopathogenic effects in Vero cells were markedly reduced in presence of the hormone. Dose dependent restriction of viral replication was evaluated by infectivity titration and immunological antigen determination. Progesterone concentrations of 5μg/ml tissue culture medium depressed the production of new viral particles nearly totally. The results obtained by the two different methods indicate that probably later stages of viral synthesis are affected when lower dosages of progesterone are used. The protective activity of progesterone against pathogenic actions of orthopox viruses in vivo was confirmed by using rabbits for intradermal infections. Es wurde der Einfluß von Progesteron auf die Virus-Wirt-Wechselbeziehung am Beispiel der Orthopocken-Viren in vitro und in vivo untersucht. Die virusinduzierten zytopathogenen Effekte in Vero-Zellkulturen wurden in Gegenwart des Hormons deutlich reduziert. Die Hemmung der Virus-Replikation in Abhängigkeit von der Dosis wurde mittels Infektionstitration sowie immunologischer Antigenbestimmung gemessen. Eine Progesteron-Konzentration von 5 μg/ml Zellkulturmedium unterdrückte die Bildung von Viruspartikeln nahezu vollständig. Die Ergebnisse der beiden unterschiedlichen Methoden lassen vermuten, daß durch niedrigere Progesteron-Konzentrationen spätere Stadien der Virussynthese gehemmt werden. Durch intradermale Infektion von Kaninchen konnte die protektive Wirkung von Progesteron gegen zytopathogene Mechanismen der Orthopox-Viren in vivo bestätigt werden.

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... Progesterone (S5) is a sex steroid hormone and the major progestogen in the body. It was found to inhibit orthopox virus in late stages of infection in Vero cells and in live rabbits (Pfahler, Reimann, and Munz 1987). Interestingly, VACV SalF7L (A44L) gene product encodes a protein with 31% identity to 3β-HSD, the enzyme that catalyses the synthesis of progesterone from pregnenolone, and its deletion led to attenuated virulence Smith 1992, Reading, Moore, and. ...
Poxviruses are a family of large, double-stranded DNA viruses that infect a wide range of organisms, from insects to humans. They possess a complex structure and an intricate replication cycle that takes place entirely in the cytoplasm. Additionally, their genome is remarkably large for viruses, encoding over 200 proteins. Historically, one representative of the orthopox genera – variola virus, the causative agent of smallpox – has claimed hundreds of millions of human lives. Despite its eradication, smallpox, and some zoonotic poxviruses, are still considered as potential threats, and new means of combating them are in demand. To this end research has continued on vaccinia virus (VACV), the prototypic orthopox virus which was used as the smallpox vaccine. In this project a library of 1,280 FDA approved molecules was screened for cell-based VACV inhibitors using a high-throughput image-based screen, following the principles of drug repurposing. After confirmation of initial hits using secondary screens, 9 Early inhibitors, 3 Late inhibitors, and 7 Spread inhibitors were identified. Additionally, 14 cardiac glycosides were identified as Early inhibitors. Using focused assays, the specific phases of the virus replication cycle at which inhibition occurs were also identified. This project led to the discovery of new compounds that block VACV infection at different stages in cell culture. Additionally, the initial hits were tested on African swine fever virus and 5 potential inhibitors were identified. Collectively, these results have furthered our insights into host – pathogen interaction, while providing potential hits for testing in animal models and against other viruses.
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SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection is a global medical challenge. Experience based medicines and therapies are being attempted and vaccines are beingdeveloped. SARS-CoV-2 infection exhibits varied patterns of infection and clinical presentations with varied disease outcomes. These attributes are strongly suggestive of some variables that vary among individuals and that affect the course of SARS-CoV-2 infection and symptoms of COVID-19 (Corona Virus Disease of 2019). Sex hormones vary with ageing, between the sexes, among individuals and populations. Sex hormones are known to play a role in immunity and infections. Progesterone is a critical host factor to promote faster recovery following Influenza A virus infection. Anti-inflammatory effects of progesterone are noted.In part 1 of the current study the regulatory role ofprogesterone for SARS-CoV-2 infection and COVID-19 is analyzed. The role of progesterone at different stages of the SARS CoV-2 infection is investigated with respect to two types of immunity status: immune regulation and immune dysregulation.Progesterone could have various alleviating impacts from SARS-CoV-2 entry till recovery: reversing of hypoxia, stabilizing of blood pressure, controlling thrombosis, balancing electrolytes, reducing the viral load, regulation of immune responses, damage repair, and clearance of debris among others. The present research adds to the available evidence by providing a comprehensive and thorough evaluation ofthe regulatory role of progesterone in SARS COV-2 infection, COVID-19 pathogenesis, and immune dysregulation. The available evidencehas implications for upcoming studies about pathophysiology of COVID-19, as well as the roles of progesterone and other hormones in other infectious diseases.
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Effect of progesterone and 17α-hydroxyprogesterone on human erythrocyte membrane was investigated by three methods. 1) Prompt hemolysis test: Progesterone progressively reduced the membrane fragility at the concentration of 1.25×10-5-2.0×10-4 M, but 17α-hydroxyprogesterone had almost no effect. 2) Continuous MCV analysis: When erythrocytes were transferred into 0.9 (w/v) % NaCl solution without progesterone after incubation with 0.5 M d-glucose for 2 hr at 37°C, erythrocytes markedly expanded up to about 140 μm3 and subsequently returned to nearly the original volume (about 95 μm3) within 30-40 sec. Progesterone reduced the reversibility of expanded erythrocytes at the concentration of 1.25×10-5-1.0×10-4 M. 17α-Hydroxyprogesterone had little effect on the reversibility. 3) Scanning electron microscopy: After incubation in isotonic buffered saline solution without progesterone for 12 hr at 37°C, most of the erythrocytes were transformed from discocytes to echinocytes and spheroechinocytes (echinocytes+sphero-echinocytes, >80%). Progesterone (5.0×10-5 and 1.O×10-4 M) inhibited this transformation, so that a greater number of erythrocytes remained as discocytes than in the control. Moreover, at higher concentration of progesterone, stomatocytes emerged prominently (1.0×10-4 M progesterone), followed by the increase in spherocytes (2.0×10-4 M). 17α-Hydroxyprogesterone, however, merely prevented the echinocytic progress from I to II or III at the concentration of 5.0×10-5-2.0×10-4 M and slightly increased the number of discocytes at the higher concentration (2.0×10-4 M). Therefore, progesterone has a direct and prompt effect on the erythrocyte membrane, and it seems to be inserted into the inner half of the membrane bilayer.
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The chicken lysozyme gene can be induced in oviduct cells by four classes of steroid hormones, including glucocorticosteroids and progestins. The glucocorticosteroid receptor of rat liver and the progesterone receptor of rabbit uterus both bind, although with different relative affinities, to two sites in the promoter region of the chicken lysozyme gene located, respectively, between 50 and 80 and between 160 and 200 base pairs upstream of the transcription start point. Now we show that the purified progesterone binding unit of the chicken oviduct progesterone receptor (Mr 110,000, or so-called B subunit) generates a DNase I protection pattern ("footprint") in the promoter-distal site that is longer than the footprint generated by the glucocorticosteroid receptor. Methylation protection studies within the promoter-distal binding site identify four contact points for the chicken progesterone receptor and three contact points for the glucocorticosteroid receptor, of which only one is shared by both receptors. Computer graphics models allow one to envisage a different interaction of each receptor with the B form of the DNA double helix.
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Specific binding of [3H]progesterone to cytosol of Trichophyton mentagrophytes was demonstrated. Scatchard analysis of [3H]progesterone binding showed a single class of binding sites with a dissociation constant of 9.5 X 10(-8) [corrected] +/- 2.4 X 10(-8) M (standard deviation) and a maximal binding capacity of 4,979 +/- 3,489 fmol/mg of cytosol protein. Deoxycorticosterone and dihydrotestosterone competitively inhibited binding by 50% at molar ratios of 10:1 and 20:1, respectively. Other steroid hormones that were tested had minimal activity, indicating binding specificity. Steroid hormone actions in T. mentagrophytes were examined in growth studies. Growth was assessed by determination of cellular ATP content. Progesterone inhibited growth in a dose-responsive manner, with a 50% inhibition concentration of 5.5 X 10(-6) M. Partial recovery from inhibition occurred after 24 to 48 h; inhibition could be enhanced by dividing the amount of added progesterone every 24 h. In the same rank order as was their relationship to each other and progesterone in binding studies, deoxycorticosterone and dihydrotestosterone were less effective inhibitors; other steroid hormones that were tested showed no consistent effect. We hypothesize that the binder described, acting as a hormone receptor, is the molecular site of action for the functional effect of the hormone. The functional effect may be related to the observed resistance of females to dermatophytosis.
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Evidence that disease due to the thermally dimorphic fungus Paracoccidioides brasiliensis occurs post-puberty predominantly in males led us to hypothesize that hormonal factors critically affect its pathogenesis. We show here that estrogens inhibit mycelial- to yeast-form transformation of P. brasiliensis in vitro. Transformation of three isolates was inhibited to 71, 33, and 19% of the control values in the presence of 10(-10), 10(-8), and 10(-6) M 17 beta-estradiol, respectively. The synthetic estrogen diethylstilbestrol was active but less potent than estradiol, whereas testosterone, 17 alpha-estradiol, tamoxifen, and corticosterone were inactive. This function was specifically inhibited, since yeast-to-mycelium transformation, yeast growth, and yeast reproduction by budding were unaffected by 17 beta-estradiol. Of note is the fact that mycelium-to-yeast transformation occurs as the first step in vivo in the establishment of infection. The cytosol of the three isolates studied possesses a steroid-binding protein which has high affinity for 17 beta-estradiol. We believe that this binding protein represents a P. brasiliensis hormone receptor which can also recognize mammalian estrogens. We hypothesize that the ability of estrogen to decrease or delay mycelium-to-yeast transformation at the initial site of infection contributes to or is responsible for the marked resistance of females, and that the binder described is the molecular site of action.
Some 3-keto-Δ4 steroids and diethylstilboestrol significantly inhibited the growth of Entamoeba invadens in a bacteria-free medium containing fresh liver. The inhibitory action of the steroids is not as great in the presence of fresh liver as in the presence of bacteria. The possible relationship between the degree of inhibition and steroid structural formulae is considered. No compound tested affected the growth of Acanthamoeba castellanii or Hartmanella rhysoides.
A biotin-avidin amplified enzyme immunoassay has been established for detection of antibodies to camelpox virus. Test conditions were optimized and sera of 60 camels previously examined by a conventional ELISA were tested at a 1: 100 dilution level. Results were expressed as antibody activities and could be transformed to corresponding endpoint titres using a calibration curve. Sensitivity, specificity and technical performance of the biotin-avidin approach presented in this paper seem to be superior to the standard ELISA which involved direct conjugation of enzymes to antibodies. Ein Biotin-Avidin verstärkter Enzym-Immun-Test zum Nachweis und zur Quantifizierung von Orthopoxvirus cameli Antikörpern in Dromedaren Zum Nachweis von Antikörpern gegen Kamelpockenviren wurde ein mittels Biotin und Avidin verstärkter Enzym-Immun-Test ausgearbeitet. Die Versuchsbedingungen wurden optimiert und 60 — bereits mit einem herkömmlichen ELISA untersuchte — Sera von Kamelen wurden bei einer Verdünnung von 1: 100 getestet. Die Ergebnisse wurden als Antikörperaktivität ausgedrückt und konnten mit Hilfe einer Eichkurve in entsprechende Endtiter übergeführt werden. Empfindlichkeit, Spezifität und technische Durchführung der in dieser Arbeit dargestellten Biotin-Avidin-Methode scheinen einem — auf der Verwendung von direkt an Antikörper konjugierte Enzyme beruhenden — Standard-ELISA überlegen zu sein.
Progesterone was examined for action on the virulence of Listeria monocytogenes and the toxicity of its haemolysin. Progesterone at concentrations between 5 and 20 micrograms/ml reduced the numbers of L. monocytogenes over the first two hours of growth. Virulence and haemolysin toxicity were assessed using the allantoic sac route of inoculation into embryonated hens eggs. Increasing the concentrations of progesterone in the culture medium resulted in a decrease in the mortality of chick embryos inoculated with either organisms, or cell-free extracts or purified haemolysin. Progesterone had no effect on the lethality of pre-formed haemolysin.
Serum samples from progesterone-oestrogen-treated ovariectomized Holstein cows (N = 4) were compared with samples from control ovariectomized Holstein cows (N = 4) to determine the effects of physiological levels (0-6 ng/ml) of circulating progesterone. The average progesterone level in treated animals rose from 1 ng/ml (Day 0) to plateau at 5 ng/ml (Days 12 to 36). Sera from progesterone-oestrogen-treated cows during Days 4 to 10 significantly suppressed stimulation of lymphocytes by phytohaemagglutinin as compared with sera from control cows (P = 0.02), whereas no differences were detected in serum samples from Days 12 to 36. Serum samples from progesterone-oestrogen-treated or control cows did not affect the stimulation of lymphocytes by pokeweed mitogen. Sialyltransferase activity (P = 0.0002) and sialic acid content (P = 0.006) were both significantly elevated in serum from progesterone-oestrogen-treated animals compared with controls during Days 8 to 16, whereas no significant differences were observed at later times. The results suggest that suppression of phytohaemagglutinin-induced stimulation, sialic acid content, and sialyltransferase activity are sensitive not to the circulating level of progesterone but rather to increases in progesterone concentration, with maximal effects observed at Days 8, 12 and 12, respectively, after the start of progesterone treatment. The work provides a preliminary basis for further studies on the mechanism of immunosuppression by steroids and during pregnancy.
[4-14C]Progesterone was incubated with homogenate and mitochondrial, microsomal and soluble fraction preparations of healthy and inflamed gingiva from human subjects of both sexes. The subcellular preparations were supplemented with an NADPH-regenerating system and incubated for 2 h at pH 7.4 and 37 degrees C. The metabolites were identified by column, multiple TLC and radioautography and quantified with liquid scintillation counting. In inflamed tissue the metabolic activity was higher than in healthy gingiva. On the basis of the identified metabolites it can be concluded that the human gingiva of both sexes contains marked 3 alpha-, 3 beta- and 20 alpha-hydroxysteroid dehydrogenase, delta 4-5 alpha- and delta 4-5 beta-steroid hydrogenase activities, and less 20 beta-hydroxysteroid dehydrogenase activity.
Yotis, William (Loyola University, Hines, Ill.), and Ronald Stanke. Bacteriostatic action of progesterone on staphylococci and other microorganisms. J. Bacteriol. 92 1285–1289. 1966.—Progesterone has been examined in vitro for antibacterial activity against 10 microorganisms. Turbidimetric and manometric techniques were used to assay the antibacterial activity of progesterone. The organisms tested consisted of Staphylococcus aureus, S. epidermidis, Gaffkya tetragena, Bacillus subtilis, Listeria monocytogenes, Candida albicans, Escherichia coli, Aerobacter aerogenes, Salmonella paratyphi, and Proteus vulgaris. Antibacterial action was shown by progesterone only against the gram-positive microorganisms when they were grown in tryptic soy broth containing 10 to 20 μg of progesterone per ml. Pregnenolone, 4-pregnen-20β-ol-3-one, and 5α-pregnane also possessed antistaphylococcal properties, whereas pregnanolone, pregnandione, 11α-hydroxyprogesterone, and 17α-hydroxyprogesterone did not. The bacteriostatic action of progesterone on staphylococci was exerted primarily during the first 8 hr of incubation, and it was reduced in the presence of oxygen. In the presence of 20 μg of progesterone per ml, there was significant reduction in the oxidation by resting staphylococcal suspensions or utilization by staphylococci of pyruvate as an energy source during growth.
The yield of Aspergillus niger mycelium from a synthetic medium can be increased by the addition of microgram quantities of cholesterol, ergosterol, cholestanol, 7-dehydrocholesterol, stigmasterol, sitosterol, pregnenolone, and the vitamins D. The stimulation is not due to degradation to the acetate level. It is obtained only in highly aerated cultures. The rate of growth of Torula utilis was not increased. Both organisms were inhibited by desoxycorticosterone, testosterone, androstenedione, cortisone acetate, progesterone, and diethylstilbestrol. T. utilis was also inhibited by estradiol. A small decrease in progesterone inhibition of T. utilis was obtained by adding ergosterol, cholesterol, or pregnenolone. Of the compounds which have been adequately tested the order of stimulatory activity for A. niger is: ergosterol > cholesterol > stigmasterol > 7-dehydrocholesterol > cholestanol > pregnenolone. Progesterone was inhibitory at low concentrations but stimulatory at higher ones, while 17-hydroxyprogesterone was neither inhibitory nor stimulatory. Desoxycorticosterone and testosterone were inhibitory at all concentrations. Complete inhibition of the growth of the fungus was not obtained with any of the steroids. It is concluded that A. niger has a metabolic requirement for a steroid with a hydroxy group on carbon 3, a double bond in the 5–6 position, and a side chain similar to that in ergosterol or cholesterol and that this material is growth-limiting in the early stages of the cultures described.
Progesterone binding and inhibition of growth in Trichophyton mentagrophytes Immunsuppres-sion, sialic acid, and sialyltransferase of bovine serum as a function of progesterone concentra-tion
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