Adenovirus

The capsid of Adenoviruses has a diameter of 70–90 nm and contains a double-stranded DNA, which is released into the host cell cytosol after the infection. Adenoviruses are the major cause of the common cold in humans [35]. In human cells, cGAS is sensing DNA released from Adenoviruses, which activates anti-viral type-I IFN synthesis and the activation of transcription factors signal transducer and activator of transcription 1 (STAT1) and STAT2 [36]. In murine macrophages and endothelial cells, knockdown of cGAS, STING, or TBK1 significantly reduced the IFN response to Adenovirus infection [36]. In mice, the loss of cGAS or STING genes significantly lowered the secretion of IFN-β and pro-inflammatory cytokines, indicating an impaired early anti-viral innate immune response. However, silencing cGAS-STING signaling had no effect on the long-term clearance of the virus [37]. In another study, it was indicated that Adenovirus specific protein E1A acts as an inhibitor of the cGAS-STING pathway, and would thereby reduce the host IFN response [38]. In young chickens, the inhibition of cGAS-STING signaling resulted in more potent infections with Fowl Adenovirus serotype IV [39]. In a variety of human cells including embryonic kidney cells, fibroblasts, and HeLa cells, Adenovirus induced cGAS-STING signaling was counteracted by the activation of oligoadenylate synthase-like (OASL) [40]. In COPD patients, infection with Adenovirus leads to exacerbation, which might be explained by the inhibition of STING and IFN-β signaling by cigarette smoke [41].

However, there are other DNA sensing proteins such as DNA-dependent protein kinase (DNA-PK), which initiate human host defense upon Adenovirus infection [42]. DNA-PK is activated by the viral E1A protein and leads to the phosphorylation of heat shock cognate 71kDa protein (Hsc70/HSPA8), which is a member of the heat shock protein (HSP) 70 family, and is known to control apoptosis and autophagy [43]. Adenovirus infection also suppresses the innate immune response and IFN synthesis by activating the ubiquitination of STING through the expression of MYSM1 (Myb-like SWIRM and MPN domains 1) [44]. There is also evidence that the immune response of a human to Adenoviruses requires the interaction of several anti-viral sensing mechanisms. In humans who have antibodies to recognize adenoviruses, the first response is the capture of the virus by the antibodies, which activates nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing-3 (NLRP3) and subsequently interleukin-1β (IL-1β). Antibody-captured Adenoviruses might still be entering the host cells and are then recognized by tripartite motif-containing protein 21 (TRIM21) and cGAS, leading to IFN synthesis [45], as summarized in Figure 2.

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Figure 2. 

Inhibitory (red line) and stimulating (green arrow) effects of Adenovirus infection on cGAS-STING signaling. It has been reported that cigarette smoke can inhibit STING activation in COPD, thereby reducing IFN synthesis and leading to exacerbation

Bocavirus

Bocaviruses have only recently been described as pathogenic for humans and were linked to upper respiratory tract infections and the common cold [46]. Bocavirus has been suggested to cause severe asthma exacerbation in children [47]. An increasing number of reports implies that bocaviruses are found worldwide, and can infect both children and adults [48, 49]. Unfortunately, Bocaviruses can re-infect adults and may cause neurological damage or death [50]. In addition, it has been shown that Bocavirus infection can become persistent at least in tonsillitis [51]. From China, there are reports that Bocavirus infection can be transmitted through rats [52]. Like SARS-CoV-2, high dose glucocorticoids have been successfully used to prevent the death of Bocavirus lung infections [53]. Bronchial epithelial cells are the first target cell type for Bocaviruses and allow the virus to replicate and spread [54, 55].

So far, there is no direct evidence that bocaviruses affect the cGAS-STING signaling, but indirectly data suggest its suppression. The viral load of Bocavirus correlated with the expression of STING but was not correlated with COPD or smoking [56]. In human cells, Bocavirus non-structural protein 1 (NP1) inhibited IFN-β synthesis by suppressing IRF3, which is also a part of the cGAS-STING signaling [57]. This may occur through inhibition of TNF-α and NFκB, which are both needed for IFN synthesis through cGAS-STING signaling [58], as shown in Figure 3.

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Figure 3. 

Bocavirus has been reported to inhibit IRF3 activity and reduce IFN gene expression in different studies, but there is no evidence of the direct link between these two events

Coronaviruses

Human Coronaviruses are single-stranded RNA viruses with a diameter of 60–220 nm and an RNA genome consisting of 15–20,000 nucleotides. All human Coronaviruses infect preferentially host cells carrying a protein that interacts with the Coronavirus spike protein [59], such as angiotensin converting enzyme 2 (ACE2) for SARS-CoV-2.

Despite the current SARS-CoV-2 pandemic, human Coronaviruses occurred seasonally causing a variety of lung diseases ranging from the common cold to pneumonia [60, 61]. The latter study suggested that the production of antibodies to human Coronaviruses declines with age [61]. Such an age-dependent decline of anti-coronavirus antibodies might in part explain the observed increased severity of SARS-CoV-2 infections in the elderly and be a feature of all Coronaviruses [62].

The effect of coronaviruses on host defense is incompletely understood. Transcriptome analysis of patients who died of acute respiratory distress syndrome during the first SARS-CoV outbreak, indicated that IFNs and IRF3 were upregulated, thus, suggesting the activation of cGAS-STING signaling [63]. In human kidney (HEK-293T) and epithelial (HeLa) cells, transfection with SARS-CoV-2 open reading frame 9b (ORF9b) suppressed type-I and -III IFN synthesis by interfering with IRF3, TBK1, RIG-1 and STING [64]. The interference with RIG-1 might suggest that SARS-CoV-2 modifies STING signaling by activating damage-associated molecular pattern (DAMP) regulated mechanisms. Similarly, SARS-CoV-2 ORF3a interfered with cGAS-STING signaling by disrupting the complex formed by STING and IKK, thereby inhibiting the activation of NFκB [65].

However, recent studies showed that STING activation blocked the infection of various human cell lines with coronaviruses including SARS-CoV-2 [66, 67]. Furthermore, SARS-CoV-2 infection has also been reported to activate cGAS-STING signaling by different mechanisms. Micronuclei formation induced by SARS-CoV-2 spike protein binding to ACE2 activated cGAS-STING signaling [68]. In human epithelial cells, knockout of different cGAS-STING components implied that the interaction of the SARS-CoV-2 spike protein with ACE2 host cells is sufficient to initiate the formation of cytoplasmic chromatin by cell fusion, thereby inducing the host defense [24]. This observation is in line with the induction of pro-inflammatory cytokines through cGAS-STING and NFκB activation in SARS-CoV-2 infected immortalized human epithelial cells [69]. SARS-CoV-2 infection stimulates immune defense by type-I IFN in lung-on-chip models and skin samples of coronavirus disease 2019 (COVID-19) patients [70]. It should be mentioned that extended type-I IFN in response to SARS-CoV-2 infection might explain the tissue damage reported in the lungs of COVID-19 patients [70]. Furthermore, SARS-CoV-2 binding to ACE2 over-activated STING signaling and resulted in symptoms characteristic of Kawasaki syndrome [71].

Interestingly, T- and B-cells respond to SARS-CoV-2 infection by the activation of the cGAS-STING signaling, but these cells do not carry ACE2, and would not be infected by the virus [72]. The authors suggested that the activation of lymphocytes might occur through the import of cGAMP released by other SARS-CoV-2 infected cells. Such a mechanism has been reported for macrophages activated by secreted cGAMP from tumor cells [34]. In this context, it is interesting to note that the addition of cGAMP to virus-like particles improved the anti-viral response to SARS-CoV-2 spike protein-triggered immune response, and was suggested as an additive to vaccination [73]. The interactions of coronavirus proteins on cGAS-STING signaling are summarized in Figure 4.

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Figure 4. 

Coronaviruses can activate (green arrow) and inhibit (red line) cGAS-STING signaling. All inhibitory actions have been shown to involve direct interaction of ORF9 proteins with specific signaling proteins of the STING protein complex. mtDNA: mitochondrial DNA

Influenza and Parainfluenza viruses

Influenza viruses type-A and type-B are the most frequent cause of the common cold and belong to the RNA viruses. Their interaction with the cGAS-STING signaling has not been well investigated. In 2016, it was reported that the Influenza A virus targets cGAS-independent, but STING-controlled immune response, leading to type-I IFN synthesis [74]. STING was activated by two components of the Influenza A virus, namely the hemagglutinin-fusion-peptide and the enveloped virus. In a mouse model, infection by Influenza Virus M2 activated the cGAS-STING signaling indirectly by causing mtDNA release into the cytosol of the host cells. Therefore, one can argue that Influenzavirus may activate cGAS-STING signaling through DAMP receptors including TLR-2 to TLR-9 and RIG-1.

Moreover, the STING-dependent anti-viral effect was mediated to neighboring non-infected cells through gap junctions, suggesting a role of cGAMP [75]. In another mouse model, it was reported that fever/hyperthermia promoted influenza virus-induced cGAS signaling, leading to IFN-β dependent virus defense [76]. Viral defense to RNA viruses, such as Influenza viruses, seems to be independent of cGAS but involves the activation of STING. Such a mechanism has been shown for Influenza A virus activating STING by directly binding to one of its complex members synaptotagmin binding cytoplasmic RNA interacting protein (SYNCRIP) [77]. In human bronchial epithelial cells, the replication of Influenza A virus varied with the cell line used. Higher resistance to viral infection correlated with the expression of IRF-7, STING, and IFNs, which was controlled through Janus-activated kinase [78].

STING activation through synthetic agonists reduced the replication of human Parainfluenza Virus 3, but there is no direct evidence for activation of the cGAS-STING by this virus type [79]. The known effects of Influenza and Para Influenza viruses on cGAS-STING activation are shown in Figure 5.

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Figure 5. 

Influenza viruses activate cGAS-STING signaling through two different independent mechanisms. Parainfluenza virus replication can be directly inhibited by STING

Rhinovirus

The replication of human Rhinovirus 16 was inhibited by activating STING through a synthetic agonist [79]. Rhinovirus A and Rhinovirus C have been reported to activate STING signaling, which however, seems to be independent from cGAS, followed by the synthesis of IFN-β [80]. This observation confirms the earlier hypothesis that the activation of cGAS-STING signaling and type-I IFN suppresses Rhinovirus A replication [81]. The same mechanism seems to apply to the inhibition of human Rhinovirus C in the human airway epithelium [82].

Indirect evidence in asthma and COPD patients implies the impaired function of cGAS-STING signaling and therefore reduced anti-viral defense in both diseases [83–85]. In asthma, the modification of IRF3 and NFκB controlled the immune defense against rhinovirus infection [86]. As described above, IRF3 and NFκB are essential to initiate the expression of IFN genes, and therefore the viral defense (Figure 6).

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Figure 6. 

Rhinovirus may activate STING directly, but the underlying mechanism has not been proven. Furthermore, STING and IRF3 action has been reported to be impaired in COPD and asthma, thus leading to exacerbation

RSV

RSV is the most common cause of respiratory tract infection in, but not limited to, young age children. RSV is an RNA virus and consists of a double-layered capsid with intrusive glycol-proteins and one adhesion regulating G-protein. The major host cell type in humans is ciliated epithelial cells [87]. In COPD patients, it was shown that bronchial epithelial cells secret IFN-β when infected with RSV [88]. In a mouse model of RSV infection, it was reported that cAMP plays a role in the activation of host immune defense through the transfer protein Epac2 (exchange protein directly activated by cAMP 2) [89]. However, there was no report describing the activation of host defense by RSV through cGAS-STING signaling.

Other lung relevant viruses

Despite the most frequent viruses causing respiratory tract infections, Cytomegalovirus and Herpesvirus have been reported to affect cGAS-STING signaling. Several independent studies reported in 2016 that Herpesvirus and Cytomegalovirus can activate the cGAS-STING signaling and thereby host defense [90–92]. However, both viruses can escape the host defense by reducing the acetylation of lysine 198 in the cGAS protein, thereby downregulating the activation of IFNs in various human lung cell lines [93]. Several proteins of Cytomegaloviruses can inhibit cGAS-STING signaling, by direct interference with specific human proteins. Two Cytomegalovirus proteins namely UL31 and pUL83 directly bind to cGAS and block its action [94, 95]. The Cytomegalovirus protein UL94 inhibits cGAS and mediator of IRF3 activation (MITA) [96]. In addition, three Cytomegalovirus proteins, namely UL82, US9, and IE86 directly inhibit STING [97–99]. A detailed overview of how Herpesviruses escape DNA sensing and even use cGAS-STING signaling for their replication has been provided by Stempel et al. [100].

Measles Virus might also affect lung function [2], and triggers host immune defense through indirect activation of cGAS-STING signaling, which depends on mitochondria degradation and release of mtDNA into the cytosol [101].