Possible role of CNS microRNAs in Human Mpox virus encephalitis—a mini-review

Human monkeypox (mpox) virus was first detected as a human pathogen in the Democratic Republic of Congo (DRC, formerly Zaire) in 1970 (Mauldin et al. 2022). In May 2022, the World Health Organization (WHO) reported an mpox-infected person who had returned to the UK from Nigeria (Multi-country mpox outbreak in non-endemic countries". 2022). In the recent mpox outbreak, more than 85,000 confirmed cases have been reported from 110 countries as of February 15, 2023. WHO declared the mpox outbreak a public health emergency because of its spread in several countries. It should be noted that the West African subtype of mpox is the predominant viral strain worldwide with an estimated mortality rate of 1%, which is significantly lower than that of the less dominant strain from the Congo Basin (up to 10%) (Tan et al. 2023; Lim et al. 2023). The International Committee on Taxonomy of Viruses (ICTV) has classified mpox virus in the genus Orthopoxvirus, the subfamily Hordopoxvirinae, the family Poxviridae, and the order Chitovirales (Karagoz et al. 2023). Mpox virus is genetically distinct from other members of the Poxviridae, such as variola, vaccinia, ectromelia, camelpox, and cowpox viruses (Giulio and Eckburg 2004). Mpox virus is an enveloped double-stranded DNA virus with a brick-shaped structure and a size of approximately 200–250 nm (Mauldin et al. 2022; Cho and Wenner 1973). Transmission of mpox virus usually occurs through close contact with respiratory droplets, disease lesions, and body fluids from ic (Kaler et al. 2022). The clinical presentation of mpox virus is similar to that of smallpox virus, and the estimated incubation period is up to 21 days (Kaler et al. 2022; Miura et al. 2022). After replication, mpox particles can spread from local lymph nodes to distant lymph nodes and other organs via the bloodstream, and in the prodromal phase, skin, lung, eye, and gastrointestinal tract can cause mucosal lesions and lymphadenopathy (Kaler et al. 2022). Fever, lymphadenopathy, malaise, headache, and muscle pain are the classic symptoms of mpox (Meaney-Delman et al. 2022; Shafaati and Zandi 2023; Shafaati and Zandi 2022a, b).

Two types of vaccines against mpox virus are currently available: JYNNEOSTM (live replication incompetent vaccinia virus) and ACAM2000® (live replication competent vaccinia virus). It should be noted that therapeutic support measures such as Tecovirimat, Brincidofovir, Cidofovir, and Vaccinia immunoglobulin intravenous (VIGIV) have proven their suitability for the treatment of infected individuals (Rizk et al. 2022).

DNA and RNA viruses such as herpes simplex virus, varicella zoster virus, Japanese encephalitis virus (JEV), dengue virus, West Nile virus, and Zika virus can cause encephalitis in humans (Chhatbar and Prinz 2021; Chen and Zhong 2019; Zandi et al. 2022 Nov). Smallpox virus, which belongs to the same family of orthopoxviruses as mpox virus, can cause various forms of neurologic complications, including encephalitis. The estimated incidence of encephalitis in the variola major strain of poxvirus is approximately 1 in 500 infected persons characterised by reduced consciousness and 1 in 2000 infected persons in variola minor (Badenoch et al. 2022). Similar to smallpox virus, neurologic complications such as encephalitis have been observed after mpox infection (Badenoch et al. 2022). A recent meta-analysis and systematic review study showed that the rate of encephalitis in mpox-infected patients was 2.0% (Badenoch et al. 2022). There is documented evidence that microRNA plays an important role in encephalitis caused by viruses such as herpes simplex virus and Japanese encephalitis virus (Slota 2019). Except neurological disorders, psychiatric symptoms such as emotional lability, depression, and acute alcohol withdrawal were among the recently described psychological manifestations. In a study in Nigeria during an earlier mpox outbreak, 27.5% of infected individuals exhibited anxiety and depression (Mittal et al. 2022).

Despite the association between microRNA and viral encephalitis, there are almost no articles examining the role of CNS microRNA in mpox neurologic complications, including encephalitis. Therefore, in this study, we attempted to investigate some of the possible CNS microRNA associated with mpox encephalitis.

MiR-301a

MiR-301a is a potential oncogene, which have dual role including oncogene-specific effect, and pro-inflammatory regulator (Li et al. 2019). Mpox virus is able to bypass the host immune system by regulating several proteins related to the antiviral response. Mpox virus can interfere with receptor signaling pathways for pathogen recognition or disrupt key transcription factors involved in the inflammatory response, such as IRF3 and NF-κB. The virus is also able to inhibit IFNα/β production by targeting pathways mediated by protein kinase R (PKR) (Lum et al. 2022). A recent bioinformatics study found that mpox strongly suppresses the expression of antiviral genes, including interferon type I and II. Their results from the analysis of gene expression data from HELA cells infected with mpox virus also showed that IRF1 could potentially regulate interferon type I and II (Tang et al. 2022). The increased expression of miR-301a was reported after infection of human and mouse neurons with JEV. MiR-301a prevented the production of type I IFNs by inhibiting IRF1 and SOCS5, thereby suppressing the IRF1-supported neuronal immune response to JEV infection. On the other hand, targeting miR-301a restored IRF-1 expression and increased IFN1 production. Altogether, miR-301a could mediate JEV pathogenesis by inhibiting IFN production (Hazra et al. 2017).

MiR-15b

Mir-15b could be another possible miRNA involved in mpox encephalitis. This microRNA plays an important role in different types of cancer such as gastric cancer and colorectal cancer (Liu et al. 2020). Inhibition of ring finger protein 125 (RNF125), a negative regulator of RIG-1, by miR-15b resulted in higher production of proinflammatory cytokines and IFN-1 by increasing RIG-I during JEV infection of glial cells and mouse brains. The results also showed that treatment with antagomir-15b attenuated glial activation, reduced neuronal damage, and improved animal survival (Zhu et al. 2015). Another study showed that detection of JEV infection by RIG led to activation of ERK and NF-κB signalling pathways. It appears that the upregulation of mir-15 is mediated by c-Rel and CREB and that JEV increases mir-15 expression via the RIG-1 pathway. Inhibition of ERK and the NF-κB pathway also inhibited the induction of mir-15 (Zhu et al. 2016).

MiR-155

MiR-155 is a multifunctional microRNA, plays a crucial role in immune systems cells, and is encoded by MIR155HG located on chromosome 21q21.3 (Landeros et al. 2022). Microglia infection with virus such as JEV can lead to neuronal cell death by inappropriate pro-inflammatory cytokines production. Therefore, inhibiting the uncontrolled pro-inflammatory cytokines may minimize the inflammatory response and increases the chance of viral clearance and protection against the viral inflammation.

A research conducted by Pareek et al. reported that mir-155 expression in CHME3 microglia cells could drastically reduce the JEV replication and might decrease the proinflammatory cytokines and CFH expression (Pareek et al. 2014). Thounaojam et al. stated that mir-155 could trigger neuroinflammation in jev-infected mice through negative regulation of SHIP1 expression and subsequent activation of NF-κB leading to increased production of proinflammatory cytokines such as IFN-β. e inhibition of mir-155 decreased neuronal cell death and microglia activation (Thounaojam et al. 2014). Although Pareek et al. argued that these opposite results are because of their different experimental cell lines (Pareek et al. 2014). Thounaojam et al. used mouse BV-2 cells and Pareek conducted their experiment on human microglial cells CHME3 (Pareek et al. 2014; Thounaojam et al. 2014). A mouse model study for herpes simplex encephalitis (HSE) showed that the mice models with a deficiency of miR-155 were highly susceptible to herpes simplex encephalitis (Bhela et al. 2014). Collectively, these data suggest that mir-155 could play an antiviral at different stages of the encephalitis through different mechanism indicating that the mir-155 could also be a potential target to treat mpox encephalitis (Thounaojam et al. 2014).

MiR-19b-3p

MiR-19b-3p belongs to the miR-17∼92 miRNAs cluster and has divergent roles in development of several tumors and other disorders (Hühn et al. 2015; Lewis et al. 2015). Inhibition of ring finger protein 11 (RNF11) by miR-19b-3p positively modulated JEV-mediated inflammation in vivo. MiR-19b-3p enhanced NF-κB pathway activity by increasing the production of TNF-α, IL-6, IL-1β, and CCL5, leading to JEV neuroinflammation. The researchers also indicated that treatment of JEV-infected mice with antagomir-19b-3p could inhibit cytokine production and improve their survival rate (Ashraf et al. 2016). The results may reveal the molecular mechanism of JEV inflammatory response, which can be extended to potential therapeutic approaches for mpox encephalitis.

MiR-142

Mir-142 is a conserved miRNA between different species, including human, mouse, and is a tumor-suppressor miRNA via targeting the 3′UTR of Rac1 (Xu et al. 2020). Mir-142-3p and 5p are expressed in hippocampal neurons and CD163-positive macrophages/microglial nodules in HIV and SIV encephalitis (SIVE) (Chaudhuri et al. 2013). Overexpression of miR-142 led to a decrease in SIRT1, and SIRT1 was a direct target of miR-142-5p. The decrease in SIRT1 due to the upregulation of miR-142 in the brain may be directly involved in the inflammatory and neurodegenerative presentation of SIVE. Activation of SIRT1 or inhibition of miR-142 could help reduce these manifestations (Chaudhuri et al. 2013). The possible role of miR-142 and SIRT1 in mpox encephalitis may raise a question for further research.

MiR-146a

Mir-146a primarily operates as a regulator of adaptive and innate immunity responses and exhibit opposite expression pattern in viral encephalitis. In microglial cells infected with JEV strain JaOArS982, upregulation of mir-146a suppressed NF-κB activity and disrupted the antiviral Jak- STAT pathway, leading to downregulation of IFIT-1 and IFIT-2 and mediating JEV immune evasion (Sharma et al. 2015). Upregulation of mir-146a was observed in HIV-infected microglia. The increased level of mir-146a could suppress the release of HIV-induced CCL8/MCP-2, leading to the suppression of the inhibitory effect of CCL8/MCP-2 on HIV entry (38). Upregulation of mir-146a in HSV-1-infected human glial cells was associated with downregulation of complement factor H (CFH), which is a repressor of the complement signaling pathway (Hill et al. 2009). Another report by Majer et al. demonstrated the upregulation of mir-146a during HSV-1 encephalitis (HSVE) in a mouse model. They also suggested that upregulation of this microRNA may protect brain tissue from damage caused by an excessive immune response to the virus (Majer et al. 2017).

MiR-200

It has been reported that six members of the family including mir-200a, b, c /mir141, and mir-429 were highly expressed during HSV-1 encephalitis. Mir-141 and mir-200c could potentially downregulate the Sdc2 gene expression in an in vivo mouse model of HSVE. Sdc2 encodes a HSPGs core protein involves in HSV-1 entry to the host cells (Majer et al. 2017).

MiR-21-5p

Another microRNA, which possibly can play role in mpox virus encephalitis, is miR-21-5p that can regulate different immunological responses. A recent study showed the elevation of miR-21-5p expression level infected with Chandipura virus (CHPV); a single-stranded RNA virus belongs to Rhabdoviridae family causing acute encephalitis with a fatality rate of 70%, in human microglial cells. The study showed that the microRNA upregulation suppress PTEN expression and activate NF-ĸB through PI3K/AKT pathway. NF-ĸB activation induce pro-inflammatory responses and may participate in CHPV induced neuroinflammation (Pandey et al. 2021).

Let-7

The lethal-7 family is one of the first discovered microRNA. Ten microRNA including let-7a, b, c, d, e, f, g, i, and miR-98 and miR-202 are included in this family in mice and human. Let-7 microns exhibit a major regulatory role in inflammatory responses especially in CNS. It has been shown that let-7a and let-7c upregulation improved responses to spinal cord ischemia/reperfusion and provided protection against neuroinflammatory reaction (Bernstein et al. 2021). A study conducted by Mukherjee et al. explored the role of let-7 family in viral encephalitis. They showed that inhibition of let-7a/b restricted jev-induced notch pathway activation and decreased TNFα production in JEV-infected microglial cells (Mukherjee et al. 2019) (Table 1).

Table 1 The selective human CNS-related miRNAs and their sources

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