Based on a survey of CMV seropositivity, approximately 83% of the world’s population is infected with the virus. In comparison, in developing countries, it is almost 100% [1]. It will become a lifelong chronic infection in the infected host. Most patients have no symptoms or only show mild disease status, but under immunosuppressive conditions, such as AIDS patients and transplant recipients, the virus can be reactivated, resulting in mental retardation, seizures, and encephalitis [2, 3]. In addition to affecting nervous system diseases, it also affects the occurrence and progression of atherosclerosis, tumors, and other diseases, even endangering life [4,5,6]. As a result, it remains a serious public health issue.

CMV belongs to the β Herpesvirus subfamily and is a double-stranded DNA virus [7]. CMV can replicate in various cells, including epithelial cells, fibroblasts, smooth muscle cells, endothelial cells, macrophages, dendritic cells, and hepatocytes, facilitating systemic transmission, efficient proliferation, and host-to-host transmission of the virus [8, 9]. CMV relies on direct fusion or endocytic pathways to enter human cells [10]. When the viruses invade the host, the viral envelope glycoprotein trimeric complex (gH/gL/gO) binds to platelet-derived growth factor receptor α (PDGFRα), which in turn infects fibroblasts, whereas the pentameric complex (PC) (gH/gL/pUL128-pUL130-pUL131A) is required for the infection of endothelial, epithelial, and medullary-like cells [11]; in parallel, neurofibrillary protein 2, the olfactory receptor family member OR14I1, is thought to be the PC receptor that mediates viral entry into endothelial/epithelial cells [12]. After the viral envelope fuses with the cell membrane, the nucleocapsids are released into the cytoplasm and then transported through the microtubule system to the nucleus, where they release viral DNA [13]. The HCMV genome is expressed in a temporally sequential manner and is categorized into immediate early (IE) genes, early (E) genes, and late (L) genes. IE1 and IE2 are the earliest encoded and most abundantly expressed IE genes that can affect viral promoter activity and initiate transcription from viral E genes [14]. Typical early viral proteins include DNA polymerase (pUL54), phosphotransferase (pUL97), and terminal enzymes (pUL51, pUL52, pUL56, pUL77, pUL89, pUL93, and pUL104), which facilitate viral DNA replication and packaging processes [15]. L genes primarily encode structural proteins required for virion assembly and expulsion that make up the capsid, envelope, or tegument, such as pUL77, pUL93, pUL115, pp28, and pp150 [16]. After DNA replication is complete, it is encapsulated into a capsid, and the nucleocapsid first forms a primary envelope at the inner nuclear membrane, then crosses the nuclear membrane, subsequently unwraps at the outer nuclear membrane, and finally reaches the cytoplasm and coils in the middle compartment of the endoplasmic reticulum (ER)-Golgi apparatus, after which the viral particles are released by budding [17, 18] (Fig. 1).Viral particles can infect various tissues and organs, and in certain cell types, such as hematopoietic stem cells and undifferentiated myeloid cells, the virus can remain silent and latent [19].

CMV life cycle. (1) CMV glycoproteins interact with specific cellular receptors, leading to (2) endocytosis and plasma membrane fusion. (3) The nucleocapsid enters the nucleus through microtubules, and linear DNA is released into the nucleus. (4) (5) Transcription and translation of viral IE genes. (6) (7) Transcription and translation of viral E genes. (8) The viral genome replicates within the nucleus. (9) (10) L proteins, mainly capsid proteins, are expressed and assembled into a new nucleocapsid (11). (12) Membrane proteins and glycoproteins are assembled in the endoplasmic reticulum and Golgi apparatus to form mature viral particles. (14) (15) The virus is released into the extracellular space by budding

The innate immune system is the first line of defence against pathogens invading the body. When viruses enter a host cell, host-pattern recognition receptors (PRRs) detect pathogen-associated molecular patterns (PAMPs), which activate intracellular signal transduction and gene expression programs, leading to the production of a series of mediators, such as inflammatory factors, cytokines, and chemokines, ultimately promoting the body’s natural immune response [20, 21]. However, in the long-term coevolution process, viruses, such as herpes simplex virus-1 (HSV-1), have developed various mechanisms to evade host antiviral innate immunity, including the Toll-like receptor (TLR) signaling pathway, the retinoic acid-induced gene I-like receptor (RLR) signaling pathway, the DNA sensing signaling pathway and intrinsic cellular defences [22,23,24,25,26,27]. To date, CMV has coevolved with mammalian hosts for millions of years; the battle between them has never stopped, and multiple strategies have been developed to evade innate immunity [28].

Among PRRs, the most fully characterized are TLRs [29]. During CMV infection, viral proteins and nucleic acids, including single- or double-stranded RNA (ssRNA or dsRNA), CpG-rich genomes, and envelope glycoproteins, are the true PAMPs recognized by TLRs [30, 31]. The second subfamily comprises RLRs, including retinoic acid-inducible gene 1 (RIG-1), melanoma differentiation-associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2), which can sense the viral replication intermediate dsRNA and trigger the signal cascade reaction of interferon transcription [32, 33]. The third subfamily is the nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family, which includes NOD1, absent in melanoma 2 (AIM2), NLRP1 and NLRP3 [34]. Finally, some DNA sensors, such as stimulators of interferon genes (STING), also recognize CMV and induce an antiviral innate immune response, helping to control early CMV infection and triggering the IFN-I response, thus exerting antiviral effects [35, 36]. Accordingly, it is speculated that CMV has the opportunity to promote autoimmune evasion by blocking the above PRR-related transduction pathways.

When viruses infect the body, host cells are in a state of stress, which triggers a series of stress reactions (autophagy, apoptosis, necrosis, and ER stress), and these stress responses also act as an important part of the innate immune response process [37,38,39]. Therefore, it is not surprising that the cunning virus may also create intracellular environments conducive to its replication and transmission by interfering with these stress pathways [40,41,42].

This review summarizes and updates strategies employed by CMV to evade host innate immune surveillance, including typical PRR-mediated induction of IFN-I and its downstream interferon-stimulated genes (ISGs), as well as intrinsic cellular defences, such as apoptosis, autophagy and ER stress-mediated antiviral innate immunity. A comprehensive evaluation of the battle between host innate antiviral immunity and viral immune evasion is beneficial for familiarizing ourselves with the pathogenesis of the virus and for identifying new drug targets and potential immunotherapies to combat CMV infection-associated diseases.

The innate immune system utilizes PRRs to detect the invasion of pathogenic microorganisms, thereby achieving precise recognition and immune response to harmful stimuli [43]. Once PAMPs bind to the corresponding ligands, they activate multiple adapter molecules, ultimately triggering the activation of interferon regulatory factor (IRF) and NF-κB, leading to the expression of proinflammatory cells and chemokines. Meanwhile, IFN-I also induces hundreds of ISGs, thereby endowing the host with strong innate antiviral ability [44, 45]. Nonetheless, viruses evolve various strategies to evade host antiviral innate immunity [46,47,48]. Here, we will summarize how CMV evades PRRs, such as TLRs, RLRs, NLRs, DNA sensors, and their downstream signaling pathways.

In humans, the TLR family consists of ten members [49]: TLR1, TLR2, TLR4, TLR5, and TLR6 are located on the cell surface, while TLR3, TLR7, TLR8, and TLR9 are located inside the cell [50] and contain a ligand recognition domain rich in leucine repeat sequences, a transmembrane domain, and a Toll/interleukin-1 receptor (TIR) homologous domain [51]. TLRs activate a series of innate immune signaling pathways by recognizing PAMPs, leading to the production of interferons, proinflammatory cytokines, and chemokines, such as IL-1, IL-6, and TNFα, ultimately leading to early identification and defence against foreign pathogens [52,53,54].

The activation status of TLRs in the host plays a crucial role in initial virus replication and persistence [55], and TLRs are involved in almost the entire process of the virus life cycle and are able to recognize virus envelope glycoproteins to promote virus entry into host cells and recognize nucleic acid to induce the production of inflammatory factors [20, 56]. Studies have shown that TLR2 and TLR4 can recognize and participate in the detection of CMV envelope proteins such as glycoproteins gB and gH [57, 58]. Moreover, other studies have suggested that the envelope glycoproteins gB and gH interact with TLR2 and TLR1 and that TLR2/1 heterodimers are functional sensors of HCMV [59, 60]. It is believed that PRRs may initiate the innate immune response before CMV enters cells. In pregnant women with early-onset preeclampsia, the percentage of CMV IgG-positive serum significantly increases, while the expression level of TLR2/4 mRNA is upregulated [61]. During the differentiation of monocytes into macrophages, infection with HCMV promotes the expression of TLR4 and TLR5 to enhance macrophage inflammation significantly [62]. In addition, TLR3 and 9 located within cells can induce the production of IFN-I and proinflammatory cytokines by recognizing dsRNA and CpG-rich genomes [63].

Single nucleotide polymorphisms (SNPs) of TLRs can also affect the immunogenicity and disease status of CMV infection. A study suggested that TLR9 SNPs are associated with CMV reactivation and disease and that genetic polymorphisms may downregulate TLR9 signaling and lead to reduced antiviral response efficiency [64]. TLR2 and TLR7 genetic polymorphisms are also associated with CMV status in late pregnancy in women and regulate the immune response to CMV [65]. However, some studies have found no statistically significant association between SNPs in the TLR gene and congenital CMV infection or disease status [66]. Therefore, more studies are needed to determine the relationship between TLR SNPs and CMV infection.

To date, various viruses, such as HSV and hepatitis B virus, have evolved specific proteins targeting TLRs that interfere with the innate immune response [56, 67]. To respond to immune system attacks, CMV has also developed various evasion mechanisms (Fig. 2). US7 utilizes the ER-related degradation components Derlin-1 and Sect. 61 to promote the ubiquitination of TLR3 and TLR4. US8 not only disrupts the binding of TLR3-UNC93B1 but also targets TLR4 to lysosomes, leading to its rapid degradation. Therefore, US7 and US8 are considered key inhibitors of TLR3 and TLR4 in human foreskin fibroblasts (HFFs) [68]. HCMV encodes miR-UL112-3p, which effectively inhibits endogenous TLR2 protein levels during CMV infection of normal human dermal fibroblasts (NHDFs), thereby significantly downregulating the TLR/IRAK1/NF-κB signaling pathway [69]. Currently, few studies investigated the correlation between CMV and TLRs in terms of immune evasion, and there is still a significant gap in knowledge of the mechanism by which viral protein targeting blocks the antiviral signaling pathway of TLRs. More studies on the immune evasion mechanism by which CMV targets TLRs in the future may provide new insights for disease prevention and control.

The immune evasion of the TLR signaling pathway by CMV. virus-encoded products antagonizes the TLR signaling pathway to promote immune evasion. US7 promotes the ubiquitination of TLR3 and TLR4, and US8 promotes their degradation. miR-UL112-3p decreases endogenous TLR2 protein levels. CMV proteins can also interfere with multiple other steps in the TLR pathway, such as TBKI, IRF3, IKK, p65, and p50, to promote immune evasion

The three members of the RLR family are highly homologous, with the same DExD/H-box RNA helicase domain at the center and the same zinc-binding domain at the C-terminus [70]. However, LGP2 lacks a signal domain (CRAD) and needs to interact with MDA5 to play a role in viral sensing [71]. After RLRs recognize and bind to the corresponding PAMPs, their conformation changes and a pair of CRADs are released, recruiting and activating downstream mitochondrial antiviral signaling proteins (MAVSs) containing CRADs. Subsequently, the downstream protein TANK binding kinase 1/IkappaB kinase (TBK1/IKK) is recruited to activate the transcription factors IRF3/7 and nuclear factor κB (NF-κB), which produce IFN and proinflammatory cytokines [72, 73].

Undoubtedly, RLRs have become key cytoplasmic receptors for detecting RNA viruses [74]. However, it has been shown that both viral and host RNA can also act as RLR ligands during DNA virus infection [75]. In 2017, for the first time, the immunoreactivity of RIG-I, MDA5, and LGP2 in placental, chorionic, and amniotic tissues was reported and might be related to CMV sensing in pregnancy-related tissues [76]. When the placenta was infected with CMV, the secretion of IFN-β increased, further enhancing the expression of RIG-I and MDA5 at the mRNA level, and it also upregulated the expression of DDX58 and IFIH1. This study suggested that RLRs may be involved in CMV sensing, but more studies are needed [77].

The NLR family consists of more than 20 members, among which NLRP3 is one of the most studied DNA sensors related to inflammasomes. Activation of the NLRP3 inflammasome by PAMPs and damage-associated molecular patterns (DAMPs) leads to the secretion of the proinflammatory cytokines IL-1β and IL-18, which play crucial roles in the antiviral innate immune response [78]. Available evidence suggests that the viral glycoprotein components of CMV, as well as increased levels of mtDNA released into the cytoplasm during CMV infection, can activate the NLRP3 inflammasome [34, 79]. NLRC5 is also upregulated in human fibroblasts after CMV infection and activates IFN-γ-mediated antiviral signaling pathways [80]. In addition, activating NOD1 also induces an IFN response and is suppressed by HCMV [81]. Due to their role in the antiviral response, these inflammasomes seem to play a protective role, but the inflammatory response is also involved in the occurrence and development of many diseases. Inhibiting the inflammatory response is a key mechanism for treating certain diseases, so it may also cause serious pathological damage to the body. For example, MCMV infection can cause neuronal death and hearing loss by activating the NLRP3 inflammasome [82]. Downregulation of NLRP3 is beneficial for hypertensive vascular and myocardial remodeling [83]. Therefore, during infection, the roles of these inflammasomes are diverse and worthy of further investigation.

AIM2 can also detect the genetic material of CMV entering the cytoplasm to promote the activation of inflammatory factors [84]. Compared to those in wild-type cells, the ability of AIM2-deficient macrophages to induce IL-1β expression and cell death is reduced, and the transcription of the viral DNA polymerase gene UL54 and the capsid protein-encoding gene UL83 is greater, which indicates that AIM2-deficient cells cannot effectively control HCMV infection [85]. In a CMV-induced sensorineural hearing loss (SNHL) mouse model, a significant increase in AIM2 levels was detected, and the expression of IL-1, IL-18, IL-6, and TNF-α increased to resist CMV infection [86]. Interestingly, the expression of AIM2 is time-dependent, with an increase in AIM2 levels in the early stages of HCMV infection and a decrease in AIM2 levels 24 h after infection. This decrease may be related to the viral immune evasion mechanism [87]. pUL83 interacts with AIM2 in the cytoplasm during the early stages of HCMV infection, thereby interfering with the activation of AIM2 [87]. Subsequently, the immediate early 86 kD