Analysis of the cellular molecular pathways affected by HCMV IL-10 isoforms A, B and E and their oncogenic properties

• Grant number: 24/06994-2
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2025
• End date: February 29, 2028
• Field of knowledge: Biological Sciences - Microbiology - Biology and Physiology of Microorganisms
• Principal Investigator: Maria Cristina Carlan da Silva
• Grantee: Maria Cristina Carlan da Silva
• Host Institution: Centro de Ciências Naturais e Humanas (CCNH). Universidade Federal do ABC (UFABC). Ministério da Educação (Brasil). Santo André , SP, Brazil
• Associated researchers: Ana Carolina Santos de Souza Galvão ; Dr Michael M Nevels ; Emma Poole

Abstract

Human Cytomegalovirus (HCMV) can cause a variety of health disorders that can lead to death in immunocompromised individuals and neonates. In addition, increasing evidence indicate an association of HCMV with cancer, especially Glioblastoma Multiforme (GBM). HCMV might not only have oncomodulatory properties in GBM favouring tumor progression, a paradigm termed oncomodulation, but can also directly transform primary cells with HCMV strains named high-risk HCMV strains. Several viral proteins have been associated with cellular malignancy, such as IE1, IE2, US28 and UL76 and, in particular, a viral homologue of the cellular IL-10, encoded by the HCMV UL111A. The UL111A gene is expressed in both lytic and latent stages of viral infection and by alternative splicing produces different vIL-10 protein isoforms. The most studied isoforms are cmvIL-10 (also termed the 'A' transcript) and LAcmvIL-10 (also termed the 'B' transcript). Both isoforms can downregulate MHC class II, however they differ in a number of other immunomodulatory properties, such as the ability to bind the IL10 receptor and induce signalling through STAT3. There are also a number of other isoforms which have been identified, which are expressed by differential splicing during lytic infection, termed C, D, E, F and G, although these have been less extensively studied. Importantly, previous work demonstrated that a region, named mtrII (morphologic transforming region II), in the UL111A gene was previously shown to transform fibroblasts in culture. We have studied the expression of these isoforms in infected cells and in samples from immunosuppressed patients. We also observed, for the first time, the expression of these isoforms in GBM tissues. HCMV IL-10, mainly cmvIL-10, has immunosuppressive functions that may act in the tumor environment promoting malignancy. In this project we aim to study the cellular pathways affected and the possible oncogenic mechanisms of the most expressed isoforms (A, B, E and F and D) detected in GBM tumors. Human Cytomegalovirus (HCMV) can cause a variety of health disorders that can lead to death in immunocompromised individuals and neonates. In addition, increasing evidence indicate an association of HCMV with cancer, especially Glioblastoma Multiforme (GBM). HCMV might not only have oncomodulatory properties in GBM favouring tumor progression, a paradigm termed oncomodulation, but can also directly transform primary cells with HCMV strains named high-risk HCMV strains. Several viral proteins have been associated with cellular malignancy, such as IE1, IE2, US28 and UL76 and, in particular, a viral homologue of the cellular IL-10, encoded by the HCMV UL111A. The UL111A gene is expressed in both lytic and latent stages of viral infection and by alternative splicing produces different vIL-10 protein isoforms. The most studied isoforms are cmvIL-10 (also termed the 'A' transcript) and LAcmvIL-10 (also termed the 'B' transcript). Both isoforms can downregulate MHC class II, however they differ in a number of other immunomodulatory properties, such as the ability to bind the IL10 receptor and induce signalling through STAT3. There are also a number of other isoforms which have been identified, which are expressed by differential splicing during lytic infection, termed C, D, E, F and G, although these have been less extensively studied. Importantly, previous work demonstrated that a region, named mtrII (morphologic transforming region II), in the UL111A gene was previously shown to transform fibroblasts in culture. We have studied the expression of these isoforms in infected cells and in samples from immunosuppressed patients. We also observed, for the first time, the expression of these isoforms in GBM tissues. HCMV IL-10, mainly cmvIL-10, has immunosuppressive functions that may act in the tumor environment promoting malignancy. In this project we aim to study the cellular pathways affected and the possible vironcogenic mechanisms. (AU)