abstract - Istituto Pasteur

Area 5: Cellular and molecular immunology
INTERLEUKIN 32: MOLECULAR EXPRESSION, EPIGENETIC REGULATION AND BIOLOGICAL
ACTIVITIES IN HUMAN IMMUNODEFICIENCY VIRUS-1 INFECTION
Carolina Scagnolari
Assistant professor
Department of Molecular Medicine
Ph +390644741246 Email: [email protected]
Abstract
Interleukin-32 (IL-32), previously called natural killer cell transcript 4, has been recently
recognized as a proinflammatory cytokine. It also participates in the responses to infection
with viruses such as HIV-1 and influenza and, unexpectedly, is able to trigger classical
interferon (IFN) pathways. More recently, it has been demonstrated that IL-32 promoter
methylation modulates antiviral activity of this cytokine in the course of influenza virus
infection. However, whether such epigenetic modifications may modulate IL-32
expression also during other viral infections, such as HIV, remains unclear. Given the
mounting evidence for a role of IL-32 in the immune response to viral infections and its
regulation by and induction of several proinflammatory cytokines, we set out to
investigate both in vitro and in vivo the role of this cytokine in HIV-1 infection. In particular
we plan to perform a research project mainly aimed to address the following main issues:
a) to characterize the biological activities of IL-32 in experimental models of HIV-1
infection; b) to examine the IL-32 epigenetic regulation during HIV-1 infection; c) to
evaluate the prognostic value of IL-32 single-nucleotide polymorphisms and its expression
in HIV-1 infected patients.
The project will start by evaluating the effect of IL-32, used alone or combined with
antiviral drugs, on viral transcription and replication in experimental models of HIV-1
infections. Furthermore, considering that microRNAs (miRNAs) are significantly involved in
the modulation of cytokine activity, we will examine whether IL-32 could alter the
expression of cellular miRNAs who target HIV-1 genes and/or regulate IL-32 pathways. To
further investigate the role of HIV-1 in regulating the IL-32 expression, we will explore
whether the epigenetic mechanisms, such as DNA methylation, and/or HIV-induced
miRNAs contributed to IL-32 expression during HIV-1 infection. In addition, considering
that a growing body of evidence suggests that host genetic factors play an important role
both in susceptibility to HIV-1 infection and in progression to AIDS, we will focus on the
evaluation of the influence of the IL-32 polymorphisms on the clinical progression of HIV
infection, as well as on IL-32 protein/mRNA production. To determine whether IL-32
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participate in the regulation of IFN pathways, we will also determine whether there are
any relationships between IL-32 production and activation of type I-III IFN antiviral
signaling.
We firmly believe that performing such a project may help to understand the delicate
balance between IL-32 activation and HIV replication and will improve our knowledge on
the processes by which HIV hijacks immune response. In addition the characterization of
IL-32 mediated miRNAs production and HIV-1 induced epigenetic regulation of IL-32 may
help in a better understanding of the ability of pro-inflammatory cytokines and/or virus to
regulate immune response by using epigenetic mechanisms and will provides a basis for
identifying novel gene targets, mechanisms and cross-talk between antiviral immune
response pathways.
GROUP COMPONENTS
The current project will be carry out at Sapienza University of Rome by a multidisciplinary
team of young researchers with proven expertise in HIV infection, immunology and viral
infectious diseases.
Dot. Corrado De Vito Assistant professor (Ricercatore MED42)
(Department of Public Health and Infectious Diseases)
Dott.ssa Gabriella D’Ettore Medical Doctor in Infectious Diseases/Post-doc researcher
(Department of Public Health and Infectious Diseases)
Dott.ssa Simona Trombetti Post-doc researcher
(Department of Molecular Medicine)
Dott.ssa Katia Monteleone PhD student in Experimental Medicine
(Department of Molecular Medicine)
Dott.ssa Lucia Spano PhD student in Infectious Diseases
(Department of Public Health and Infectious Diseases)
Dott.ssa Carla Selvaggi Postgraduate student of Microbiology and Virology Specialization
(Department of Molecular Medicine)
Dott.ssa Giulia Cacciotti PhD student in Experimental Medicine
(Department of Molecular Medicine)
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RELEVANT PUBLICATIONS FROM 2008 TO 2012
1.Riva E, Scagnolari C, Monteleone K, Selvaggi C, Picardi A, Mazzarelli C, Pizzigallo E,
Vincenzi B, Carducci A, Antonaci S, Gianneli G, Antonelli G. Interleukin-28B (IL-28B) singlenucleotide polymorphisms and interferon plus ribavirin treatment outcome in
Italianchronically HCV-infected patient Journal of Viral Hepatitis 2012. IF 3.502
2.Midulla F, Pierangeli A, Cangiano G, Bonci E, Salvadei S, Scagnolari C, Moretti C,
Antonelli G, Ferro V, Papoff P. Rhinovirus bronchiolitis and recurrent wheezing: 1-year
follow-up. Eur Respir J. 2012. IF 5.527
3.Scagnolari C, Midulla F, Riva E, Monteleone K, Solimini A, Bonci E, Cangiano G, Papoff P,
Moretti C, Pierangeli A, Antonelli G. Evaluation of interleukin 28B single nucleotide
polymorphisms in infants suffering from bronchiolitis. Virus Res. 2012. IF 2.905
4.Scagnolari C, Midulla F, Selvaggi C, Monteleone K, Bonci E, Papoff P, Cangiano G, Marco
PD, Moretti C, Pierangeli A, Antonelli G. Evaluation of viral load in infants hospitalized with
bronchiolitis caused by respiratory syncytial virus. Med Microbiol Immunol. 2012. IF 3.326
5.Scagnolari C, Trombetti S, Soldà A, Milella M, Gaeta GB, Angarano G, Scotto G, Caporaso
N, Morisco F, Cozzolongo R, Giannelli G, Fasano M, Santantonio T, Antonelli G.
Development and specificities of anti-interferon neutralizing antibodies in patients with
chronic hepatitis C treated with pegylated interferon-α. Clin Microbiol Infect. 2011. IF
4.784
6.Scagnolari C, Trombetti S, Soldà A, Selvaggi C, Monteleone K, Spano L, Pierangeli A,
Clementi M, Turriziani O, Antonelli G. Pandemic 2009 H1N1 influenza virus is resistant to
the antiviral activity of several interferon alpha subtypes. J Interferon Cytokine Res. 2011.
IF 2.576
7. Scagnolari C, Midulla F, Pierangeli A, Moretti C, Bonci E, Berardi R, De Angelis D,
Selvaggi C, Di Marco P, Girardi E, Antonelli G. Gene expression of nucleic acid-sensing
pattern recognition receptors in children hospitalized for respiratory syncytial virusassociated acute bronchiolitis. Clin Vaccine Immunol 2009. IF 2.471
8.Scagnolari C, Selvaggi C, Chiavuzzo L, Carbone T, Zaffiri L, d'Ettorre G, Girardi E, Turriziani
O, Vullo V, Antonelli G. Expression levels of TLRs involved in viral recognition in PBMCSs
from HIV-1-infected patients failing antiretroviral therapy. Intervirology. 2009. IF 1.756
9.Pierangeli A, Scagnolari C, Degener AM, Bucci M, Ciardi A, Riva E, Indinnimeo M, Mancini
G, D'Ettorre G, Vullo V, Antonelli G. Type-specific human papillomavirus-DNA load in anal
infection in HIV-positive men. AIDS. 2008. IF 6.348
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