Cytomegaloviruses persist permanently in the body and are a constant stimulant of the immune system. Does this make 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 Čičin-Šain 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 (Čičin-Šain 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, RESIST-Kohorte

CV & Contact

Project B6 Publications

Publikations of the Year 2021

Cytomegalovirus subverts macrophage identity. Baasch S, Giansanti P, Kolter J, Riedl A, Forde AJ, Runge S, Zenke S, Elling R, Halenius A, Brabletz S, Hengel H, Kuster B, Brabletz T, Cicin-Sain L, Arens R, Vlachos A, Rohr JC, Stemmler MP, Kopf M, Ruzsics Z, Henneke P. Cell. 2021 Jun 5:S0092-8674(21)00626-7. doi: 10.1016/j.cell.2021.05.009. Online ahead of print. PMID: 34115982

A Novel Triple-Fluorescent HCMV Strain Reveals Gene Expression Dynamics and Anti-Herpesviral Drug Mechanisms. Rand U, Kubsch T, Kasmapour B, Čičin-Šain L. Front Cell Infect Microbiol. 2021 Jan 8;10:536150. doi: 10.3389/fcimb.2020.536150. eCollection 2020. PMID: 33489928 Free PMC article

Publikations of the Year 2020

The avid competitors of memory inflation. Abassi L, Čičin-Šain L.  Curr Opin Virol. 2020 Oct;44:162-168. doi: 10.1016/j.coviro.2020.08.007. Epub 2020 Oct 8. PMID: 33039898.

Seropositivity for pathogens associated with chronic infections is a risk factor for all-cause mortality in the elderly: findings from the Memory and Morbidity in Augsburg Elderly (MEMO) Study. Zeeb M, Kerrinnes T, Čičin-Šain L, Guzman CA, Puppe W, Schulz TF, Peters A, Berger K, Castell S, Karch A. Geroscience. 2020 Oct;42(5):1365-1376. doi: 10.1007/s11357-020-00216-x. Epub 2020 Jul 9. PMID: 32648237; PMCID: PMC7525922.

Cytomegalovirus inhibition of extrinsic apoptosis determines fitness and resistance to cytotoxic CD8 T cells. Chaudhry MZ, Casalegno-Garduno R, Sitnik KM, Kasmapour B, Pulm AK, Brizic I, Eiz-Vesper B, Moosmann A, Jonjic S, Mocarski ES, Čičin-Šain L. Proc Natl Acad Sci U S A. 2020 Jun 9;117(23):12961-12968. doi: 10.1073/pnas.1914667117. Epub 2020 May 22. Erratum in: Proc Natl Acad Sci U S A. 2020 Aug 3;: PMID: 32444487; PMCID: PMC7293702.

Reverse TCR repertoire evolution toward dominant low-affinity clones during chronic CMV infection. Schober K, Voit F, Grassmann S, Müller TR, Eggert J, Jarosch S, Weißbrich B, Hoffmann P, Borkner L, Nio E, Fanchi L, Clouser CR, Radhakrishnan A, Mihatsch L, Lückemeier P, Leube J, Dössinger G, Klein L, Neuenhahn M, Oduro JD, Čičin-Šain L, Buchholz VR, Busch DH. Nat Immunol. 2020 Apr;21(4):434-441. doi: 10.1038/s41590-020-0628-2. Epub 2020 Mar 16. PMID: 32205883.

Advances in cytomegalovirus (CMV) biology and its relationship to health, diseases, and aging. Nikolich-Žugich J, Čicin-Šain L, Collins-McMillen D, Jackson S, Oxenius A, Sinclair J, Snyder C, Wills M, Lemmermann N. Geroscience. 2020 Apr;42(2):495-504. doi: 10.1007/s11357-020-00170-8. Epub 2020 Mar 11. PMID: 32162210; PMCID: PMC7205956.

Publikations of the Year 2019

Cytomegalovirus memory inflation and immune protection. Čičin-Šain L. Med Microbiol Immunol. 2019 Aug;208(3-4):339-347. doi: 10.1007/s00430-019-00607-8. Epub 2019 Apr 10. PMID: 30972476.
Life-long control of cytomegalovirus (CMV) by T resident memory cells in the adipose tissue results in inflammation and hyperglycemia. Contreras NA, Sitnik KM, Jeftic I, Coplen CP, Čičin-Šain L, Nikolich-Žugich J. PLoS Pathog. 2019 Jun 20;15(6):e1007890. doi: 10.1371/journal.ppat.1007890. PMID: 31220189; PMCID: PMC6605679.
Distinct Surface Expression of Activating Receptor Ly49H Drives Differential Expansion of NK Cell Clones upon Murine Cytomegalovirus Infection. Grassmann S, Pachmayr LO, Leube J, Mihatsch L, Andrae I, Flommersfeld S, Oduro J, Čičin-Šain L, Schiemann M, Flossdorf M, Buchholz VR. Immunity. 2019 Jun 18;50(6):1391-1400.e4. doi: 10.1016/j.immuni.2019.04.015. Epub 2019 May 15.

Project B6
Publications