Intracellularly Released Cholesterol from Polymer-Based Delivery Systems Alters Cellular Responses to Pneumolysin and Promotes Cell Survival

Cholesterol is highly abundant within all human body cells and modulates critical cellular functions related to cellular plasticity, metabolism, and survival. The cholesterol-binding toxin pneumolysin represents an essential virulence factor of Streptococcus pneumoniae in establishing pneumonia and other pneumococcal infections. Thus, cholesterol scavenging of pneumolysin is a promising strategy to reduce S. pneumoniae induced lung damage. There may also be a second cholesterol-dependent mechanism whereby pneumococcal infection and the presence of pneumolysin increase hepatic sterol biosynthesis. Here we investigated a library of polymer particles varying in size and composition that allow for the cellular delivery of cholesterol and their effects on cell survival mechanisms following pneumolysin exposure. Intracellular delivery of cholesterol by nanocarriers composed of Eudragit E100–PLGA rescued pneumolysin-induced alterations of lipid homeostasis and enhanced cell survival irrespective of neutralization of pneumolysin.

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Antimicrobial resistance profile and multidrug resistance patterns of Streptococcus pneumoniae isolates from patients suspected of pneumococcal infections in Ethiopia

Annals of Clinical Microbiology and Antimicrobials ◽

10.1186/s12941-021-00432-z ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Bekele Sharew ◽

Feleke Moges ◽

Gizachew Yismaw ◽

Wondwossen Abebe ◽

Surafal Fentaw ◽

...

Keyword(s):

Multidrug Resistance ◽

Streptococcus Pneumoniae ◽

Antimicrobial Resistance ◽

Addis Ababa ◽

Pneumococcal Infection ◽

Test Method ◽

Resistance Testing ◽

Global Public Health ◽

Pneumococcal Infections ◽

Resistance Patterns

Abstract Background Antimicrobial-resistant strains of Streptococcus pneumoniae have become one of the greatest challenges to global public health today and inappropriate use of antibiotics and high level of antibiotic use is probably the main factor driving the emergence of resistance worldwide. The aim of this study is, therefore, to assess the antimicrobial resistance profiles and multidrug resistance patterns of S. pneumoniae isolates from patients suspected of pneumococcal infections in Ethiopia. Methods A hospital-based prospective study was conducted from January 2018 to December 2019 at Addis Ababa city and Amhara National Region State Referral Hospitals. Antimicrobial resistance tests were performed from isolates of S. pneumoniae that were collected from pediatric and adult patients. Samples (cerebrospinal fluid, blood, sputum, eye discharge, ear discharge, and pleural and peritoneal fluids) from all collection sites were initially cultured on 5% sheep blood agar plates and incubated overnight at 37 °C in a 5% CO2 atmosphere. Streptococcus pneumoniae was identified and confirmed by typical colony morphology, alpha-hemolysis, Gram staining, optochin susceptibility, and bile solubility test. Drug resistance testing was performed using the E-test method according to recommendations of the Clinical and Laboratory Standards Institute. Results Of the 57 isolates, 17.5% were fully resistant to penicillin. The corresponding value for both cefotaxime and ceftriaxone was 1.8%. Resistance rates to erythromycin, clindamycin, tetracycline, chloramphenicol and trimethoprim-sulfamethoxazole were 59.6%, 17.5%, 38.6%, 17.5 and 24.6%, respectively. Multidrug resistance (MDR) was seen in 33.3% isolates. The most common pattern was co-resistance to penicillin, erythromycin, clindamycin, and tetracycline. Conclusions Most S. pneumoniae isolates were susceptible to ceftriaxone and cefotaxime. Penicillin has been used as a drug of choice for treating S. pneumoniae infection. However, antimicrobial resistance including multidrug resistance was observed to several commonly used antibiotics including penicillin. Hence, it is important to periodically monitor the antimicrobial resistance patterns to select empirical treatments for better management of pneumococcal infection.

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Antimicrobial resistance profile and multidrug resistance patterns of Streptococcus pneumoniae isolates from patients suspected for pneumococcal infections in Ethiopia

10.21203/rs.3.rs-97782/v1 ◽

2020 ◽

Author(s):

BEKELE SHAREW ◽

Feleke Moges ◽

Gizachew Yismaw ◽

Wondiwossen Abebe ◽

Surafal Fentaw ◽

...

Keyword(s):

Multidrug Resistance ◽

Streptococcus Pneumoniae ◽

Antimicrobial Resistance ◽

Addis Ababa ◽

Pneumococcal Infection ◽

Test Method ◽

Resistance Testing ◽

Global Public Health ◽

Pneumococcal Infections ◽

Resistance Patterns

Abstract Backgrounds: Streptococcus pneumoniae is one of the leading causes of bacterial meningitis and pneumoniae in elderly people and children. Antimicrobial resistant strains of Streptococcus pneumoniae has been detected in all parts of the world and become one of the greatest challenges to global public health today. The aim of this study is therefore, to assess the antimicrobial resistance profiles and multidrug resistance patterns of S. pneumoniae isolates from patients suspected for pneumococcal infections in Ethiopia. Methods: A hospital-based prospective study was conducted from 2018 to 2019 at Addis Ababa and Amhara region referral hospitals. Antimicrobial resistance tests were performed on 57 isolates of S. pneumoniae that were collected from pediatric and adult patients. Samples (cerebrospinal fluid, blood, sputum, eye discharge, ear discharge, pleural and peritoneal fluids) from all collection sites were initially cultured onto 5 % sheep blood agar plates and incubated overnight at 370C in 5% CO2 atmosphere. S. pneumoniae was identified and confirmed by typical colony morphology, alpha-hemolysis, Gram staining, optochin susceptibility and bile solubility test. Drug resistance testing was performed using E-test method according to recommendations of the Clinical and Laboratory Standards Institute.Results: Of the 57 isolates, 17.5% were fully resistant to penicillin. Corresponding value for both cefotaxime and ceftriaxone was 1.8%. Resistance rates to erythromycin, clindamycin, tetracycline, chloramphenicol and trimethoprim-sulfamethoxazole were 59.6%, 17.5%, 38.6%, 17.5% and 24.6%, respectively. Multidrug resistance (MDR) was seen in 33.3% isolates. The most common pattern was co-resistance to penicillin, erythromycin, clindamycin and tetracycline.Conclusions: Most bacterial isolates were susceptible to Ceftriaxone and Cefotaxime. Penicillin has been used as a drug of choice for treating S. pneumoniae infection. However, antimicrobial resistance including multidrug resistance was observed to a number of commonly used antibiotics including penicillin. Hence, it is important to periodically monitor the antibiotic resistance patterns to choose empirical treatments for better management of pneumococcal infection.

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Chronic graft versus host disease is associated with long-term risk for pneumococcal infections in recipients of bone marrow transplants

Blood ◽

10.1182/blood.v95.12.3683 ◽

2000 ◽

Vol 95 (12) ◽

pp. 3683-3686 ◽

Cited By ~ 99

Author(s):

Samar Kulkarni ◽

Ray Powles ◽

Jennie Treleaven ◽

Unell Riley ◽

Seema Singhal ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Chronic Gvhd ◽

Pneumococcal Infection ◽

Pneumococcal Infections ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Increased Risk ◽

Penicillin Prophylaxis

Abstract Incidences of and risk factors for Streptococcus pneumoniaesepsis (SPS) after hematopoietic stem cell transplantation were analyzed in 1329 patients treated at a single center between 1973 and 1997. SPS developed in 31 patients a median of 10 months after transplantation (range, 3 to 187 months). The infection was fatal in 7 patients. The probability of SPS developing at 5 and 10 years was 4% and 6%, respectively. Age, sex, diagnosis, and graft versus host disease (GVHD) prophylaxis did not influence the development of SPS. Allogeneic transplantation (10-year probability, 7% vs 3% for nonallogeneic transplants; P = .03) and chronic GVHD (10-year probability, 14% vs 4%; P = .002) were associated with significantly higher risk for SPS. All the episodes of SPS were seen in patients who had undergone allograft or total body irradiation (TBI) (31 of 1202 vs 0 of 127;P = .07). Eight patients were taking regular penicillin prophylaxis at the time of SPS, whereas 23 were not taking any prophylaxis. None of the 7 patients with fatal infections was taking prophylaxis for Pneumococcus. Pneumococcal bacteremia was associated with higher incidences of mortality (6 of 15 vs 1 of 16;P = .04). We conclude that there is a significant long-term risk for pneumococcal infection in patients who have undergone allograft transplantation, especially those with chronic GVHD. Patients who have undergone autograft transplantation after TBI-containing regimens also appear to be at increased risk. These patients should receive lifelong pneumococcus prophylaxis. Consistent with increasing resistance to penicillin, penicillin prophylaxis does not universally prevent SPS, though it may protect against fatal infections. Further studies are required to determine the optimum prophylactic strategy in patients at risk.

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Progesterone Activates a Progesterone Receptor Membrane Component 1-Dependent Mechanism That Promotes Human Granulosa/Luteal Cell Survival But Not Progesterone Secretion

Endocrinology ◽

10.1210/endo.150.7.9997 ◽

2009 ◽

Vol 150 (7) ◽

pp. 3434-3434

Author(s):

John J. Peluso ◽

Xiufang Liu ◽

Anna Gawkowska ◽

Erika Johnston-MacAnanny

Keyword(s):

Progesterone Receptor ◽

Cell Survival ◽

Luteal Cell ◽

Membrane Component ◽

Progesterone Secretion ◽

Receptor Membrane ◽

Dependent Mechanism

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Prevention ofStreptococcus pneumoniae(pneumococcal) infections in adults

Orvosi Hetilap ◽

10.1556/oh.2014.30070 ◽

2014 ◽

Vol 155 (50) ◽

pp. 1996-2004 ◽

Cited By ~ 2

Author(s):

Endre Ludwig ◽

Zsófia Mészner

Keyword(s):

Conjugate Vaccine ◽

Pneumococcal Conjugate Vaccine ◽

Pneumococcal Infection ◽

Polysaccharide Vaccine ◽

Diagnostic Tools ◽

Renal Diseases ◽

Pneumococcal Polysaccharide Vaccine ◽

Pneumococcal Infections ◽

Incidence And Mortality ◽

One Year

Infections caused by Streptococcus pneumoniae (pneumococcus) are still meaning a serious health problem, about 40% of community acquired pneumonia (CAP) is due to pneumococcal bacteria in adults requiring hospitalization. The incidence and mortality rate of pneumococcal infections is increasing in the population above 50 years of age. Certain congenital and acquired immunocompromised conditions make the individual susceptible for pneumococcal infection and other chronic comorbidities should be considered as a risk factor as well, such as liver and renal diseases, COPD, diabetes mellitus. Lethality of severe pneumococcal infections with bacteraemia still remains about 12% despite adequate antimicrobial therapy in the past 60 years. Underestimation of pneumococcal infections is mainly due to the low sensitivity of diagnostic tools and underuse of bacteriological laboratory confirmation methods. 13-valent pneumococcal conjugate vaccine (PCV-13) became available recently beyond the 23-valent polysacharide vaccine (PPV-23) which has been using for a long time.The indication and proper administration of the two vaccines are based on international recommendations and vaccination guideline published by National Centre for Epidemiology (NCE):Pneumococcal vaccination is recommended for: Every person above 50 years of age. Patients of all ages with chronic diseases who are susceptible for severe pneumococcal infections: respiratory (COPD), heart, renal, liver disease, diabetes, or patients under immunsuppressive treatment. Smokers regardless of age and comorbidities. Cochlear implants, cranial-injured patients. Patients with asplenia.Recommendation for administration of the two different vaccines:Adults who have not been immunized previously against pneumococcal disease must be vaccinated with a dose of 13-valent pneumococcal conjugate vaccine first. This protection could be extended with administration of 23-valent pneumococcal polysaccharide vaccine at least two month later. Adults who have been immunized previously, but above 65 years of age, with a 23-valent polysaccharide vaccine are recommended to get one dose of conjugate vaccine at least one year later. Adults who have been immunized previously, but under 65 years of age, with a 23-valent polysaccharide vaccine are recommended to get one dose of conjugate vaccine at least one year later. After a minimal interval of two months one dose of 23-valent pneumococcal polysaccharide vaccine is recommended if at least 5 years have elapsed since their previous PPSV23 dose. Vaccination of immuncompromised patients (malignancy, transplantation, etc.) and patients with asplenia should be defined by vaccinology specialists. Pneumococcal vaccines may be administered concommitantly or any interval with other vaccines. Orv. Hetil., 2014, 155(50), 1996–2004.

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Chronic graft versus host disease is associated with long-term risk for pneumococcal infections in recipients of bone marrow transplants

Blood ◽

10.1182/blood.v95.12.3683.012k19_3683_3686 ◽

2000 ◽

Vol 95 (12) ◽

pp. 3683-3686 ◽

Cited By ~ 10

Author(s):

Samar Kulkarni ◽

Ray Powles ◽

Jennie Treleaven ◽

Unell Riley ◽

Seema Singhal ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Chronic Gvhd ◽

Pneumococcal Infection ◽

Pneumococcal Infections ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Increased Risk ◽

Penicillin Prophylaxis

Incidences of and risk factors for Streptococcus pneumoniaesepsis (SPS) after hematopoietic stem cell transplantation were analyzed in 1329 patients treated at a single center between 1973 and 1997. SPS developed in 31 patients a median of 10 months after transplantation (range, 3 to 187 months). The infection was fatal in 7 patients. The probability of SPS developing at 5 and 10 years was 4% and 6%, respectively. Age, sex, diagnosis, and graft versus host disease (GVHD) prophylaxis did not influence the development of SPS. Allogeneic transplantation (10-year probability, 7% vs 3% for nonallogeneic transplants; P = .03) and chronic GVHD (10-year probability, 14% vs 4%; P = .002) were associated with significantly higher risk for SPS. All the episodes of SPS were seen in patients who had undergone allograft or total body irradiation (TBI) (31 of 1202 vs 0 of 127;P = .07). Eight patients were taking regular penicillin prophylaxis at the time of SPS, whereas 23 were not taking any prophylaxis. None of the 7 patients with fatal infections was taking prophylaxis for Pneumococcus. Pneumococcal bacteremia was associated with higher incidences of mortality (6 of 15 vs 1 of 16;P = .04). We conclude that there is a significant long-term risk for pneumococcal infection in patients who have undergone allograft transplantation, especially those with chronic GVHD. Patients who have undergone autograft transplantation after TBI-containing regimens also appear to be at increased risk. These patients should receive lifelong pneumococcus prophylaxis. Consistent with increasing resistance to penicillin, penicillin prophylaxis does not universally prevent SPS, though it may protect against fatal infections. Further studies are required to determine the optimum prophylactic strategy in patients at risk.

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Pneumonia: Regional experience with prevention programs

Terapevticheskii arkhiv ◽

10.17116/terarkh201688887-92 ◽

2016 ◽

Vol 88 (8) ◽

pp. 87-92 ◽

Cited By ~ 4

Author(s):

A G Chuchalin ◽

G G Onishchenko ◽

V P Kolosov ◽

O P Kurganova ◽

N L Tezikov ◽

...

Keyword(s):

High Efficiency ◽

Viral Infections ◽

Pneumococcal Infection ◽

Prevention Programs ◽

Efficiency Index ◽

Amur Region ◽

Pneumococcal Infections ◽

Epidemiological Monitoring ◽

Comparative Statistical Analysis ◽

Regional Programs

Aim. To generalize the regional experience in implementing a package of organizational and methodical and antiepidemic measures for preventing pneumococcal infections. Materials and methods. How the prevention programs were implemented using the materials and methods of the epidemiological and statistical monitoring of the incidence of pneumonia in the Amur Region was analyzed. Pneumococcal conjugate vaccine (Prevenar-13) and influenza vaccines were used for immunoprophylaxis against acute respiratory viral and pneumococcal infections. Information on the incidence of acute respiratory viral infections and pneumonia over time in the period 2010 to 2015 must be taken into account. Indicators and special criteria are used to evaluate the efficiency of vaccination. Results. The comparative statistical analysis revealed the high efficiency of regional programs using the methods for immunoprophylaxis against pneumococcal infections: the vaccination prophylactic efficiency index in terms of the incidence of pneumonia might be as high as 75—100%. Pneumonia morbidity rates became 2.3 times lower in the vaccinated population of the region. Conclusion. The results of the investigation suggest that the Program for the clinical and epidemiological monitoring and prevention of community-acquired pneumonias, by using the vaccine against pneumococcal infection in the Amur Region, has a high medical and socioeconomic efficiency.

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mTORC2 promotes cell survival through c-Myc–dependent up-regulation of E2F1

The Journal of Cell Biology ◽

10.1083/jcb.201411128 ◽

2015 ◽

Vol 211 (1) ◽

pp. 105-122 ◽

Cited By ~ 17

Author(s):

Zhipeng Zou ◽

Juan Chen ◽

Anling Liu ◽

Xuan Zhou ◽

Qiancheng Song ◽

...

Keyword(s):

Cell Survival ◽

Tumor Model ◽

Xenograft Tumor ◽

In Vivo Experiments ◽

Xenograft Tumor Model ◽

Cancer Cell Survival ◽

Consequent Reduction ◽

Dependent Mechanism

Previous studies have reported that mTORC2 promotes cell survival through phosphorylating AKT and enhancing its activity. We reveal another mechanism by which mTORC2 controls apoptosis. Inactivation of mTORC2 promotes binding of CIP2A to PP2A, leading to reduced PP2A activity toward c-Myc serine 62 and, consequently, enhancement of c-Myc phosphorylation and expression. Increased c-Myc activity induces transcription of pri-miR-9-2/miR-9-3p, in turn inhibiting expression of E2F1, a transcriptional factor critical for cancer cell survival and tumor progression, resulting in enhanced apoptosis. In vivo experiments using B cell–specific mTORC2 (rapamycin-insensitive companion of mTOR) deletion mice and a xenograft tumor model confirmed that inactivation of mTORC2 causes up-regulation of c-Myc and miR-9-3p, down-regulation of E2F1, and consequent reduction in cell survival. Conversely, Antagomir-9-3p reversed mTORC1/2 inhibitor–potentiated E2F1 suppression and resultant apoptosis in xenograft tumors. Our in vitro and in vivo findings collectively demonstrate that mTORC2 promotes cell survival by stimulating E2F1 expression through a c-Myc– and miR-9-3p–dependent mechanism.

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