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Antibiotic resistance is one of the greatest crises in human medicine. Increased incidents of antibiotic resistance are linked to clinical overuse and overreliance on antibiotics. Among the ESKAPE pathogens, Acinetobacter baumannii,... more
Antibiotic resistance is one of the greatest crises in human medicine. Increased incidents of antibiotic resistance are linked to clinical overuse and overreliance on antibiotics. Among the ESKAPE pathogens, Acinetobacter baumannii, especially carbapenem-resistant isolates, has emerged as a significant threat in the context of blood, urinary tract, lung, and wound infections. Therefore, new approaches that limit the emergence of antibiotic resistant A. baumannii are urgently needed. Recently, we have shown that random peptide mixtures (RPMs) are an attractive alternative class of drugs to antibiotics with strong safety and pharmacokinetic profiles. RPMs are antimicrobial peptide mixtures produced by incorporating two amino acids at each coupling step, rendering them extremely diverse but still defined in their overall composition, chain length, and stereochemistry. The extreme diversity of RPMs may prevent bacteria from evolving resistance rapidly. Here, we demonstrated that RPMs ra...
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This article cites 39 articles, 21 of which can be accessed free
A polarized macrophage response into inflammatory (M1) or regenerative/anti-inflammatory (M2) phenotypes is critical in host response to multiple intracellular bacterial infections. Ehrlichia is an obligate Gram-negative intracellular... more
A polarized macrophage response into inflammatory (M1) or regenerative/anti-inflammatory (M2) phenotypes is critical in host response to multiple intracellular bacterial infections. Ehrlichia is an obligate Gram-negative intracellular bacterium that causes human monocytic ehrlichiosis (HME): a febrile illness that may progress to fatal sepsis with multi-organ failure. We have shown that liver injury and Ehrlichia-induced sepsis occur due to dysregulated inflammation. Here, we investigated the contribution of macrophages to Ehrlichia-induced sepsis using murine models of mild and fatal ehrlichiosis. Lethally-infected mice showed accumulation of M1 macrophages (iNOS-positive) in the liver. In contrast, non-lethally infected mice showed polarization of M2 macrophages and their accumulation in peritoneum, but not in the liver. Predominance of M1 macrophages in lethally-infected mice was associated with expansion of IL-17-producing T, NK, and NKT cells. Consistent with the in vivo data, ...
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Human monocytic ehrlichiosis, a tick transmitted infection, ranges in severity from apparently subclinical to fatal toxic shock-like disease. Models in immunocompetent mice range from abortive to uniformly lethal infection, depending on... more
Human monocytic ehrlichiosis, a tick transmitted infection, ranges in severity from apparently subclinical to fatal toxic shock-like disease. Models in immunocompetent mice range from abortive to uniformly lethal infection, depending on the Ehrlichia species, inoculum dose, and inoculation route. Effective immunity is mediated by CD4+ T lymphocytes and gamma interferon. Lethal infection occurs with early overproduction of proinflammatory cytokines and overproduction of TNF alpha and IL-10 by CD8+ T lymphocytes. Furthermore, fatal ehrlichiosis is associated with TLR 9/MyD88 signaling, upregulation of several inflammasome complexes, and secretion of IL-1 beta, IL-1 alpha, and IL-18 by hepatic mononuclear cells, thus suggesting activation of canonical and noncanonical inflammasome pathways, a deleterious role of IL-18, and a protective role of caspase 1. Autophagy promotes ehrlichial infection, whereas MyD88 signaling hinders ehrlichial infection by inhibiting autophagy induction and f...
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Uterine fibroids (UF; aka leiomyoma, myomas) are the most common benign tumors of female reproductive tract. They are highly prevalent, with 70 to 80% of women burdened by the end of their reproductive years. Fibroids are a leading cause... more
Uterine fibroids (UF; aka leiomyoma, myomas) are the most common benign tumors of female reproductive tract. They are highly prevalent, with 70 to 80% of women burdened by the end of their reproductive years. Fibroids are a leading cause of pelvic pain, abnormal vaginal bleeding, pelvic bulk symptoms, miscarriage, and infertility. They are the leading indication for hysterectomy, and costs exceed 34 billion dollars annually in the United States alone. Recently, somatic mutations in exons 1 and 2 of Med12 gene emerged as common UF driver mutations. Unfortunately, the detailed etiology of UF is not fully realized. Particularly, very little is known about possible dysregulation of inflammatory and immune processes and their possible contribution to UF pathogenesis. The notion on possible impact of altered estrogen and progesterone signaling in UF on inflammatory responses and DNA repair machinery that can conceivably lead to tumor-specific somatic mutation is indeed an intriguing conce...
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Our murine models of human monocytic ehrlichiosis (HME) have shown that severe and fatal ehrlichiosis is due to generation of pathogenic T cell responses causing immunopathology and multi-organ failure. However, the early events in the... more
Our murine models of human monocytic ehrlichiosis (HME) have shown that severe and fatal ehrlichiosis is due to generation of pathogenic T cell responses causing immunopathology and multi-organ failure. However, the early events in the liver, the main site of infection, are not well understood. In this study, we examined the liver transcriptome during the course of lethal and nonlethal infections caused by Ixodes ovatus Ehrlichia and Ehrlichia muris, respectively. On day 3 post-infection (p.i.), although most host genes were down regulated in the two groups of infected mice compared to naı̈ve counterparts, lethal infection induced significantly higher expression of caspase 1, caspase 4, nucleotide binding oligomerization domain-containing proteins (Nod1), tumor necrosis factor-alpha, interleukin 10, and CCL7 compared to nonlethal infection. On day 7 p.i., lethal infection induced highly significant upregulation of type-1 interferon, several inflammatory cytokines and chemokines, whi...
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This article cites 43 articles, 25 of which can be accessed free
Inflammasomes are an important innate immune host defense against intracellular microbial infection. Activation of inflammasomes by microbial or host ligands results in cleavage of caspase‐1 (canonical pathway) or caspase‐11 (noncanonical... more
Inflammasomes are an important innate immune host defense against intracellular microbial infection. Activation of inflammasomes by microbial or host ligands results in cleavage of caspase‐1 (canonical pathway) or caspase‐11 (noncanonical pathway), release of interleukin (IL)‐1β, IL‐18, high mobility group box 1 (HMGB1), and inflammatory cell death known as pyroptosis. Ehrlichia are obligate, intracellular, gram‐negative bacteria that lack lipopolysaccharide but cause potentially life‐threatening monocytic ehrlichiosis in humans and mice that is characterized by liver injury followed by sepsis and multiorgan failure. Employing murine models of mild and fatal ehrlichiosis caused by infection with mildly and highly virulent Ehrlichia muris (EM) and Ixodes ovatus Ehrlichia (IOE), respectively, we have previously shown that IOE infection triggers type I interferon (IFN‐I) response and deleterious caspase‐11 activation in liver tissues, which promotes liver injury and sepsis. In this study, we examined the contribution of IFN‐I signaling in hepatocytes (HCs) to Ehrlichia‐induced liver injury. Compared to EM infection, we found that IOE enter and replicate in vitro cultured primary murine HCs and induce secretion of IFNβ and several chemokines, including regulated upon activation, normal T‐cell expressed, and secreted (RANTES), monocyte chemoattractant protein 1 (MCP1), monokine induced by gamma (MIG)/chemokine (C‐X‐C motif) ligand 9 (CXCL9), macrophage inflammatory protein 1 alpha (MIP1α), keratinocyte‐derived chemokine (KC), and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). Notably, in vitro stimulation of uninfected and Ehrlichia‐infected HCs with recombinant IFNβ triggered activation of caspase‐1/11, cytosolic translocation of HMGB1, and enhanced autophagy and intracellular bacterial replication. Secretion of HMGB1 by IOE‐infected HCs was dependent on caspase‐11. Primary HCs from IOE‐ but not EM‐infected mice also expressed active caspase‐1/11. Conclusion: HC‐specific IFN‐I signaling may exacerbate liver pathology during infection with obligate intracellular Ehrlichia by promoting bacterial replication and detrimental caspase‐11‐mediated inflammasome activation.
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Purpose. The number of individuals affected by job stress is growing day by day in almost every industry. According to Health and Safety Executive (2006) workplace stress is now the fastest growing cause of absence from work. The current... more
Purpose. The number of individuals affected by job stress is growing day by day in almost every industry. According to Health and Safety Executive (2006) workplace stress is now the fastest growing cause of absence from work. The current study aims to verify the effectiveness of management stress in performance level of manager's productivity of youth centers in Cairo. Methods. The sample contains 40 mangers and 80 sports specialists, to collect the research data the researchers have built a questionnaire to measure the administrative empowerment which contains 5 factors, the initial questionnaire consists of 106 items. Results. statistical analyses showed that the stress natural was connected of planning and make decision , organize, control and guidance ( according its importance). Conclusions. Finally, the leaders in youth centers face many of stress which affected of their performance.
Background Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in reproductive-age women. Excessive inflammation and elevated androgen production from ovarian theca cells are key features of PCOS. Human... more
Background Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in reproductive-age women. Excessive inflammation and elevated androgen production from ovarian theca cells are key features of PCOS. Human bone marrow mesenchymal stem cells (BM-hMSC) and their secreted factors (secretome) exhibit robust anti-inflammatory capabilities in various biological systems. We evaluated the therapeutic efficacy of BM-hMSC and its secretome in both in vitro and in vivo PCOS models. Methods For in vitro experiment, we treated conditioned media from BM-hMSC to androgen-producing H293R cells and analyzed androgen-producing gene expression. For in vivo experiment, BM-hMSC were implanted into letrozole (LTZ)-induced PCOS mouse model. BM-hMSC effect in androgen-producing cells or PCOS model mice was assessed by monitoring cell proliferation (immunohistochemistry), steroidogenic gene expression (quantitative real-time polymerase chain reaction [qRT-PCR] and Western blot,...
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Background. Despite the high prevalence of type 2 diabetes mellitus in Gulf countries, standards of diabetes care at the primary care level have not been widely studied. Aim. To compare the results of diabetes clinical indicators from the... more
Background. Despite the high prevalence of type 2 diabetes mellitus in Gulf countries, standards of diabetes care at the primary care level have not been widely studied. Aim. To compare the results of diabetes clinical indicators from the American Diabetes Association (ADA) 2017 guidelines to the reference benchmarks in the Behavioral Risk Factor Surveillance System. Materials and Methods. A cross-sectional analysis of electronic medical records in 643 randomly selected adult patients with type 2 diabetes was undertaken. A checklist enabled the collection of sociodemographic, clinical, biochemical, and quality measurement data. Data were analyzed using Stata 9.0. The chi-squared test was used to compare two or more proportions. Results. There were 643 patients (male = 60.3%; female = 39.7%), and the majority (71.7%) aged between 40 and 64 years. Common comorbidities were dyslipidemia (72.3%), hypertension (70%), obesity (50.1%), and preobesity (overweight) (37.9%). Over 15% were smo...
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Gram-negative bacterial infections are a significant public health concern, and the lack of new drug classes for these pathogens is linked to the inability of most drug leads to accumulate inside Gram-negative bacteria 1 – 7 . Here, we... more
Gram-negative bacterial infections are a significant public health concern, and the lack of new drug classes for these pathogens is linked to the inability of most drug leads to accumulate inside Gram-negative bacteria 1 – 7 . Here, we report the development of a web application—eNTRyway—that predicts compound accumulation (in Escherichia coli ) from its structure. In conjunction with structure–activity relationships and X-ray data, eNTRyway was utilized to re-design Debio-1452—a Gram-positive-only antibiotic 8 —into versions that accumulate in E. coli and possess antibacterial activity against high-priority Gram-negative pathogens. The lead compound Debio-1452-NH3 operates as an antibiotic via the same mechanism as Debio-1452, namely potent inhibition of the enoyl-acyl carrier protein reductase FabI, as validated by in vitro enzyme assays and the generation of bacterial isolates with spontaneous target mutations. Debio-1452-NH3 is well tolerated in vivo, reduces bacterial burden in mice and rescues mice from lethal infections with clinical isolates of Acinetobacter baumannii , Klebsiella pneumoniae and E. coli . This work provides tools for the facile discovery and development of high-accumulating compounds in E. coli , and a general blueprint for the conversion of Gram-positive-only compounds into broad-spectrum antibiotics. Hergenrother and colleagues develop a web portal to help predict key permeation aspects of query compounds using the eNTRy rules they recently developed. They use this approach to screen antibiotics that are effective against Gram-positive bacteria and engineer a modified version of a FabI inhibitor that is an effective Gram-negative antibiotic.
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Previously, we reported a significantly higher prevalence of uterine fibroids (UFs) in African American women. This minority group also commonly suffers from vitamin D deficiency. We have demonstrated that 1,25(OH)D attains a fibroid... more
Previously, we reported a significantly higher prevalence of uterine fibroids (UFs) in African American women. This minority group also commonly suffers from vitamin D deficiency. We have demonstrated that 1,25(OH)D attains a fibroid growth inhibitory impact through its ability to block the G1/S (gap 1/synthesis) phase of the cell cycle. Vitamin D is involved in DNA damage as well as in immune response regulation, anti-inflammation, autoimmunity and cancer. Since most of the prior data on vitamin D and UF were generated in vitro via established cell lines, it was necessary to verify and validate this observation in vivo using a diet-induced vitamin D-deficient mouse model. Our model of vitamin D lacking function was established using 8-week exposure of C57/BL6 mice to vitamin D-deficient diet provides evidence of different functions accomplished by vitamin D in the regulation of myometrium homeostasis disrupted in the context of uterine fibroid. We found that vitamin D deficiency wa...
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To determine a quantitative herpes simplex virus (HSV) DNA threshold in lower respiratory tract specimens that correlates with positive viral culture and clinical outcomes. Bronchoalveolar lavage and bronchial wash samples from 53 HSV... more
To determine a quantitative herpes simplex virus (HSV) DNA threshold in lower respiratory tract specimens that correlates with positive viral culture and clinical outcomes. Bronchoalveolar lavage and bronchial wash samples from 53 HSV culture-positive and 61 culture-negative matched controls were tested using HSV-1 and HSV-2 quantitative polymerase chain reaction (qPCR). Median viral culture turnaround time was 21.8 days and 9.9 days for culture-negative and culture-positive specimens, respectively. Using an HSV-1 viral load threshold of 1.62 × 103 copies/mL, there was 93% agreement with viral culture. An HSV-1 viral load ≥1.3 × 104 copies/mL was associated with worse clinical outcome compared to a viral load <1.3 × 104 copies/mL (hazard ratio [HR] = 4.27, P = .017), and there was a trend of worse outcome compared to patients with undetectable HSV-1 DNA (HR = 1.60, P = .056). qPCR has clinical utility for rapid accurate identification of HSV-1 in lower respiratory tract specimens.
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is a causative pathogen of potentially fatal visceral leishmaniasis (VL). Therapeutic agents are available; however, their use is limited because of high cost, serious side effects, and development of antimicrobial resistance. Protective... more
is a causative pathogen of potentially fatal visceral leishmaniasis (VL). Therapeutic agents are available; however, their use is limited because of high cost, serious side effects, and development of antimicrobial resistance. Protective immunity against VL depends on CD4 Th1 cell-mediated immunity. Studies have shown that progression of VL is due to exhaustion of T cells; however, the mechanism involved is not clearly understood. Here, we examined the role of PD1/PDL-1 in the pathogenesis of VL by using a murine model of VL. Our data indicate that is able to elicit initial expansion of gamma interferon-producing CD4 Th1 and CD8 T cells at day 7 postinfection (p.i.); however, the frequency of those cells and inflammatory response decreased at day 21 p.i., despite persistence of parasites. Persistent infection-induced expansion of interleukin-10 FOXP3 Treg and CD4 and CD8 T cells expressing PD1. Blocking of PDL-1 signaling resulted in restoration of protective type 1 responses by bot...
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Severe hepatic inflammation is a common cause of acute liver injury following systemic infection with Ehrlichia, obligate Gram-negative intracellular bacteria that lack lipopolysaccharide (LPS). We have previously shown that type I IFN... more
Severe hepatic inflammation is a common cause of acute liver injury following systemic infection with Ehrlichia, obligate Gram-negative intracellular bacteria that lack lipopolysaccharide (LPS). We have previously shown that type I IFN (IFN-I) and inflammasome activation are key host-pathogenic mediators that promote excessive inflammation and liver damage following fatal Ehrlichia infection. However, the underlying signals and mechanisms that regulate protective immunity and immunopathology during Ehrlichia infection are not well understood. To address this issue, we compared susceptibility to lethal Ixodes ovatus Ehrlichia (IOE) infection between wild type (WT) and MyD88-deficient (MyD88-/-) mice. We show here that MyD88-/- mice exhibited decreased inflammasome activation, attenuated liver injury, and were more resistant to lethal infection than WT mice, despite suppressed protective immunity and increased bacterial burden in the liver. MyD88-dependent inflammasome activation was ...
Research Interests: Microbiology, Immunology, Flow Cytometry, Medical Microbiology, Biology, and 15 moreTransmission Electron Microscopy, Autophagy, Confocal Microscopy, Medicine, Western blotting, Mice, Septic Shock, Female, Animals, Fluorescent Antibody Technique, Ehrlichiosis, Inflammasomes, Ehrlichia, Enzyme Linked Immunosorbent Assay, and real time polymerase chain reaction
Uterine fibroids (UF) are the most common pelvic tumors in women of reproductive-age and they usually cause heavy menstrual bleeding, pain and infertility. Autophagy is a collection of processes that enables the cells to digest and... more
Uterine fibroids (UF) are the most common pelvic tumors in women of reproductive-age and they usually cause heavy menstrual bleeding, pain and infertility. Autophagy is a collection of processes that enables the cells to digest and recycle their cytoplasmic contents, such as toxic protein aggregates, defunct or disused organelles and invading microorganisms. Dysregulation in autophagy process were described in neoplasms; however, the contribution of autophagy to the pathogenesis of UF remains unknown. In this study, we demonstrate that autophagy is deregulated in human UF as evidenced by significant accumulation of autophagosome in human UF cells compared to normal myometrium cells. Analysis of the autophagy markers revealed an enhanced initiation of the autophagy in UF tissues compared to their adjacent myometrial tissues (MyoF). However, autophagosome maturation and flux was blocked in UF tissues, as marked by accumulation of LC3-B and P62 protein. This block was associated with defective expression of autophagy-related protein 4 (ATG4) in the UF tissues compared to MyoF in ~90% of patient samples. Silencing of ATG4D in normal human myometrial cells resulted in defective autophagy flux, enhanced cell proliferation and increased extracellular matrix production, which phenocopy UF cell line. This study indicates that impairment of autophagy flux secondary to defective expression of ATG4D expression is a new mechanistic aberration that contributes to UF pathogenesis. Targeting autophagy pathway could provide novel medical therapeutic approach for non-surgical treatment of UF.
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Research Interests: Endocrinology, Biology, Medicine, Gene Silencing, Biological Sciences, and 12 moreHumans, Female, Beta-Catenin, Transforming Growth Factor Beta, Cell Proliferation, Cell Cycle Proteins, Smad proteins, Leiomyoma, Mediator complex, Estrogen receptor alpha, Medical and Health Sciences, and Collagen type I
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Study of feeding habits of freshwater fishes collected from ponds at World Fish Center (ICLARM) showed that the African catfish, Clarias gariepinus and Forskal catfish, Bagras bayad had the highest proportion of full stomachs (31-58% &... more
Study of feeding habits of freshwater fishes collected from ponds at World Fish Center (ICLARM) showed that the African catfish, Clarias gariepinus and Forskal catfish, Bagras bayad had the highest proportion of full stomachs (31-58% & 44-45% respectively). In cichlid fishes, the rate of full stomachs was much lower, being 0.0-12.5% and showed higher incidence of empty stomachs that varied from 37.5% for Oreochromis niloticus to 78.3% for Sarotherodon galilaeus. Food items were analyzed by the percentage of point assessment (P%), abundance (N%) and frequency of occurrence (F%). Results of the three methods of analyses (Index of relative importance, I.R.I) emphasized the importance of plants (1214.7) as a major food resource in the stomach of Nile tilapia, O. niloticus followed by shell fragments (628.5), whereas, snail soft bodies were the main food category in the diet of hybrid tilapia O. niloticus x O. aureus (2539.3). Shell fragments (652) and snail soft bodies (296.9) were the 1st in relative importance as foods of O. aurea. In case of S. galillae, shell fragments (338) came 2nd in I.R.I. after plants (559). Present investigation shows that shell fragments were represented by 11.1% and 15.1% in the diet of African catfish, C. gariepinus by (N%) and (P%) methods, however, they came as the second food item in its diet by I.R.I (1237.3). According to F% method, both shell fragments and Crustacea were present in the diet of C. gariepinus considerable proportions each of 47.4%. Shell fragments were represented by low proportions in the diet of B. bayad 3.9, 2.1 and 22.2 by N%, P% and F% respectively.
Research Interests: Biology, Egypt, Fish Diseases, Medicine, Animal Feed, and 7 moreAnimals, Fishes, Snails, Feeding Behavior, Eating, Fresh water, and Food Chain
Rickettsiae actively escape from vacuoles and replicate free in the cytoplasm of host cells, where inflammasomes survey the invading pathogens. In the present study, we investigated the interactions of Rickettsia australis with the... more
Rickettsiae actively escape from vacuoles and replicate free in the cytoplasm of host cells, where inflammasomes survey the invading pathogens. In the present study, we investigated the interactions of Rickettsia australis with the inflammasome in both mouse and human macrophages. R. australis induced a significant level of IL-1β secretion by human macrophages, which was significantly reduced upon treatment with an inhibitor of caspase-1 compared to untreated controls, suggesting caspase-1-dependent inflammasome activation. Rickettsia induced significant secretion of IL-1β and IL-18 in vitro by infected mouse bone marrow-derived macrophages (BMMs) as early as 8-12 h post infection (p.i.) in a dose-dependent manner. Secretion of these cytokines was accompanied by cleavage of caspase-1 and was completely abrogated in BMMs deficient in caspase-1/caspase-11 or apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), suggesting that R. austral...
Research Interests: Biology, Macrophages, Medicine, Multidisciplinary, Spleen, and 10 moreHumans, Liver, Mice, Animals, Lung, PLoS one, Caspase, Inflammasomes, Rickettsia, and Interleukin
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Rickettsiae escape from the vacuole into the cytosol, where they replicate and inflammasomes recognize the cytosolic infectious pathogens via Nod-like receptors leading to secretion of IL-1β and IL-18. However, the interaction of... more
Rickettsiae escape from the vacuole into the cytosol, where they replicate and inflammasomes recognize the cytosolic infectious pathogens via Nod-like receptors leading to secretion of IL-1β and IL-18. However, the interaction of rickettsiae with inflammasomes has never been investigated. In this study, we found that secretion of mature IL-1β and IL-18 from Rickettsia australis-infected macrophages is caspase-1 and ASC-dependent, suggesting that Rickettsia activates ASC inflammasome. All R. australis-infected ASC-/- mice succumbed to infection (100% mortality) while all infected wild type (WT) mice survived (0% mortality). Rickettsial loads in liver in infected ASC-/- mice were significantly increased with less cellular infiltration compared to infected WT mice. In vivo production of IL-18 was completely dependent on ASC in R. australis-infected mice as evidenced by abolished IL-18 production in infected ASC-/- mice compared to infected WT mice. R. australis-induced-IL-1β and IL-18 concentrations were only reduced, but not abolished in macrophages from NLRP3-/- mice compared to WT controls. Host survival and rickettsial loads in lung and liver of NLRP3-/- mice were comparable with those of WT mice, suggesting a negligible role of NLRP3 in host defense. Taken together, our results suggest that R. australis are recognized by ASC inflammasome in vitro and in vivo via a NLRP3-independent pathway. ASC inflammasome mediates host protection against this intracellular bacterium.
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In this thesis, experiments were undertaken to analyze the cellular mechanisms controlling the differentiation of naive CD4+ T cells to functionally distinct Th1 or Th2 type cells, by employing in vivo and adoptive transfer systems.... more
In this thesis, experiments were undertaken to analyze the cellular mechanisms controlling the differentiation of naive CD4+ T cells to functionally distinct Th1 or Th2 type cells, by employing in vivo and adoptive transfer systems. Immune responses were analyzed by enumerating ex vivo single IgM and IgG-forming B cells and IFNa- and IL-4-producing T cells, employing a plaque assay and a modified ELISPOT assay, respectively. I find that: The Th1/Th2 nature of the splenic immune response of normal mice, immunized intravenously, is determined by the dose of xenogeneic red blood cells (XRBC) used for immunization. Low doses induce an exclusive Th1 response, whereas higher doses induce either a mixed Th1/Th2 or a predominant Th2 type response and stimulate the production of specific antibodies. The Th1/Th2 nature of the response generated in the spleens of irradiated mice depends conjointly on the amount of immunizing antigen and the number of unprimed syngeneic CD4+ T cells employed for reconstitution. Higher amounts of antigen and higher numbers of CD4+ T cells favoring the generation of Th2 type cells. Lowering either the antigen dose or the number of unprimed CD4+ T cells or both, but not the number of antigen-presenting cells favors the exclusive generation of Th1 type cells. Thus, more CD4+ T cell/CD4+T cell interactions is required for the primary generation of Th2 than Th1 type cells. The Th1/Th2 nature of the response is determined by CD4+ T cell/CD4+ T cell interactions mediated by operational linked recognition of antigenic epitopes. Immunization of C57BL/6 hen egg lyzozyme (HEL)-transgenic mice, tolerant to HEL, and their wild type counterparts with low doses of sheep RBC, generates predominantly a SRBC-specific Th1 type response in both mice. In contrast, immunization with a low dose of SRBC physically coupled to HEL results in a modulation of the anti-SRBC response from a Th1 to Th2 mode, in normal C57BL/6 mice but not in the HEL-transgenic mice. Such modulation requires that HEL physically linked to SRBC and not to other non-crossreacting antigen. The Th1/Th2 nature of concurrent immune responses, generated in the same secondary lymphoid organ upon immunization with two non-crossreacting antigens, can be independently determined. Thus, the Th1/Th2 nature of the response to two XRBC, given in different doses, in doubly immunized mice was indistinguishable from that of the corresponding immune response in singly immunized mice. Furthermore, the Th1/Th2 response to one kind of XRBC is independent of ongoing immune responses to another noncrossreacting RBC.
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Uterine fibroids (UFs) are benign smooth muscle neoplasms affecting up to 70% of reproductive age women. Treatment of symptomatic UFs places a significant economic burden on the US health-care system. Several specific genetic... more
Uterine fibroids (UFs) are benign smooth muscle neoplasms affecting up to 70% of reproductive age women. Treatment of symptomatic UFs places a significant economic burden on the US health-care system. Several specific genetic abnormalities have been described as etiologic factors of UFs, suggesting that a low DNA damage repair capacity may be involved in the formation of UF. In this study, we used human fibroid and adjacent myometrial tissues, as well as an in vitro cell culture model, to evaluate the expression ofMutS homolog 2(MSH2), which encodes a protein belongs to the mismatch repair system. In addition, we deciphered the mechanism by which polycomb repressive complex 2 protein, EZH2, deregulatesMSH2in UFs. The RNA expression analysis demonstrated the deregulation ofMSH2expression in UF tissues in comparison to its adjacent myometrium. Notably, protein levels ofMSH2were upregulated in 90% of fibroid tissues (9 of 10) as compared to matched adjacent myometrial tissues. Human fi...
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Ehrlichiae are gram-negative obligate intracellular bacteria that cause potentially fatal human monocytic ehrlichiosis. We previously showed that natural killer (NK) cells play a critical role in host defense against Ehrlichia during... more
Ehrlichiae are gram-negative obligate intracellular bacteria that cause potentially fatal human monocytic ehrlichiosis. We previously showed that natural killer (NK) cells play a critical role in host defense against Ehrlichia during primary infection. However, the contribution of NK cells to the memory response against Ehrlichia remains elusive. Primary infection of C57BL/6 mice with Ehrlichia muris provides long-term protection against a second challenge with the highly virulent Ixodes ovatus Ehrlichia (IOE), which ordinarily causes fatal disease in naïve mice. Here, we show that the depletion of NK cells in E. muris-primed mice abrogates the protective memory response against IOE. Approximately, 80% of NK cell-depleted E. muris-primed mice succumbed to lethal IOE infection on days 8-10 after IOE infection, similar to naïve mice infected with the same dose of IOE. The lack of a recall response in NK cell-depleted mice correlated with an increased bacterial burden, extensive liver ...
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Research Interests: Biology, Medicine, Humans, Mice, Animals, and 4 moreNorth America, Anti-Bacterial Agents, Doxycycline, and Ehrlichiosis
Gene therapy is a potentially effective non-surgical approach for the treatment of uterine leiomyoma. We demonstrated that targeted adenovirus vector, Ad-SSTR-RGD-TK/GCV, was highly effective in selectively inducing apoptosis and... more
Gene therapy is a potentially effective non-surgical approach for the treatment of uterine leiomyoma. We demonstrated that targeted adenovirus vector, Ad-SSTR-RGD-TK/GCV, was highly effective in selectively inducing apoptosis and inhibiting proliferation of human leiomyoma cells in vitro while sparing normal myometrial cells. An in-vivo study, to compare efficacy and safety of modified adenovirus vector Ad-SSTR-RGD-TK/GCV versus untargeted vector for treatment of leiomyoma. Female nude mice were implanted with rat leiomyoma cells subcutaneously. Then mice were randomized into three groups. Group 1 received Ad-LacZ (marker gene), Group 2 received untargeted Ad-TK, and Group 3 received the targeted Ad-SSTR-RGD-TK. Tumors were measured weekly for 4 weeks. Then mice were sacrificed and tissue samples were collected. Evaluation of markers of apoptosis, proliferation, extracellular matrix, and angiogenesis was performed using Western Blot & Immunohistochemistry. Statistical analysis was d...
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Uterine fibroids are benign smooth muscle tumors that occur in approximately 70%-80% of women by age 50. The cellular and molecular mechanism(s) by which uterine fibroids develop are not fully understood. Accumulating evidence... more
Uterine fibroids are benign smooth muscle tumors that occur in approximately 70%-80% of women by age 50. The cellular and molecular mechanism(s) by which uterine fibroids develop are not fully understood. Accumulating evidence demonstrates that several genetic abnormalities including deletions, rearrangements, translocations, as well as mutations have been found in uterine fibroids. These genetic anomalies suggest that low DNA damage repair capacity may be involved in uterine fibroid formation. The objective of this study was to determine whether expression levels of DNA damage repair related genes were altered, and how they were regulated in the pathogenesis of uterine fibroids. Expression levels of DNA repair related genes RAD51 and BRCA1 were deregulated in fibroid tissues as compared to adjacent myometrial tissues. Expression levels of chromatin protein EZH2 were higher in a subset of fibroids as compared to adjacent myometrial tissues by both immunohistochemistry and western bl...
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Infectious diseases remain the leading cause of death around the world, causing more than 12 million deaths each year. The long-term effects of these illnesses, as a major public health problem, have raised particular concerns since some... more
Infectious diseases remain the leading cause of death around the world, causing more than 12 million deaths each year. The long-term effects of these illnesses, as a major public health problem, have raised particular concerns since some infectious agents have been associated with different types of chronic diseases, including cancer. Although cancer development can be multi-factorial in origin, several types of solid organ or hematologic cancers are caused by infectious agents (Shurin MR, Immunol Targets Ther 1:1–6, 2012). Approximately 15 % of all cancers occurring worldwide could be attributed to infections, a global total of 1.2 million cases per year (Kuper H, Adami HO, Trichopoulos D et al., J Intern Med 248:171–183, 2000). A substantial body of evidence also support the notion that infection itself or associated production of pro-inflammatory cytokines such as tumor necrosis factor (TNF), which can cause genetic mutations, thus promoting cancer development or enhancing epithelial-mesynchymal transition (EMT), an important mechanism that enable cancer metastasis (Voronov E et al., Proc Natl Acad Sci USA 100:2645–2650, 2003; Grivennikov SI and Karin M, Curr Opin Genet Dev 20:65–71, 2010). On the other hand, immunosuppression caused by the cancer itself or immunosuppressive drugs used for cancer treatment increase the risk and severity of infections, which in turn provide positive feedback mechanism that further enhance cancer metastasis (Khayr W, Haddad RY, Noor SA, Dis Mon 58:239–249, 2012). For instance, ~50–80 % of patients suffering from various hematological malignancies develop infections, which contribute to a higher incidence of mortality in these patients (Yadegarynia D, Tarrand J, Raad I, Rolston K, Clin Infect Dis 37:1144–1145, 2003).
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Inflammasome complexes such as NLRP3 play a major role in antimicrobial defense to infection. Canonical and non-canonical pathways activate caspase 1 and caspase 11 to secrete IL-1β and induce inflammatory cell death. Ehrlichia, obligate... more
Inflammasome complexes such as NLRP3 play a major role in antimicrobial defense to infection. Canonical and non-canonical pathways activate caspase 1 and caspase 11 to secrete IL-1β and induce inflammatory cell death. Ehrlichia, obligate intracellular bacteria that cause fatal toxic shock in humans and mice, activate inflammasomes and induce expression of type 1 interferon (IFN1). The contribution of the NLRP3 and IFN1 to Ehrlichia-induced toxic shock is not known. We show that NLRP3-/- and Caspase 1-/- mice succumb to lethal Ehrlichia infection similar to wild type (WT) mice. Unlike caspase 1-/- and WT, NLRP3-/- mice have lower bacterial burdens with higher IFNγ, suggesting that NLRP3 impairs bacterial clearance in a caspase 1-independent manner. Unexpectedly, infected IFNαR-/- mice were protected against a normally lethal dose of Ehrlichia with effective bacterial clearance, altered pathology with less apoptosis, increased IFNγ, decreased IL-10 and IL-10 producing Treg cells, and increased number of protective CD4+ Th1 and NKT cells. Lack of IFN1 signaling abrogated caspase 11 activation and IL-1β secretion, suggesting that IFN1 activates the non-canonical inflammasome. Our data also show that WT, but not IFNαR-/-, cells exhibit defective autophagy. Together, these data demonstrate that IFN 1 signaling suppresses autophagy and activates the non-canonical inflammasome pathway contributing to impaired protective immunity and development of fatal Ehrlichia-induced toxic shock.
Research Interests: Immunology and Biology
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Macro-invertebrates including freshwater snails collected from 643 sites over 8 successive seasons among the River Nile, branches, main canals and certain drains in eight Egyptian Governorates. Thirteen snail species and one bivalve... more
Macro-invertebrates including freshwater snails collected from 643 sites over 8 successive seasons among the River Nile, branches, main canals and certain drains in eight Egyptian Governorates. Thirteen snail species and one bivalve species were identified. The most distributed were Lanistus carinatus and Physa acuta while the most abundant were Cleopatra bulimoides and Physa acuta during the whole study. The sites that harbored each snail species in all the examined water-courses were grouped seasonally and their biological assessment was determined by their minimum and maximum total point similarity percentage to that of the corresponded reference site and mean of the total points. Habitats for most snail species attained minimum total point's similarity percentage less than 21% (very poor habitat) during autumn and winter then spring while during summer very poor habitat was harbored by only few snail species. P. acuta was the only survived snails in habitat which attained 0 ...
Research Interests: Demography, Egypt, Animals, Snails, Ecosystem, and 4 moreTime Factors, Fresh water, Seasons, and Species Specificity
Chlamydia trachomatis conjunctivitis may present with extended symptoms, and it can have social ramifications as a sexually transmitted disease. For appropriate therapy, C. trachomatis conjunctivitis should be diagnosed definitively. This... more
Chlamydia trachomatis conjunctivitis may present with extended symptoms, and it can have social ramifications as a sexually transmitted disease. For appropriate therapy, C. trachomatis conjunctivitis should be diagnosed definitively. This study presents the verification of nucleic acid amplification testing (NAAT; Gen-Probe Aptima Combo 2 assay) for detection of C. trachomatis ribosomal RNA (rRNA) from direct ocular samples. Retrospective laboratory verification study. Patients with infectious conjunctivitis. A battery of 25 true-positive specimens (direct ocular specimens from patients with symptoms consistent with C. trachomatis conjunctivitis and with previously demonstrated positive polymerase chain reaction [PCR] results for C. trachomatis DNA by Roche Amplicor) and 25 true-negative specimens (direct ocular specimens with culture-positive results for herpes simplex virus [n = 5], adenovirus [n = 5], Haemophilus influenzae [n = 5], and Streptococcus pneumoniae [n = 5]), and transport medium (n = 5) were tested for C. trachomatis rRNA by NAAT. These true-negative specimens have differential etiologic agents of infectious conjunctivitis. The 25 C. trachomatis specimens with PCR-positive results (obtained May 1994-May 2012) and 20 true-negative infectious ocular specimens (obtained December 2008-August 2013) were collected with soft-tipped applicators and placed in transport medium. All excess specimens were stored at -80°C. All samples were centrifuged at 13,000 rpm for 1 hour at 6°C. For each sample, using the Aptima Unisex collection blue swab, a specimen was collected from the conical apex of the storage tube where a pellet was formed. The Aptima Unisex collection swab was placed in a tube of Aptima swab transport medium for testing. All samples were tested in duplicate. Detection of C. trachomatis rRNA. Of 25 true-positive samples, 24 (96%) were positive by NAAT, whereas 25 of 25 true-negative samples (100%) showed negative results. The sensitivity, specificity, positive predictive value, negative predictive value, and efficiency were determined to be 96%, 100%, 100%, 96%, and 98%, respectively. The detection of C. trachomatis in ocular specimens by NAAT was verified for laboratory diagnosis. The test will be evaluated prospectively to determine future test performance precisely.