Cytomegaloviruses remain permanently in the body and stimulate continuously the immune system. Make this the course of atherosclerosis or diabetes worse?

What is this research project about?

Human cells infected with cytomegalovirus (CMV) are shown here in green.

What is this research project about?

Human Cytomegalovirus (HCMV) is an extremely common β-herpesvirus, persistently infecting the majority of the human population worldwide and inducing an unparalleled cellular immune response in the affected individuals. While HCMV infection reactivation from latency is well-known to cause severe disease that can affect numerous organ systems of immunocompromised patients, less is known about its effects on the general population. A role for cytomegalovirus in the onset of immune aging has been suspected, but has been largely refuted by incoming clinical and experimental evidence to which others and our lab have contributed. Nevertheless, the footprint of HCMV infection on the host immune responses is very large and it remains unclear whether this phenomenon is clinically relevant.

What’s the current status?

Circumstantial evidence argues that the ongoing stimulation of the immune system during CMV latency may prompt or aggravate the course of chronic inflammatory conditions, such as atherosclerosis or diabetes. This idea has been compounded by the distinct tropism of latent CMV infection for endothelial cells or stromal cells, as well as for immune cells of the myeloid lineage. Unfortunately, the evidence has remained correlative and largely based on retrospective studies, which were unable to determine if HCMV infection and immunity is a consequence of underlying conditions (e.g. genetic susceptibility of the host to infections), or the cause of immune responses that aggravate the chronic clinical conditions.

Two cells infected with cytomegalovirus: The cell nuclei are blue and the genetic material of the cytomegalovirus is red.

What are the project goals?

Our project aims to study the effects of HCMV virus load on T-cell responses and link the size of the ongoing HCMV specific T-cell effector response and their functional capacity to repress HCMV reactivation from latency and replication with clinical outcomes in the aging population. We hypothesize that decreased functional capacity of T cells in repressing HCMV replication may results in the increase of the virus burden and adverse inflammatory immune responses in older individuals. The study will define the size, the phenotypes and the functional capacity of the responding CD4 and CD8 T cells in elderly volunteers, and we will quantify the latent genomic burden of the latent virus in cellular compartments that can be studied within reason in human cohorts. In collaboration with the epidemiology department at HZI (G. Krause) and the organizers of the senior cohort (T. Werfel, M. Stengel) we will define the clinical scoring of these patients for diseases with a cardiovascular or metabolic component and identify the association of the clinical scores to viral load and the magnitude of HCMV-induced immune responses.

How do we get there?

The Cicin-Sain lab has been at the front of studies on immune imprinting by CMV infection for the past ten years. We have demonstrated by experimental evidence a causative role of CMV infection in the life-long persistence of strong T-cell based immune responses (Cicin-Sain et al. 2012). We have also identified the role of antigen expression (Dekhtiarenko et al. 2013), processing (Dekhtiarenko et al. 2016), and TCR-mediated recognition on MHC molecules (Borkner et al. 2017) in the inflation of memory responses against CMV antigens in the latently infected host. More recently, we have shown that the obsession of the immune system with HCMV does not affect the ability of the host to respond and control numerous other viral infections (Marandu et al. 2015), but rather that CMV infection induces a persistent inflammation of adipose tissues due to a viral persistence in non-hematopoietic cells in the fat tissue (Contreras et al. 2019). We have now expanded our technical expertise to the study of primary human lymphocytes, and to the identification of HCMV genomes in human cell subsets. The availability of the senior cohort of older adults will allow us to identify the functionality of HCMV specific T cells late in life.

Projectleader

Project title: Cellular immune responses in the senescent and unresponsive immune system

Prof. Dr. Luka Čičin-Šain

Projekte: B6, B9

CV & Contact

Project B6 Publications

Čičin-Šain L* Cytomegalovirus memory inflation and immune protection 2019 Medic. Microbiol. Immunol. Apr 10. doi: 10.1007/s00430-019-00607-8. [Epub ahead of print]

Grassmann S, Pachmayr L, Leube J, Mihatsch L, Andrae I, Flossdorf M, Oduro JD, Čičin-Šain L, Schiemann M, Buchholz VR Single-cell fate mapping reveals clonal dynamics of adaptive NK-cell responses Immunity pii: S1074-7613(19)30195-5. doi: 10.1016/j.immuni.2019.04.015. [Epub ahead of print] PMID:31103380

Contreras, NA; Sitnik, KM; Jeftic, I; Coplen, C; Čičin-Šain, L; Nikolich-Zugich, J. Lifelong control of cytomegalovirus (CMV) by T resident memory cells in the adipose tissue results in inflammation and hyperglycemia. PLOS Pathogens 15(6):e1007890. doi: 10.1371/journal.ppat.1007890

Project B6
Publications