Editorial: Cytomegalovirus Pathogenesis and Host Interactions

Abstract

Editorial on the Research Topic Cytomegalovirus Pathogenesis and Host Interactions Human cytomegalovirus (HCMV) is a very widespread and highly prevalent β-herpesvirus, which sometimes causes mononucleosis following primary infection but is rarely associated with severe disease in immunocompetent individuals (Boeckh and Geballe, 2011; Griffiths et al., 2015). However, like all herpesviruses, HCMV establishes infections that last for the life of the host in part by residing in a dormant state referred to as ‘latency’ (Sinclair and Poole, 2014; Dupont and Reeves, 2016). Reactivation from latency or primary infection can cause debilitating damage in unborn children or life-threatening disease in immunosuppressed patients including recipients of solid organ or hematopoietic cell transplants (Collins-McMillen et al., 2018; Heald-Sargent et al., 2020). Besides human cell culture systems of HCMV productive and latent infection (Peppenelli et al., 2021; Poole et al., 2021), mice infected with murine cytomegalovirus (MCMV) have served as invaluable models to understand host immune responses, viral immune evasion strategies and the mechanisms of pathogenesis (Brizic et al., 2018; Reddehase and Lemmermann, 2018). HCMV replicates productively in a wide variety of terminally differentiated cell types (‘lytic’ infection) while targeting select undifferentiated cells, including myeloid progenitors and monocytes, for latent infection (Sinclair and Poole, 2014; Goodrum, 2016). CMVs are highly sophisticated pathogens encoding hundreds of proteins and non-coding RNAs that engage in a myriad of host interactions (Stern-Ginossar et al., 2012; Weekes et al., 2014). The study of these interactions is constantly revealing new and surprising insights into both the replication and persistence strategies of the virus as well as the biology of the host cell and organism. The recently published Research Topic ‘Cytomegalovirus Pathogenesis and Host Interactions’ combines 28 articles (8 Original Research Articles, 10 Brief Research Reports, 8 Reviews, 1 Mini Review and this Editorial), involving 138 authors, 45 reviewers and 5 editors working in the field. Below, we are providing an overview of the articles published in this Research Topic, dividing them into the four sections ‘innate and adaptive immune control of CMV pathogenesis’ (11 articles), ‘host interactions during CMV latency and reactivation’ (6 articles), ‘host interactions during productive CMV infection’ (6 articles) and ‘targeting CMV pathogenesis by anti-viral therapy’ (4 articles). The lifelong relationship with HCMV is based on our intrinsic, innate and adaptive immune responses as well as manifold viral countermeasures which collectively enable a dynamic balance between host and pathogen that largely precludes disease without eliminating the virus from our bodies (Berry et al., 2020; Schilling et al., 2021). Major disease or even death caused by HCMV is often linked to inflammation, including pro-inflammatory cytokine production and is usually limited to situations where the immune system is significantly suppressed or still immature (Boeckh and Geballe, 2011; Griffiths et al., 2015). Viral infections often induce autophagy, which has been considered an intrinsic cellular defense mechanism, and herpesviruses have developed strategies to evade and manipulate this host response (Lussignol and Esclatine, 2017; Tognarelli et al., 2021). López Giuliani et al. report that HCMV inhibits autophagy in renal tubular epithelial cells and promotes cellular enlargement. Their findings have potential implications for HCMV-related kidney disease. As in other infectious pathogens, the innate immune responses to CMV are thought to be triggered by pathogen-associated molecular patterns that engage pattern recognition receptors including Toll-like receptors (TLRs), resulting in the release of anti-viral and pro-inflammatory cytokines (West et al., 2012; Zheng et al., 2020). Frascaroli et al. analyzed TLR genotypes and responses in immunocompetent patients with primary symptomatic HCMV infection presenting as mononucleosis. Although the study identified no difference in TLR2, 3, 4, 7 and 9 single nucleotide polymorphisms between symptomatic and asymptomatic individuals, TLR2 and TLR7/8 responses were altered in patients with CMV mononucleosis compared to healthy control subjects. The former exhibited higher levels of the pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α), but not interleukin 10 (IL-10). Interestingly, HCMV encodes its own homologs of cellular IL-10, which is a largely anti-inflammatory and immunosuppressive cytokine (Avdic et al., 2014; Poole and Sinclair, 2015). Poole et al. review the expression, structure and function of the different viral IL-10 isoforms identified to date as well as the effects HCMV confers on the expression of cellular IL-10. Furthermore, Lau et al. identified a novel viral suppressor of pro-inflammatory cytokine production during HCMV infection. They demonstrate that the HCMV long non-coding RNA1.2 antagonizes the expression and release of IL-6 through a mechanism involving the tumor protein p63-regulated gene 1-like protein (TPRG1L) and nuclear factor kappa B (NFκB) but not TNF-α. Mast cells are part of the innate immune system, acting as first-line sentinels for environmental antigens, but also provide a link to the adaptive immune system by secreting chemokines that recruit CD8+ T-cells to sites of infection (Podlech et al., 2015; Dahlin et al., 2021). Schmiedeke et al. reveal an unanticipated function of the viral mitochondria-localized inhibitor of apoptosis (vMIA) m38.5, encoded by MCMV, in inducing mast cell degranulation. It has long been known that CD8+ T-cells play a critical role in controlling CMV infection and disease...