Laboratory of Molecular Microbiology
Laboratory of Molecular Microbiology
Ortiz A.M.,Laboratory of Molecular Microbiology |
Klase Z.A.,Laboratory of Molecular Microbiology |
Klase Z.A.,University of the Sciences in Philadelphia |
DiNapoli S.R.,Laboratory of Molecular Microbiology |
And 13 more authors.
Mucosal Immunology | Year: 2016
Increased mortality in antiretroviral (ARV)-treated, HIV-infected individuals has been attributed to persistent immune dysfunction, in part due to abnormalities at the gastrointestinal barrier. In particular, the poor reconstitution of gastrointestinal Th17 cells correlates with residual translocation of dysbiotic, immunostimulatory microflora across a compromised intestinal epithelial barrier. We have previously demonstrated that oral probiotics promote increased intestinal CD4 + T-cell reconstitution during ARV treatment in a non-human primate model of HIV infection; however, essential mucosal T-cell subsets, such as Th17 cells, had limited recovery. Here, we sought to promote Th17 cell recovery by administering interleukin (IL)-21 to a limited number of ARV-treated, probiotic-supplemented, Simian Immunodeficiency Virus (SIV)-infected pigtailed macaques. We demonstrate that probiotic and IL-21 supplementation of ARVs are associated with enhanced polyfunctional Th17 expansion and reduced markers of microbial translocation and dysbiosis as compared with infected controls receiving ARVs alone. Importantly, treatment resulted in fewer morbidities compared with controls, and was independent of increased immune activation or loss of viral suppression. We propose that combining ARVs with therapeutics aimed at restoring intestinal stasis may significantly improve disease prognosis of ARV-treated, HIV-infected individuals.
Lugli E.,U.S. National Institutes of Health |
Lugli E.,Humanitas Clinical and Research Center |
Dominguez M.H.,U.S. National Institutes of Health |
Gattinoni L.,U.S. National Cancer Institute |
And 13 more authors.
Journal of Clinical Investigation | Year: 2013
Long-lived memory T cells are able to persist in the host in the absence of antigen; however, the mechanism by which they are maintained is not well understood. Recently, a subset of human T cells, stem cell memory T cells (TSCM cells), was shown to be self-renewing and multipotent, thereby providing a potential reservoir for T cell memory throughout life. However, their in vivo dynamics and homeostasis still remain to be defined due to the lack of suitable animal models. We identified T cells with a TSCM phenotype and stem cell-like properties in nonhuman primates. These cells were the least-differentiated memory subset, were functionally distinct from conventional memory cells, and served as precursors of central memory. Antigen-specific TSCM cells preferentially localized to LNs and were virtually absent from mucosal surfaces. They were generated in the acute phase of viral infection, preferentially survived in comparison with all other memory cells following elimination of antigen, and stably persisted for the long term. Thus, one mechanism for maintenance of long-term T cell memory derives from the unique homeostatic properties of TSCM cells. Vaccination strategies designed to elicit durable cellular immunity should target the generation of TSCM cells.
Grainger J.R.,Laboratory of Parasitic Diseases |
Wohlfert E.A.,Laboratory of Parasitic Diseases |
Fuss I.J.,Laboratory of Host Defenses |
Bouladoux N.,Laboratory of Parasitic Diseases |
And 7 more authors.
Nature Medicine | Year: 2013
The commensal flora can promote both immunity to pathogens and mucosal inflammation. How commensal-driven inflammation is regulated in the context of infection remains poorly understood. Here, we show that during acute mucosal infection of mice with Toxoplasma gondii, inflammatory monocytes acquire a tissue-specific regulatory phenotype associated with production of the lipid mediator prostaglandin E2 (PGE2). Notably, in response to commensals, inflammatory monocytes can directly inhibit neutrophil activation in a PGE2-dependent manner. Further, in the absence of inflammatory monocytes, mice develop severe neutrophil-mediated pathology in response to pathogen challenge that can be controlled by PGE2 analog treatment. Complementing these findings, inhibition of PGE2 led to enhanced neutrophil activation and host mortality after infection. These data demonstrate a previously unappreciated dual action of inflammatory monocytes in controlling pathogen expansion while limiting commensal-mediated damage to the gut. Collectively, our results place inflammatory monocyte-derived PGE2 at the center of a commensal-driven regulatory loop required to control host-commensal dialog during pathogen-induced inflammation. © 2013 Nature America, Inc. All rights reserved.
Sellam F.,University Djilali Liabes |
Harir N.,University Djilali Liabes |
Harir N.,Laboratory of Molecular Microbiology |
Khaled M.B.,University Djilali Liabes |
And 7 more authors.
Pancreatology | Year: 2015
Objective: Evaluating tissue samples of normal and exocrine cancerous human pancreas on the expression of CCK2/gastrin receptor. We performed an immunohistochemical protocol that allows efficient detection of this receptor in formalin-fixed, paraffin-embedded human tissues. Methods: Twenty (20) paraffin blocks of pancreatic tissue sections were collected from the Departments of pathology, Central University Hospital of Sidi-bel-Abbes City (Western Algeria) for the period 2004-2013; ten (10) of them were normal pancreatic samples; and ten (10) cancerous pancreatic sections. The samples were studied using an immunohistochemical protocol for CCK-2/gastrin receptors. Results: Our immunohistochemical analysis revealed that CCK-2/gastrin receptors were expressed in both normal and malignant pancreatic cells but with different immunoreactivity levels and different immunostaining intensity i.e., CCK-2/gastrin receptors were highly expressed within the cytoplasmic area of cancerous cells; 40% of the samples had an immunoreactivity (IR) of (+++) and 60% (++++); the immunostaining was as well very intense since we reported a dark brown staining of the malignant cells. However; in normal pancreatic tissues; CCK-2/gastrin receptors IR levels were very low; 80% of the samples had an IR of (+); and 20% had (++) and the immunostaining was less intense; we noted a light brown staining of few normal pancreatic cells. Conclusion: The gastrointestinal peptides CCK could be very interesting targets for exocrine pancreatic cancer therapies; thus further surveys such as western blotting and RTPCR could indentify CCK-2/gastrin receptors as a helpful biomarker for exocrine pancreatic cancer diagnosis and treatment. © 2015 IAP and EPC.
Murakami-Tonami Y.,Aichi Cancer Center Research Institute |
Ohtsuka H.,Laboratory of Molecular Microbiology |
Ohtsuka H.,Nagoya University |
Aiba H.,Laboratory of Molecular Microbiology |
And 2 more authors.
Cell Cycle | Year: 2014
In eukaryotes, the cyclin-dependent kinase Cdk1p (Cdc2p) plays a central role in entry into and progression through nuclear division during mitosis and meiosis. Cdk1p is activated during meiotic nuclear divisions by dephosphorylation of its tyrosine-15 residue. The phosphorylation status of this residue is largely determined by the Wee1p kinase and the Cdc25p phosphatase. In fission yeast, the forkhead-type transcription factor Mei4p is essential for entry into the first meiotic nuclear division. We recently identified cdc25+ as an essential target of Mei4p in the control of entry into meiosis I. Here, we show that wee1+ is another important target of Mei4p in the control of entry into meiosis I. Mei4p bound to the upstream region of wee1+ in vivo and in vitro and inhibited expression of wee1+, whereas Mei4p positively regulated expression of the adjacent pseudogene. Overexpression of Mei4p inhibited expression of wee1 + and induced that of the pseudogene. Conversely, deletion of Mei4p did not decrease expression of wee1+ but inhibited that of the pseudogene. In addition, deletion of Mei4p-binding regions delayed repression of wee1+ expression as well as induction of expression of the pseudogene. These results suggest that repression of wee1+ expression is primarily owing to Mei4p-mediated transcriptional interference. © Yuko Murakami-Tonami, Hokuto Ohtsuka, Hirofumi Aiba, and Hiroshi Murakami.
Strebel K.,Laboratory of Molecular Microbiology
Biochimica et Biophysica Acta - Biomembranes | Year: 2014
Vpu is a small membrane protein encoded by HIV-1 and some SIV isolates. The protein is best known for its ability to degrade CD4 and to enhance the release of progeny virions from infected cells. However, Vpu also promotes host-cell apoptosis by deregulating the NFκB signaling pathway and it assembles into cation-conducting membrane pores. This review summarizes our current understanding of these various functions of Vpu with particular emphasis on recent progress in the Vpu field. This article is part of a Special Issue entitled: Viral Membrane Proteins - Channels for Cellular Networking. © Published by Elsevier B.V.