Naslov
Cytomegalovirus pathogenesis - immunosurveillane and immunoevasion mechanisms involved

Autori
Jonjić, Stipan ; Krmpotić Astrid

Vrsta, podvrsta i kategorija rada
Radovi u zbornicima skupova, cjeloviti rad (in extenso), znanstveni

Izvornik
Bioinformatika i biološka fizika / Vladimir Paar - Zagreb : Hrvatska akademija znanosti i umjetnosti (HAZU), 2013, 47-62

ISBN
978-953-154-199-2

Skup
Bioinformatika i biološka fizika

Mjesto i datum
Zagreb, Hrvatska, 21.11.2012

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Domaća recenzija

Ključne riječi
cytomegalovirus; immune response; immunoevasion genes; NK cells; T cells

Sažetak
Human cytomegalovirus (HCMV), a beta-herpesvirus, is ubiquitous in human populations and establishes lifelong infection. In persons with normal immune response, HCMV does not typically cause serious disease. However, in immunosuppressed patients (e.g. AIDS and transplant patients) and immunologically immature newborns, HCMV can cause grave disease and even death. Mouse cytomegalovirus (MCMV) is biologically similar and genetically related to HCMV and is therefore considered to be an excellent model for studying cytomegalovirus (CMV) pathogenesis and immunobiology in humans. To date, studies of MCMV have dramatically advanced our understanding of these viruses. Many new viral genes that function in causing disease and evading immune responses have been characterized thanks to the studies of MCMV. Our initial study was focused on the characterization of immune response mechanisms during CMV infection using MCMV as a model. We were first to demonstrate that CD8 T cells play a key role in the protection of the host against lethal viral infections. We also showed that immunosurveillance of MCMV latency is organized in a hierarchical and redundant manner with CD8, CD4, NK cells and IFN as major players. The feature of an early CMV infection is the rapid and effective downregulation of the MHC class I molecules from the surface of infected cells. The virus does it to prevent antigen presentation and CD8 T cell response. We have investigated in vivo significance of MCMV immunoevasins of MHC-I presentation, and provided first evidence that the virus lacking one of these viral immunoevasins, m152, is attenuated in vivo due to the more stringent immune control by CD8 T cells. Infection of mice with MCMV has been particularly informative for the study of the NK cell response to viruses and viral evasion of NK cells. NK cells are considered the most important effectors in early control of CMV infection. Over the course of millions of years of co-evolution, CMVs have developed numerous immunoevasion strategies to compromise NK cell function, and vice versa, their animal hosts were equally resourceful in designing mechanisms to counter viral immunoevasion. We were first to discover that MCMV prevents NK cell activation by downmodulating cellular ligands for the activating NK cell receptor NKG2D. We found that the MCMV glycoprotein encoded by the m152 gene, apart from downregulating MHC-I molecules, downmodulates NKG2D ligands from the cell surface. The m152/gp40 protein targets RAE-1 ligands for downregulation, but our results indicated that RAE-1 isoforms differ in their susceptibility to MCMV regulation. Later on we have characterized two other MCMV proteins, m145 and m155, whose products are involved in downmodulation of expression of NKG2D ligands MULT-1 and H60, respectively. Moreover, we have shown that m138/fcr-1, originally described as a viral protein that binds the Fc portion of immunoglobulin G, also downmodulates MULT-1, H60 as well as RAE-1 isoform. The activation of NK cells depends on the sum of signals from their activating and inhibitory receptors. MHC-I molecules engage inhibitory NK receptors. The ‘missing-self’ hypothesis states that under normal conditions inhibitory NK cell receptors (e.g. Ly49A) are engaged by surface MHC-I molecules and NK cell activation is prevented. Thus, downregulation of the MHC-I molecules by MCMV makes infected cells prone to ‘missing self’-mediated recognition and killing by NK cells. We have recently characterized viral inhibitor of ‘missing-self’-dependent NK cell activation, but also provided the first evidence that this mechanism is important in virus control in vivo. We have shown that MCMV m04 protein binds to MHC-I molecules and escorts them in a complex to the cell surface, to engage inhibitory Ly49 receptor and prevent NK cell activation via ‘missing-self’. Our interest has evolved toward host response to this viral immunoevasion illustrated by several MCMV-specific NK cell activation receptors. The first discovered MCMV-specific Ly49 activating receptor was Ly49H that binds exclusively to MCMV-derived m157 protein expressed on the surface of infected cells. The importance of the Ly49H–m157 axis we demonstrated in vivo by using an MCMV mutant lacking m157, which prevented C57BL/6 mice from mounting a proper NK cell response. More recently we have shown that viral m04 not only prevents NK cell activation by escaping ‘missing-self’ recognition, but several activating Ly49 receptors also depend on its presence for their own recognition of infected cells. HCMV infection is the most common viral congenital infection. Infected infants may develop neurological damage and sequelae, of which brain damage, sensorineural hearing loss and mental retardation are the most frequent. The development of vaccines to prevent congenital HCMV infections and/or limit the morbidity of these infections has been a target of biomedical research for decades. We have established the MCMV model to study CMV infection in the developing CNS and identified key features of CNS infection in newborn animals. We have also continued our study on viral evasion of NKG2D and proposed that the virus engineered to express NKG2D ligand should behave as a good vaccine and/or vaccine vector, since NKG2D also serves as a costimulatory molecule on CD8 T cells. Our theory proved to be correct and we showed that despite dramatic attenuation, such a virus is inducing robust protective immune response. In this overview we present our major achievements in the molecular and immunological characterization and pathogenesis of CMV infection. The materials used in preparation of this overview are taken from our own published papers.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

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