Publications by authors named "Malika Aid"

22 Publications

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Plasma Proteomics of COVID-19 Associated Cardiovascular Complications: Implications for Pathophysiology and Therapeutics.

Res Sq 2021 Jun 8. Epub 2021 Jun 8.

Cardiovascular complications are common in COVID-19 and strongly associated with disease severity and mortality. However, the mechanisms driving cardiac injury and failure in COVID-19 are largely unknown. We performed plasma proteomics on 80 COVID-19 patients and controls, grouped according to disease severity and cardiac involvement. Findings were validated in 305 independent COVID-19 patients and investigated in an animal model. Here we show that senescence-associated secretory proteins, markers of biological aging, strongly associate with disease severity and cardiac involvement even in age-matched cohorts. FSTL3, an indicator of Activin/TGFβ signaling, was the most significantly upregulated protein associated with the heart failure biomarker, NTproBNP (β = 0.4;p =4.6x10 ), while ADAMTS13, a vWF-cleaving protease whose loss-of-function causes microvascular thrombosis, was the most downregulated protein associated with myocardial injury (β=-0.4;p =8x10 ). Mendelian randomization supported a causal role for ADAMTS13 in myocardial injury. These data provide important new insights into the pathophysiology of COVID-19 cardiovascular complications with therapeutic implications.
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http://dx.doi.org/10.21203/rs.3.rs-539712/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202429PMC
June 2021

Correlates of Neutralization against SARS-CoV-2 Variants of Concern by Early Pandemic Sera.

J Virol 2021 06 24;95(14):e0040421. Epub 2021 Jun 24.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

Emerging SARS-CoV-2 variants of concern that overcome natural and vaccine-induced immunity threaten to exacerbate the COVID-19 pandemic. Increasing evidence suggests that neutralizing antibody (NAb) responses are a primary mechanism of protection against infection. However, little is known about the extent and mechanisms by which natural immunity acquired during the early COVID-19 pandemic confers cross-neutralization of emerging variants. In this study, we investigated cross-neutralization of the B.1.1.7 and B.1.351 SARS-CoV-2 variants in a well-characterized cohort of early pandemic convalescent subjects. We observed modestly decreased cross-neutralization of B.1.1.7 but a substantial 4.8-fold reduction in cross-neutralization of B.1.351. Correlates of cross-neutralization included receptor binding domain (RBD) and N-terminal domain (NTD) binding antibodies, homologous NAb titers, and membrane-directed T cell responses. These data shed light on the cross-neutralization of emerging variants by early pandemic convalescent immune responses. Widespread immunity to SARS-CoV-2 will be necessary to end the COVID-19 pandemic. NAb responses are a critical component of immunity that can be stimulated by natural infection as well as vaccines. However, SARS-CoV-2 variants are emerging that contain mutations in the spike gene that promote evasion from NAb responses. These variants may therefore delay control of the COVID-19 pandemic. We studied whether NAb responses from early COVID-19 convalescent patients are effective against the two SARS-CoV-2 variants, B.1.1.7 and B.1.351. We observed that the B.1.351 variant demonstrates significantly reduced susceptibility to early pandemic NAb responses. We additionally characterized virological, immunological, and clinical features that correlate with cross-neutralization. These studies increase our understanding of emerging SARS-CoV-2 variants.
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http://dx.doi.org/10.1128/JVI.00404-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223959PMC
June 2021

Protective efficacy of an attenuated Mtb ΔLprG vaccine in mice.

PLoS Pathog 2020 12 14;16(12):e1009096. Epub 2020 Dec 14.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.

Bacille Calmette-Guerin (BCG), an attenuated whole cell vaccine based on Mycobacterium bovis, is the only licensed vaccine against Mycobacterium tuberculosis (Mtb), but its efficacy is suboptimal and it fails to protect against pulmonary tuberculosis. We previously reported that Mtb lacking the virulence genes lprG and rv1410c (ΔLprG) was highly attenuated in immune deficient mice. In this study, we show that attenuated ΔLprG Mtb protects C57BL/6J, Balb/cJ, and C3HeB/FeJ mice against Mtb challenge and is as attenuated as BCG in SCID mice. In C3HeB/FeJ mice, ΔLprG vaccination resulted in innate peripheral cytokine production and induced high polyclonal PPD-specific cytokine-secreting CD4+ T lymphocytes in peripheral blood. The ΔLprG vaccine afforded protective efficacy in the lungs of C3H/FeJ mice following both H37Rv and Erdman aerosolized Mtb challenges. Vaccine efficacy correlated with antigen-specific PD-1-negative CD4+ T lymphocytes as well as with serum IL-17 levels after vaccination. We hypothesize that induction of Th17 cells in lung is critical for vaccine protection, and we show a serum cytokine biomarker for IL-17 shortly after vaccination may predict protective efficacy.
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http://dx.doi.org/10.1371/journal.ppat.1009096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769599PMC
December 2020

Vascular Disease and Thrombosis in SARS-CoV-2-Infected Rhesus Macaques.

Cell 2020 11 9;183(5):1354-1366.e13. Epub 2020 Oct 9.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. Electronic address:

The COVID-19 pandemic has led to extensive morbidity and mortality throughout the world. Clinical features that drive SARS-CoV-2 pathogenesis in humans include inflammation and thrombosis, but the mechanistic details underlying these processes remain to be determined. In this study, we demonstrate endothelial disruption and vascular thrombosis in histopathologic sections of lungs from both humans and rhesus macaques infected with SARS-CoV-2. To define key molecular pathways associated with SARS-CoV-2 pathogenesis in macaques, we performed transcriptomic analyses of bronchoalveolar lavage and peripheral blood and proteomic analyses of serum. We observed macrophage infiltrates in lung and upregulation of macrophage, complement, platelet activation, thrombosis, and proinflammatory markers, including C-reactive protein, MX1, IL-6, IL-1, IL-8, TNFα, and NF-κB. These results suggest a model in which critical interactions between inflammatory and thrombosis pathways lead to SARS-CoV-2-induced vascular disease. Our findings suggest potential therapeutic targets for COVID-19.
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http://dx.doi.org/10.1016/j.cell.2020.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546181PMC
November 2020

Delineation and Modulation of the Natural Killer Cell Transcriptome in Rhesus Macaques During ZIKV and SIV Infections.

Front Cell Infect Microbiol 2020 29;10:194. Epub 2020 Apr 29.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.

Natural killer (NK) cells are crucial regulators of antiviral and anti-tumor immune responses. Although in humans some NK cell transcriptional programs are relatively well-established, NK cell transcriptional networks in non-human primates (NHP) remain poorly delineated. Here we performed RNA-Seq experiments using purified NK cells from experimentally naïve rhesus macaques, providing the first transcriptional characterization of pure NK cells in any NHP species. This novel NK cell transcriptomic signature (NK RMtsig) overlaps with published human NK signatures, allowing us to identify new key signaling and transcription factor networks underlying NK cell function. Finally, we show that applying NK RMtsig to an unrelated rhesus macaque cohort infected with SIVmac251 or ZIKV can sensitively detect NK cell repertoire perturbations, thus confirming applicability of this approach. In sum, we propose this NHP NK cell signature will serve as a useful resource for future studies involving infection, disease or treatment modalities in NHP.
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http://dx.doi.org/10.3389/fcimb.2020.00194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201019PMC
June 2021

Alpha-defensin 5 differentially modulates adenovirus vaccine vectors from different serotypes in vivo.

PLoS Pathog 2019 12 16;15(12):e1008180. Epub 2019 Dec 16.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston Massachusetts, United States of America.

Adenoviral vectors have shown significant promise as vaccine delivery vectors due to their ability to elicit both innate and adaptive immune responses. α-defensins are effector molecules of the innate immune response and have been shown to modulate natural infection with adenoviruses, but the majority of α-defensin-adenovirus interactions studied to date have only been analyzed in vitro. In this study, we evaluated the role of α-defensin 5 (HD5) in modulating adenovirus vaccine immunogenicity using various serotype adenovirus vectors in mice. We screened a panel of human adenoviruses including Ad5 (species C), Ad26 (species D), Ad35 (species B), Ad48 (species D) and a chimeric Ad5HVR48 for HD5 sensitivity. HD5 inhibited transgene expression from Ad5 and Ad35 but augmented transgene expression from Ad26, Ad48, and Ad5HVR48. HD5 similarly suppressed antigen-specific IgG and CD8+ T cell responses elicited by Ad5 vectors in mice, but augmented IgG and CD8+ T cell responses and innate cytokine responses elicited by Ad26 vectors in mice. Moreover, HD5 suppressed the protective efficacy of Ad5 vectors but enhanced the protective efficacy of Ad26 vectors expressing SIINFEKL against a surrogate Listeria-OVA challenge in mice. These data demonstrate that HD5 differentially modulates adenovirus vaccine delivery vectors in a species-specific manner in vivo.
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http://dx.doi.org/10.1371/journal.ppat.1008180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936886PMC
December 2019

Adenovirus Vector-Based Vaccines Confer Maternal-Fetal Protection against Zika Virus Challenge in Pregnant IFN-αβR Mice.

Cell Host Microbe 2019 11 24;26(5):591-600.e4. Epub 2019 Oct 24.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA. Electronic address:

Maternal infection with Zika virus (ZIKV) can lead to microcephaly and other congenital abnormalities of the fetus. Although ZIKV vaccines that prevent or reduce viremia in non-pregnant mice have been described, a maternal vaccine that provides complete fetal protection would be desirable. Here, we show that adenovirus (Ad) vector-based ZIKV vaccines induce potent neutralizing antibodies that confer robust maternal and fetal protection against ZIKV challenge in pregnant, highly susceptible IFN-αβR mice. Moreover, passive transfer of maternal antibodies from vaccinated dams protected pups against post-natal ZIKV challenge. These data suggest that Ad-based ZIKV vaccines may be able to provide protection in pregnant females against fetal ZIKV transmission in utero as well as in infants against ZIKV infection after birth.
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http://dx.doi.org/10.1016/j.chom.2019.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863051PMC
November 2019

NK Cells Contribute to the Immune Risk Profile in Kidney Transplant Candidates.

Front Immunol 2019 23;10:1890. Epub 2019 Aug 23.

Center for Virology and Vaccines Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.

A previously proposed immune risk profile (IRP), based on T cell phenotype and CMV serotype, is associated with mortality in the elderly and increased infections post-kidney transplant. To evaluate if NK cells contribute to the IRP and if the IRP can be predicted by a clinical T cell functional assays, we conducted a cross sectional study in renal transplant candidates to determine the incidence of IRP and its association with specific NK cell characteristics and ImmuKnow® value. Sixty five subjects were enrolled in 5 cohorts designated by age and dialysis status. We determined T and NK cell phenotypes by flow cytometry and analyzed multiple factors contributing to IRP. We identified 14 IRP+ [CMV seropositivity and CD4/CD8 ratio < 1 or being in the highest quintile of CD8+ senescent (28CD-/CD57+) T cells] individuals equally divided amongst the cohorts. Multivariable linear regression revealed a distinct IRP+ group. Age and dialysis status did not predict immune senescence in kidney transplant candidates. NK cell features alone could discriminate IRP- and IRP+ patients, suggesting that NK cells significantly contribute to the overall immune status in kidney transplant candidates and that a combined T and NK cell phenotyping can provide a more detailed IRP definition. ImmuKnow® value was negatively correlated to age and significantly lower in IRP+ patients and predicts IRP when used alone or in combination with NK cell features. NK cells contribute to overall immune senescence in kidney transplant candidates.
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http://dx.doi.org/10.3389/fimmu.2019.01890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716214PMC
September 2020

Combined HDAC and BET Inhibition Enhances Melanoma Vaccine Immunogenicity and Efficacy.

J Immunol 2018 11 24;201(9):2744-2752. Epub 2018 Sep 24.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

The combined inhibition of histone deacetylases (HDAC) and the proteins of the bromodomain and extraterminal (BET) family have recently shown therapeutic efficacy against melanoma, pancreatic ductal adenocarcinoma, testicular, and lymphoma cancers in murine studies. However, in such studies, the role of the immune system in therapeutically controlling these cancers has not been explored. We sought to investigate the effect of the HDAC inhibitor romidepsin (RMD) and the BET inhibitor IBET151, both singly and in combination, on vaccine-elicited immune responses. C57BL/6 mice were immunized with differing vaccine systems (adenoviral, protein) in prime-boost regimens under treatment with RMD, IBET151, or RMD+IBET151. The combined administration of RMD+IBET151 during vaccination resulted in a significant increase in the frequency and number of Ag-specific CD8 T cells. RMD+IBET151 treatment significantly increased the frequency of vaccine-elicited IFN-γ splenic CD8 T cells and conferred superior therapeutic and prophylactic protection against B16-OVA melanoma. RNA sequencing analyses revealed strong transcriptional similarity between RMD+IBET151 and untreated Ag-specific CD8 T cells except in apoptosis and IL-6 signaling-related genes that were differentially expressed. Serum IL-6 was significantly increased in vivo following RMD+IBET151 treatment, with recombinant IL-6 administration replicating the effect of RMD+IBET151 treatment on vaccine-elicited CD8 T cell responses. IL-6 sufficiency for protection was not assessed. Combined HDAC and BET inhibition resulted in greater vaccine-elicited CD8 T cell responses and enhanced therapeutic and prophylactic protection against B16-OVA melanoma. Increased IL-6 production and the differential expression of pro- and anti-apoptotic genes following RMD+IBET151 treatment are likely contributors to the enhanced cancer vaccine responses.
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http://dx.doi.org/10.4049/jimmunol.1800885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196294PMC
November 2018

Follicular CD4 T Helper Cells As a Major HIV Reservoir Compartment: A Molecular Perspective.

Front Immunol 2018 18;9:895. Epub 2018 Jun 18.

Pathology Department, Case Western Reserve University, Cleveland, OH, United States.

Effective antiretroviral therapy (ART) has prevented the progression to AIDS and reduced HIV-related morbidities and mortality for the majority of infected individuals. However, a lifelong administration of ART is necessary, placing an inordinate burden on individuals and public health systems. Therefore, discovering therapeutic regimens able to eradicate or functionally cure HIV infection is of great importance. ART interruption leads to viral rebound highlighting the establishment and maintenance of a latent viral reservoir compartment even under long-term treatment. Follicular helper CD4 T cells (TFH) have been reported as a major cell compartment contributing to viral persistence, consequent to their susceptibility to infection and ability to release replication-competent new virions. Here, we discuss the molecular profiles and potential mechanisms that support the role of TFH cells as one of the major HIV reservoirs.
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http://dx.doi.org/10.3389/fimmu.2018.00895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015877PMC
July 2019

Adenovirus Vector Vaccination Impacts NK Cell Rheostat Function following Lymphocytic Choriomeningitis Virus Infection.

J Virol 2018 06 14;92(11). Epub 2018 May 14.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

Natural killer (NK) cells respond rapidly as a first line of defense against infectious pathogens. In addition, NK cells may provide a "rheostat" function and have been shown to reduce the magnitude of antigen-specific T cell responses following infection to avoid immunopathology. However, it remains unknown whether NK cells similarly modulate vaccine-elicited T cell responses following virus challenge. We used the lymphocytic choriomeningitis virus (LCMV) clone 13 infection model to address whether NK cells regulate T cell responses in adenovirus vector-vaccinated mice following challenge. As expected, NK cell depletion in unvaccinated mice resulted in increased virus-specific CD4 and CD8 T cell responses and immunopathology following LCMV challenge. In contrast, NK cell depletion had minimal to no impact on antigen-specific T cell responses in mice that were vaccinated with an adenovirus serotype 5 (Ad5)-GP vector prior to LCMV challenge. Moreover, NK cell depletion in vaccinated mice prior to challenge did not result in immunopathology and did not compromise protective efficacy. These data suggest that adenovirus vaccine-elicited T cells may be less sensitive to NK cell rheostat regulation than T cells primed by LCMV infection. Recent data have shown that NK cell depletion leads to enhanced virus-elicited T cell responses that can result in severe immunopathology following LCMV infection in mice. In this study, we observed that NK cells exerted minimal to no impact on vaccine-elicited T cells following LCMV challenge, suggesting that adenovirus vaccine-elicited T cells may be less subject to NK cell regulation. These data contribute to our understanding of NK cell regulatory functions and T cell-based vaccines.
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http://dx.doi.org/10.1128/JVI.02103-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952142PMC
June 2018

Rapid Cloning of Novel Rhesus Adenoviral Vaccine Vectors.

J Virol 2018 03 26;92(6). Epub 2018 Feb 26.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

Human and chimpanzee adenovirus vectors are being developed to circumvent preexisting antibodies against common adenovirus vectors such as Ad5. However, baseline immunity to these vectors still exists in human populations. Traditional cloning of new adenovirus vaccine vectors is a long and cumbersome process that takes 2 months or more and that requires rare unique restriction enzyme sites. Here we describe a novel, restriction enzyme-independent method for rapid cloning of new adenovirus vaccine vectors that reduces the total cloning procedure to 1 week. We developed 14 novel adenovirus vectors from rhesus monkeys that can be grown to high titers and that are immunogenic in mice. All vectors grouped with the unusual adenovirus species G and show extremely low seroprevalence in humans. Rapid cloning of novel adenovirus vectors is a promising approach for the development of new vector platforms. Rhesus adenovirus vectors may prove useful for clinical development. To overcome baseline immunity to human and chimpanzee adenovirus vectors, we developed 14 novel adenovirus vectors from rhesus monkeys. These vectors are immunogenic in mice and show extremely low seroprevalence in humans. Rhesus adenovirus vectors may prove useful for clinical development.
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http://dx.doi.org/10.1128/JVI.01924-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827402PMC
March 2018

Initiation of Antiviral B Cell Immunity Relies on Innate Signals from Spatially Positioned NKT Cells.

Cell 2018 01 14;172(3):517-533.e20. Epub 2017 Dec 14.

Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; The Francis Crick Institute, London NW1A 1AT, UK; Department of Microbiology and Immunobiology & HMS Center for Immune Imaging, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

B cells constitute an essential line of defense from pathogenic infections through the generation of class-switched antibody-secreting cells (ASCs) in germinal centers. Although this process is known to be regulated by follicular helper T (TfH) cells, the mechanism by which B cells initially seed germinal center reactions remains elusive. We found that NKT cells, a population of innate-like T lymphocytes, are critical for the induction of B cell immunity upon viral infection. The positioning of NKT cells at the interfollicular areas of lymph nodes facilitates both their direct priming by resident macrophages and the localized delivery of innate signals to antigen-experienced B cells. Indeed, NKT cells secrete an early wave of IL-4 and constitute up to 70% of the total IL-4-producing cells during the initial stages of infection. Importantly, the requirement of this innate immunity arm appears to be evolutionarily conserved because early NKT and IL-4 gene signatures also positively correlate with the levels of neutralizing antibodies in Zika-virus-infected macaques. In conclusion, our data support a model wherein a pre-TfH wave of IL-4 secreted by interfollicular NKT cells triggers the seeding of germinal center cells and serves as an innate link between viral infection and B cell immunity.
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http://dx.doi.org/10.1016/j.cell.2017.11.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786505PMC
January 2018

Regulation of CD4 T cells and their effects on immunopathological inflammation following viral infection.

Immunology 2017 10 14;152(2):328-343. Epub 2017 Jul 14.

Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL.

CD4 T cells help immune responses, but knowledge of how memory CD4 T cells are regulated and how they regulate adaptive immune responses and induce immunopathology is limited. Using adoptive transfer of virus-specific CD4 T cells, we show that naive CD4 T cells undergo substantial expansion following infection, but can induce lethal T helper type 1-driven inflammation. In contrast, memory CD4 T cells exhibit a biased proliferation of T follicular helper cell subsets and were able to improve adaptive immune responses in the context of minimal tissue damage. Our analyses revealed that type I interferon regulates the expansion of primary CD4 T cells, but does not seem to play a critical role in regulating the expansion of secondary CD4 T cells. Strikingly, blockade of type I interferon abrogated lethal inflammation by primary CD4 T cells following viral infection, despite that this treatment increased the numbers of primary CD4 T-cell responses. Altogether, these data demonstrate important aspects of how primary and secondary CD4 T cells are regulated in vivo, and how they contribute to immune protection and immunopathology. These findings are important for rational vaccine design and for improving adoptive T-cell therapies against persistent antigens.
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http://dx.doi.org/10.1111/imm.12771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5588757PMC
October 2017

Zika Virus Persistence in the Central Nervous System and Lymph Nodes of Rhesus Monkeys.

Cell 2017 05 27;169(4):610-620.e14. Epub 2017 Apr 27.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. Electronic address:

Zika virus (ZIKV) is associated with severe neuropathology in neonates as well as Guillain-Barré syndrome and other neurologic disorders in adults. Prolonged viral shedding has been reported in semen, suggesting the presence of anatomic viral reservoirs. Here we show that ZIKV can persist in cerebrospinal fluid (CSF) and lymph nodes (LN) of infected rhesus monkeys for weeks after virus has been cleared from peripheral blood, urine, and mucosal secretions. ZIKV-specific neutralizing antibodies correlated with rapid clearance of virus in peripheral blood but remained undetectable in CSF for the duration of the study. Viral persistence in both CSF and LN correlated with upregulation of mechanistic target of rapamycin (mTOR), proinflammatory, and anti-apoptotic signaling pathways, as well as downregulation of extracellular matrix signaling pathways. These data raise the possibility that persistent or occult neurologic and lymphoid disease may occur following clearance of peripheral virus in ZIKV-infected individuals.
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http://dx.doi.org/10.1016/j.cell.2017.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5426912PMC
May 2017

Adenovirus serotype 5 vaccine vectors trigger IL-27-dependent inhibitory CD4 T cell responses that impair CD8 T cell function.

Sci Immunol 2016 Nov 4;1(5). Epub 2016 Nov 4.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.

Adenovirus serotype 5 (Ad5) vaccine vectors elicit robust CD8 T cell responses, but these responses typically exhibit a partially exhausted phenotype. However, the immunologic mechanism by which Ad5 vectors induce dysfunctional CD8 T cells has not previously been elucidated. Here we demonstrate that, following immunization of B6 mice, Ad5 vectors elicit antigen-specific IL-10CD4 T cells with a distinct transcriptional profile in a dose-dependent fashion. In rhesus monkeys, we similarly observed upregulated expression of IL-10 and PD-1 by CD4 T cells following Ad5 vaccination. These cells markedly suppressed vaccine-elicited CD8 T cell responses and IL-10 blockade increased the frequency and functionality of antigen-specific CD8 T cells as well as improved protective efficacy against challenge with recombinant . Moreover, induction of these inhibitory IL-10CD4 T cells correlated with IL-27 expression and IL-27 blockade substantially improved CD4 T cell functionality. These data highlight a role for IL-27 in the induction of inhibitory IL-10CD4 T cells, which suppress CD8 T cell magnitude and function following Ad5 vector immunization. A deeper understanding of the cytokine networks and transcriptional profiles induced by vaccine vectors should lead to strategies to improve the immunogenicity and protective efficacy of viral vector-based vaccines.
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http://dx.doi.org/10.1126/sciimmunol.aaf7643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322800PMC
November 2016

The sooner the better: innate immunity as a path toward the HIV cure.

Curr Opin Virol 2016 08 3;19:85-91. Epub 2016 Aug 3.

Case Western Reserve University, Department of Pathology, Cleveland, OH, USA. Electronic address:

To combat the diverse pathogens that infect humans, the immune system has evolved complex and diverse transcriptional signatures, which drive differential cellular and humoral responses. These signatures are induced by immune receptor sensing of pathogens and by cytokines produced at the earliest onset of infection. The specific nature of immune activation is as critical to pathogen clearance as the induction of an adaptive immune response. This is particularly true for HIV, which has developed numerous immune evasion mechanisms. In this review, we will highlight recent findings that show the differential role for early innate immune responses in promoting infection versus clearance and demonstrate the need for continued research on these pathways for development of effective HIV treatments.
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http://dx.doi.org/10.1016/j.coviro.2016.07.003DOI Listing
August 2016

Immediate Dysfunction of Vaccine-Elicited CD8+ T Cells Primed in the Absence of CD4+ T Cells.

J Immunol 2016 09 22;197(5):1809-22. Epub 2016 Jul 22.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; Ragon Institute of MGH, MIT, and Harvard, Boston, MA 02139

CD4(+) T cell help is critical for optimal CD8(+) T cell memory differentiation and maintenance in many experimental systems. In addition, many reports have identified reduced primary CD8(+) T cell responses in the absence of CD4(+) T cell help, which often coincides with reduced Ag or pathogen clearance. In this study, we demonstrate that absence of CD4(+) T cells at the time of adenovirus vector immunization of mice led to immediate impairments in early CD8(+) T cell functionality and differentiation. Unhelped CD8(+) T cells exhibited a reduced effector phenotype, decreased ex vivo cytotoxicity, and decreased capacity to produce cytokines. This dysfunctional state was imprinted within 3 d of immunization. Unhelped CD8(+) T cells expressed elevated levels of inhibitory receptors and exhibited transcriptomic exhaustion and anergy profiles by gene set enrichment analysis. Dysfunctional, impaired effector differentiation also occurred following immunization of CD4(+) T cell-deficient mice with a poxvirus vector. This study demonstrates that following priming with viral vectors, CD4(+) T cell help is required to promote both the expansion and acquisition of effector functions by CD8(+) T cells, which is accomplished by preventing immediate dysfunction.
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http://dx.doi.org/10.4049/jimmunol.1600591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991249PMC
September 2016

ZNF143 provides sequence specificity to secure chromatin interactions at gene promoters.

Nat Commun 2015 Feb 3;2:6186. Epub 2015 Feb 3.

The Princess Margaret Cancer Centre-University Health Network, Toronto, M5G 1L7, Ontario, Canada.

Chromatin interactions connect distal regulatory elements to target gene promoters guiding stimulus- and lineage-specific transcription. Few factors securing chromatin interactions have so far been identified. Here, by integrating chromatin interaction maps with the large collection of transcription factor-binding profiles provided by the ENCODE project, we demonstrate that the zinc-finger protein ZNF143 preferentially occupies anchors of chromatin interactions connecting promoters with distal regulatory elements. It binds directly to promoters and associates with lineage-specific chromatin interactions and gene expression. Silencing ZNF143 or modulating its DNA-binding affinity using single-nucleotide polymorphisms (SNPs) as a surrogate of site-directed mutagenesis reveals the sequence dependency of chromatin interactions at gene promoters. We also find that chromatin interactions alone do not regulate gene expression. Together, our results identify ZNF143 as a novel chromatin-looping factor that contributes to the architectural foundation of the genome by providing sequence specificity at promoters connected with distal regulatory elements.
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http://dx.doi.org/10.1038/ncomms7186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4431651PMC
February 2015

Regulation of efflux pump expression and drug resistance by the transcription factors Mrr1, Upc2, and Cap1 in Candida albicans.

Antimicrob Agents Chemother 2011 May 14;55(5):2212-23. Epub 2011 Mar 14.

Institut für Molekulare Infektionsbiologie, Universität Würzburg, Josef-Schneider-Str. 2, Bau D15, D-97080 Würzburg, Germany.

Constitutive overexpression of the Mdr1 efflux pump is an important mechanism of acquired drug resistance in the yeast Candida albicans. The zinc cluster transcription factor Mrr1 is a central regulator of MDR1 expression, but other transcription factors have also been implicated in MDR1 regulation. To better understand how MDR1-mediated drug resistance is achieved in this fungal pathogen, we studied the interdependence of Mrr1 and two other MDR1 regulators, Upc2 and Cap1, in the control of MDR1 expression. A mutated, constitutively active Mrr1 could upregulate MDR1 and confer drug resistance in the absence of Upc2 or Cap1. On the other hand, Upc2 containing a gain-of-function mutation only slightly activated the MDR1 promoter, and this activation depended on the presence of a functional MRR1 gene. In contrast, a C-terminally truncated, activated form of Cap1 could upregulate MDR1 in a partially Mrr1-independent fashion. The induction of MDR1 expression by toxic chemicals occurred independently of Upc2 but required the presence of Mrr1 and also partially depended on Cap1. Transcriptional profiling and in vivo DNA binding studies showed that a constitutively active Mrr1 binds to and upregulates most of its direct target genes in the presence or absence of Cap1. Therefore, Mrr1 and Cap1 cooperate in the environmental induction of MDR1 expression in wild-type C. albicans, but gain-of-function mutations in either of the two transcription factors can independently mediate efflux pump overexpression and drug resistance.
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http://dx.doi.org/10.1128/AAC.01343-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088179PMC
May 2011

Mechanisms of primary and secondary estrogen target gene regulation in breast cancer cells.

Nucleic Acids Res 2008 Jan 5;36(1):76-93. Epub 2007 Nov 5.

Institute for Research in Immunology and Cancer and Biochemistry Department, Université de Montréal, C.P. 6128 Succursale Centre Ville, Montréal, QC H3C 3J7, Canada.

Estrogen receptors (ERs), which mediate the proliferative action of estrogens in breast cancer cells, are ligand-dependent transcription factors that regulate expression of their primary target genes through several mechanisms. In addition to direct binding to cognate DNA sequences, ERs can be recruited to DNA through other transcription factors (tethering), or affect gene transcription through modulation of signaling cascades by non-genomic mechanisms of action. To better characterize the mechanisms of gene regulation by estrogens, we have identified more than 700 putative primary and about 1300 putative secondary target genes of estradiol in MCF-7 cells through microarray analysis performed in the presence or absence of the translation inhibitor cycloheximide. Although siRNA-mediated inhibition of ERalpha expression antagonized the effects of estradiol on up- and down-regulated primary target genes, estrogen response elements (EREs) were enriched only in the vicinity of up-regulated genes. Binding sites for several other transcription factors, including proteins known to tether ERalpha, were enriched in up- and/or down-regulated primary targets. Secondary estrogen targets were particularly enriched in sites for E2F family members, several of which were transcriptionally regulated by estradiol, consistent with a major role of these factors in mediating the effects of estrogens on gene expression and cellular growth.
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http://dx.doi.org/10.1093/nar/gkm945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2248750PMC
January 2008
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