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      Host Immune Responses to Arthritogenic Alphavirus Infection, with Emphasis on Type I IFN Responses

      1 , 2 , 3 , 1 , 2 , 3 , 1 , 2 , 3 , * ,
      alphavirus, innate immune response, Type I IFN, antagonism


            Arthritogenic alphaviruses, such as Ross River virus, chikungunya virus and O’nyong-nyong virus, cause endemic disease globally and are a major public health concern. The hallmarks of arthritogenic alphavirus disease are debilitating pain, and potentially chronic inflammation of the muscles, thus influencing quality of life. The type I IFN response is a major component of the innate immune response against arthritogenic alphaviruses, and is essential in inhibiting viral replication and dissemination. Type I IFNs are induced during early stages of infection and are essential for the activation of the antiviral innate immune response. They also link the innate immune response and the activation of adaptive immunity. This review focuses on the host immune response, particularly that involving type I IFN, in arthritogenic alphavirus disease.

            Main article text


            Alphavirus, the only genus of the Togaviridae family, currently comprises 32 members. The first reported alphavirus infection in animals dates to the 18th century and is thought to have been Eastern equine encephalomyelitis virus (EEEV), on the basis of disease symptoms [1]. Chikungunya virus (CHIKV) was first identified in 1952 in Africa [2]. CHIKV has been observed in nearly 60 countries and has caused millions of clinical cases worldwide. Human infection with Ross River virus (RRV) was first recorded in Australia in 1928 [3]. Currently, RRV is the most widespread arbovirus in Australia and can be found throughout the South Pacific [4]. Each year in Australia, approximately 5,000 cases of RRV disease are reported [5,6]. In 2015, owing to extended periods of heavy rainfall, RRV disease cases reached a 23-year high in Australia, with 9,542 cases reported [7]. Diseases caused by alphaviruses have major economic and social costs. In the United States, CHIKV outbreaks have cost the healthcare system approximately US $14.8 to $33.4 million between the years 2014 and 2015 [8]. The annual cost of RRV in Australia, including testing, supportive therapies and loss of earnings, has been estimated to be approximately AU $20 million [6]. Nonetheless, no specific treatments or approved vaccines are currently available to protect against alphavirus infection, and only supportive care with analgesics and non-steroidal anti-inflammatory drugs is provided to symptomatic patients [9]. Therefore, investigation of the pathogenesis of alphavirus disease is imperative to identify potential targets for therapeutic intervention. Host type I interferon (IFN) is the first line of defence against invading viral pathogens [10]. However, many viruses, including alphaviruses, have evolved abilities to counteract the type I IFN system [1113]. The mechanisms used by alphaviruses to antagonise the host type I IFN system have been investigated in recent years. However, very little is known in this regard, and further investigations on these mechanisms are required.

            Alphavirus structure and life cycle

            The alphavirus virion is composed of an envelope, a nucleocapsid and a positive sense single-stranded RNA genome [14]. The genomes of most alphaviruses contain approximately 12 kb nucleotides encoding two open reading frames (ORFs): a non-structural protein (nsP) ORF and a structural protein ORF [15]. The full length alphavirus genome comprises 5′-cap–nsp1–nsp2– nsp3–nsp4–(junction region)–CP–E3–E2–6k–E1–poly(A) tail-3′. The main stages of the alphavirus life cycle are shown in Fig 1 [1621]. First, the virion attaches to the target host cytoplasmic membrane through cellular receptors, such as Mxra8 [22], C-type lectin receptor (CD209, also known as DC-SIGN) [23,24], TIM-1, NRAMP2, laminin, prohibitin1 [25] and heparan sulfate [26]. The virion enters cells through endocytosis. The viral envelope fuses with a mature endosome, and the viral core nucleocapsid disassembles under the low pH environment [27]. Next, the virus non-structural proteins are translated as poly-non-structural proteins p123 or p1234 from the viral genomic non-structural protein ORF. Cis-cleavage of the poly-non-structural proteins produces the mature non-structural proteins nsP1, nsP2, nsP3 and nsP4, which form a mature viral replicase that mediates viral RNA replication. The structural proteins are translated from the viral subgenomic RNA. The viral capsid protein interacts with viral RNA, and the virion is assembled in the cytoplasm. E1 and E2 proteins are secreted through the Golgi complex and embedded in the host cell membrane, which coats the virus nucleocapsid core during budding and formation of the mature virion [14].

            FIGURE 1 |

            Schematic diagram of the alphavirus replication cycle. The main steps of the viral life cycle: (1) attachment and entry by receptor mediated endocytosis; (2) viral protein translation and viral genome replication; (3) assembly of nucleocapsid core; (4) budding out of the host cells.

            Alphavirus disease and host immune response

            Arthritogenic alphaviruses such as CHIKV, Mayaro virus (MAYV), RRV and O’nyong-nyong virus are associated with rheumatic disease and are the primary cause of infectious arthropathies worldwide [28]. Generally, acute fever, skin rash, malaise, fatigue, myalgia and arthralgia are the common clinical signs shared by most arthrogenic alphavirus infections. The main features of pathogenesis of alphavirus disease are summarised in Fig 2. Several of the host’s innate and adaptive immune responses are activated during alphavirus infection [29], including the induction of cellular responses associated with T cells [30], B cells [31], natural killer cells [32] and macrophages [33], as well as the induction of cytokines, chemokines [3438] and complement factors [39]. Inflammatory mediators such as cytokines, chemokines, reactive oxygen and nitrogen species, and prostaglandins are released from leukocytes [40]. In inflamed tissues, these immune factors, which constitute the host natural defence system, potentially contribute to viral arthropathies.

            FIGURE 2 |

            Immune responses to alphavirus infection. Alphavirus infection triggers multiple inflammatory pathways, thus leading to elevation of inflammatory mediators. These mediators recruit and activate leukocytes, thus causing them to release excessive proinflammatory cytokines, which in turn result in cartilage degradation, bone loss, muscle destruction and neuronal damage.

            Macrophages play important roles in rheumatoid arthritis (RA) [41], spondyloarthropathies [42,43] and gout-arthritis [44]. Notably, macrophages have also been found to be associated with the pathogenesis of infectious arthritis such as septic arthritis and Lyme arthritis [4547]. A major component of the cellular infiltrate in alphavirus infected tissues is macrophages. The depletion of macrophages in RRV infected mice, compared with un-depleted infected mice, significantly ameliorates rheumatic disease signs, thus suggesting that macrophages and macrophage derived factors are the primary cellular mediators of RRV induced arthritis and myositis disease [48]. A recent study has indicated a novel role of CX3CR1+ macrophages in tissue repair after RRV-induced myositis. The study has also highlighted a potential therapeutic approach using immune modifying IMP microparticles to decrease inflammation and enhance tissue repair in infected individuals [49].

            Beyond the cellular response, soluble mediators have also been reported to play roles in RRV disease. Macrophage migration inhibitory factor (MIF) is a critical contributor to the severity of alphavirus-induced musculoskeletal disease. MIF is up-regulated in the serum and musculoskeletal tissues of mice with severe RRV disease [36]. Moreover, MIF has recently been found to correlate with CHIKV viral load in patients with CHIKV in Brazil [50]. Therefore, targeting this factor might aid in treating alphaviral arthritis in humans.

            Monocyte chemotactic protein-1 (MCP-1; CCL2), tumour necrosis factor alpha (TNF-α) and IFN-γ are elevated in synovial effusions of alphavirus infected patients [48]. An in vitro study using human synovial cells infected with RRV has detected MCP-1, type I IFN, granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin (IL)-8 at high levels [37]. Notably, treatment with Bindarit, an experimental drug that inhibits MCP-1 production, has been found to decrease macrophage infiltration and ameliorate rheumatic disease in a mouse model [38,51].

            In a recent study, IL-17A has been reported to be associated with tissue inflammation as well as neutrophil infiltration in CHIKV-induced RA [28]. In another recent study on IL-17 in RRV disease, IL-17 has been found to be responsible for RRV-induced arthritis and myositis [52]. IL-17 expression is up-regulated in musculoskeletal tissues and sera of RRV infected mice and humans. Blocking IL-17 has been suggested to decrease transcription of proinflammatory genes, cellular infiltration in synovial tissues and cartilage damage, thus ameliorating arthritic alphavirus diseases.

            Interestingly, downregulation of IL-13 and MCP-3 has been observed in patients with CHIKV disease, representing a unique cytokine profile of acute CHIKV infection [53]. IL-13 negatively regulates IgG1 and IgG2a switching through IFN-γ dependent signalling, thus suggesting that IL-13 may play an important role in antibody class switching during acute CHIKV infection.

            Beyond targeting joints and skeletal muscles, CHIKV, MAYV and encephalitic alphaviruses (new-world alphaviruses such as Venezuelan, eastern and western equine encephalitis viruses (VEEV, EEEV, and WEEV, respectively)) also infects the central nervous system (CNS) in humans [5457]. VEEV and WEEV infection in the CNS is controlled by caveolin-1 (Cav-1)-mediated transcytosis across the blood brain barrier [55]. Several studies have indicated that type I IFN is highly important in preventing viral invasion into the host CNS.

            The complement system has been shown to mediate immunopathogenesis during RRV infection. Activated complement proteins have been found in synovial fluids of RRV infected patients. Complement activation is involved in tissue destruction at the site of infection [58]. Moreover, mannose binding lectin (MBL) has been shown to be the essential receptor for complement activation in RRV infection. Mice deficient in MBL, C3 or CR3 complement receptor show less severe rheumatic symptoms than do wild type mice [5860]. Another study has shown indicated that, compared with mice infected with wild type virus, infection with RRV missing both E2 glycans leads to diminished MBL binding and complement activation, thus resulting in mild tissue damage [61]. Consequently, MBL and the viral N-linked glycans appear to be highly important to the development of alphaviral disease.

            Bone lesions have been reported in patients with CHIKV disease [62]. The disruption of the Receptor activator of nuclear factor kappa-B ligand (RANKL)/Osteoprotegerin (OPG) ratio has been shown to be a major contributor to bone loss in alphavirus induced arthritis disease. Primary human osteoblasts infected by RRV and CHIKV show a disrupted RANKL/OPG ratio and high levels of IL-6. However, the bone loss and the disrupted RANKL/OPG ratio are blocked by an IL-6 neutralising antibody treatment in a mouse model, thus suggesting that IL-6 plays a role in modulation of the RANKL/OPG ratio [35]. Furthermore, MCPs have been reported to play a role in CHIKV-induced osteoclastogenesis, because Bindarit treatment decreases CHIKV-induced bone loss in vivo [63].

            Host type I IFN response

            The innate immune system is the first line of defence against viral infection [10,64]. Its roles include detection of antigens, protection against viruses and activation of the adaptive immune system [65]. The interplay between type I IFN and alphavirus infection is discussed below.

            The interplay between alphavirus and the type I IFN pathways is summarised in Fig 3. Type I IFN induction pathways start when pattern recognition receptors (PRRs) identify the pathogen-associated molecular patterns (PAMPs) associated with the invading viruses [66]. PRRs can be divided into three classes on the basis of their subcellular localisation: membrane-bound PRRs, cytoplasmic PRRs and secreted extracellular PRRs. Activation of PRRs by PAMPs induces cascades of intracellular signalling, thus leading to type I IFN production. TLR and retinoic acid-inducible gene-I-like receptor (RLR) families are the major PPRs that activate these signalling cascades [67,68]. TLRs associated with type 1 IFN production include TLR3, TLR4, TLR7, TLR6 and TLR9. TLR3, TLR7, TLR8 and TLR9 localise to endosomes, whereas TLR4 localises to the cell membrane surface [69,70]. TLR4 is a robust type I IFN inducer that signals through adapter protein, TIR-domain containing adapter inducing interferon-β (TICAM1, TRIF) recognises lipopolysaccharide from bacteria. Within endosomal compartments, TLR3, TLR7, TLR8 and TLR9 react to double-stranded RNA, single-stranded RNA and unmethylated CpG DNA [68]. The RLR family includes three members: retinoic acid inducible gene-I protein (RIG-I), melanoma differentiation-associated gene 5 protein (MDA-5) and laboratory of genetics and physiology 2 protein (LGP2). MDA-5 recognises long foreign dsRNA [71]. RIG-I detects primarily foreign ssRNA containing 5′-triphosphate or short dsRNA, and is an essential regulator of dsRNA-induced IFN signalling [67,7176]. LPG2 is a negative regulator of the RIG-I/MDA5 initiated type I IFN induction pathway [77]. Most cellular RNA contains short hairpin structures and a 5′ cap structure. In contrast, viral RNA is often double stranded, and viral ssRNAs contain a 5′ triphosphate. These structural differences allow for self/nonself discrimination by these receptors. The central downstream adaptor of the RLR family receptor is the IFN-β promoter stimulator (IPS)-1, which is attached to the mitochondrial membrane by a C-terminal hydrophobic region [78]. Downstream of IPS-1, the serine/threonine kinase TANK-binding kinase 1 (TBK-1) phosphorylates interferon regulatory factors (IRFs) 3 and 7. IRFs 3 and 7 are the key adaptor molecules in the induction of type I IFN. IPS-1 also induces the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP1) [72].

            FIGURE 3 |

            Type I IFN response during alphavirus infection. Alphavirus infection is detected by host PRRs including TLR3-TRIF, TLR7-MyD88 and RIG-I/MDA5. Type I IFN is induced through IRF3/7 dependent pathways. A range of ISGs are induced, thus counteracting the viral infection. Various mechanisms are deployed by alphavirus to counteract type I IFN.

            Type I IFN induction by alphavirus infection

            Type I IFN responses are usually associated with alphaviral infection [7985]. Multiple regulatory proteins are involved in the induction of IFN and contribute to antiviral effects. These include TLRs, IRF-3/7, 2, 5-oligoadenylate synthetase and RIG-I. During alphaviral infection, the IPS-1-dependent RIG-I pathway, Myd88-dependent TLR7 pathway and TRIF-dependent TLR3 pathway contribute to the expression of type I IFN [67,68,8694]. A recent study has indicated that TRIF is a key player in IFN production during RRV infection as well as in inducing an optimal immune response against RRV, particularly B cell proliferation and T cell responses [95]. MDA-5 may also play a role in type I IFN induction after SINV infection [96]. A recent study has demonstrated that the TLR3 and RLR families both contribute to type I IFN in response to MAYV infection [57].

            Interestingly, in RRV infected Tlr7-/- and Myd88 -/- mice, despite showing more severe disease than that in WT infected mice, the expression of type I IFN is unaffected [86]. Additionally, studies have suggested that the TLR3 initiated type I IFN induction pathway is involved in host protection against CHIKV infection [94]. Moreover, type I IFN levels differ between Trif -/- and Ips-1-/- mice infected with CHIKV [93]. These findings suggest that the three induction pathways may act independently in host protection against invading alphaviruses.

            Several factors have been associated with type I IFN induction after alphavirus infection. Viral non-structural protein processing and viral replicase are closely associated with type I IFN induction [87,97]. Mutations in the nsP1 and nsP2 regions, which are common in naturally occurring RRV strains, can increase sensitivity to type I IFN [97,98]. Temperature is another factor modulating type I IFN activity in alphaviral arthritis. A study in a CHIKV mouse model has indicated greater type I IFN activity at 30°C than 22°C, thus resulting in ~20-fold lower viral load in the animals [99]. In agreement with those findings, Lane et al. have shown that lower temperatures exacerbate CHIKV replication in mice [100]. The intestinal microbiome also plays a role in the type I IFN response following CHIKV infection. TLR7-MyD88-dependent type I IFN signalling is hampered in germ-free mice with a depleted intestinal microbiome, thus leading to more rapid CHIKV infection spread in the animals. However, the type I IFN response is restored by reconstitution with a gut microorganism derived product, bile acid deoxycholic acid [101].

            Role of type I IFN in alphavirus infection

            SINV proliferates extensively in cells lacking type I IFN induction signalling. In contrast, viral replication is impaired in cells that produce type I IFN [82,102]. Type I IFN appears to play a pivotal role in controlling alphavirus replication and protecting cells against alphaviral invasion, although alphaviruses differ in sensitivity to type I IFN [96].

            Type I IFN clearly exerts broad antiviral functions by inducing a range of cellular interferon-stimulated genes (ISGs); however, the mechanistic details of this antiviral effect in host cells remain poorly defined. Among the ISGs elevated in response to alphavirus infection, Protein kinase R (PKR), Growth arrest and DNA-damaged protein 34 (GADD34), 2′,5′-oligoadenylate synthetase (OAS)/RNase L, ISG20, Interferon-induced proteins with tetratricopeptide repeats/IFN-induced transmembrane protein (IFIT/IFITM), Bone marrow stromal antigen 2 (BST2), Radical SAM domain-containing 2 (RSAD2), Promyelocytic leukemia zinc finger protein (PLZF) and ISG15 have shown in vitro inhibitory effects against alphavirus replication (Fig 3) [103]. PKR and GADD34 exert their antiviral effects through eukaryotic initiation factor (eIF)-2α phosphorylation, thus impairing viral RNA translation [104,105]. Although SFV has been reported to overcome the effects of PKR through a stem-loop structure in the viral RNA genome [106], delayed viral clearance has been observed in SFV-infected Pkr -/- mice [107]. Similarly, in Gadd34 -/- neonate mice, CHIKV replicates to a higher titre than that in wild type mice [108]. OAS proteins are a family that catalyses 2′, 5′-oligomers of ATP [109]. These oligomers activate RNase L, which degrades viral RNAs and thereby blocks viral replication [110]. Interestingly, despite showing in vitro antiviral activity against SFV, CHIKV, and SINV, mice deficient in RNase L or PKR develop only subclinical SINV infections [83], thus suggesting that RNase L and PKR may not have major roles in antiviral mechanisms against SINV. ISG20 is a nuclear 3′-5′ exonuclease reported to inhibit viral replication through direct degradation of viral RNA [111]. ISG20 also interferes with viral protein translation in a 5′ cap-dependent manner [112,113]. However, the antiviral effect of ISG20 in mice has been observed only against an attenuated strain of VEEV, but not against CHIKV or VEEV virulent strains [113]. IFIT/IFITM family has been reported to inhibit viral replication by binding and preventing the viral RNA from recognising the 43S pre-initiation complex, thereby interfering with viral protein translation [114]. IFIT1 proteins are upregulated by ISG20 in response to alphavirus infection [113]. The antiviral role of IFITM has been demonstrated in CHIKV or VEEV-infected Ifitm3 -/- mice, which show elevated viral load and tissue damage [115]. BST2 (Tetherin) is a cell-surface protein that blocks viral particle budding and therefore hampers viral release [116]. The in vivo antiviral effect of BST2 has been evidenced by an elevated viral load of CHIKV in Bst2 -/- mice [117]. RSAD2 (Viperin) is an antiviral protein that interferes with viral replication by inhibiting viral RNA polymerase [118]. CHIKV and SINV both show elevated virulence in Rsad2 -/- mice, as evidenced by viremia and mortality [119,120]. PLZF, a host transcriptional regulator in the nucleus, is involved in multiple biological processes, including haematopoiesis, osteogenesis and immune regulations [121]. In mice lacking PLZF, compared with wild type mice, SFV replicates to a significantly higher titre [122]. Notably, several ISGs are modulated by PLZF, including IFIT and RSAD2 [122]. Ubiquitin-like protein ISG15 is critical for the host antiviral response [123]. In mice deficient in ISG15, compared with wild type mice, CHIKV and SINV infection leads to higher levels of lethality [124,125].

            The type I IFN response is also involved in RA pathogenesis [126]. Interestingly, IFNα and IFNβ have different roles in inflammatory arthritis. IFNα promotes TLR3, TLR4 and TLR7-associated signalling pathways, and increases the production of IL-6, TNF-α, IL-1β and IL-18 in synovial cells from patients with RA [127]. In contrast, IFNβ shows an anti-inflammatory effect by inhibiting the production of IL-1β and TNF-α in RA [128]. However, the role of elevated type I IFN in the pathogenesis of arthritic disease after alphavirus infection has not been fully studied. Notably, compared with healthy osteoblasts, osteoblasts from patients with osteoarthritis show a remarkable delay in the type I IFN response, thus resulting in higher susceptibility to RRV infection, higher RANKL/OPG ratios, and elevated production of osteotropic factors, such as IL-6, IL-1β, TNF-α and CCL2 [129]. The delayed type I IFN response in osteoblasts has therefore been suggested to be the cause of the increased alphaviral osteoclastogenesis. Further studies are warranted to elucidate the role of type I IFN in alphavirus disease pathogenesis.

            Alphaviral antagonism of the type I IFN system

            Many viruses have evolved mechanisms to counteract the host IFN system [130]. The main viral strategies for circumventing the IFN system can be classified into three types: 1) concealing the viral RNA to make the viral dsRNA inaccessible to host RLRs; 2) masking the viral RNA to change the viral dsRNA PAMP signatures and avoid recognition by RLRs; and 3) blocking of host signalling pathways to inhibit immune functions [131].

            The antagonistic effect of alphavirus infection on type I IFN production has been described in several reports. Viral proteins are widely recognised to be the primary factors in the antagonism of type I IFN. For New World alphaviruses, such as VEEV and EEEV, the capsid protein is associated with IFN antagonism [11,132]. In EEEV, a region of the capsid between 55 and 75 amino acids is associated with inhibition of host gene expression and interferon sensitivity, whereas WEEV has a nucleocapsid arrangement targeting the PRR pathways downstream of IRF3 [133, 134]. In contrast, a study on VEEV and SINV has shown that the suppression of IFN-β and ISG mRNA production in neuron cells is associated with structural protein of VEEV but nonstructural protein of SINV [135]. SINV deficient in poly non-structural protein cleavage induces a much higher level of type I IFN than wild type SINV, and is quickly eliminated from infected cells [136]. Similarly, the descriptions of mutations at the cleavage site between nsP1 and nsP2 suggest that antagonism of type I IFN may be based on non-structural proteins [97,98]. A shutoff effect is one route of type I IFN antagonism: mutant viruses that are defective in the shutoff effect have been shown to be stronger IFN inducers [137]. The shutoff effect has been suggested to result from the nuclear localisation of nsP2 and the associated degradation of the host (DNA-directed RNA polymerase II subunit A) Rpb1 [138]. In a recent study on MAYV, nsP2 has been shown to interact with Rpb1 and transcription initiation factor II E subunit 2 (TFIIE2), thus inhibiting type I and type III IFN induction [139].

            However, the growth, shutoff effect and type I IFN induction of an SFV mutant lacking nsP2 NLS have suggested that the viral shutoff effect may not be the main mechanism underlying type I IFN antagonism [12]. Another putative mechanism of IFN antagonism comes from the alphavirus transmission cycle. The highly structured glycans on alphavirus E1/E2 protein synthesised in mosquito cells are efficient ligands for cell entry [24]. In contrast, E1/E2 carbohydrate structures derived from mammalian host cells cannot efficiently attach to host cells. In a study in 2007, murine bone marrow-derived culture myeloid DCs infected with insect cell-derived RRV, VEEV or Barmah forest virus were found to produce much lower levels of type I IFN than myeloid DCs infected with mammalian cell-derived virus [140]. These findings suggest that different glycan structures on E1/E2 result in different type I IFN induction levels in certain cell types.

            Antagonism of the type I IFN by invading alphaviruses is probably performed at multiple stages of the type I IFN system, including modulation of the signalling proteins in the IFN induction pathways and subversion of proteins in the canonical JAK-STAT pathway. SINV targets IPS-1 and consequently impedes the type I IFN system [90], whereas VEEV and CHIKV antagonise type I IFN by disrupting STAT signalling [91,141,142]. CHIKV has also been reported to play a role in suppressing activation of the IFN-β promoter induced MDA5/RIG-I receptor signalling pathway through nsP2, E1 and E2 [143]. The A532V mutation of RRV nsP1 has been shown to upregulate phosphorylated IRF3 [144], thus indicating that upstream effectors of the induction pathways may play roles in type I IFN modulation.


            Type I IFN plays a critical role in controlling the host’s innate antiviral responses and is known to trigger multiple downstream antiviral pathways. Through PRR dependent cascades, alphavirus infection in humans and animals is usually associated with a type I IFN response activating a range of downstream antiviral ISGs, including ISG15, PKR, OAS and ISG20. The activation of ISGs interferes with viral replication via various mechanisms including viral element degradation and modulation of immune responses. Alphavirus antagonises type I IFN mainly through viral non-structural proteins including nsP2 and capsid protein. However, the mechanisms through which alphavirus modulates type I IFN and the manner in which type I IFN orchestrates the activation of cellular immunity after alphavirus infection remain poorly understood. Because alphavirus infections have been gradually escalating worldwide, developing from periodic endemic outbreaks to global epidemics, understanding the mechanism of type I IFN responses to alphavirus infection is imperative to develop more targeted and effective therapeutic against these viruses as quickly as possible.


            We thank Prof. Suresh Mahalingam (MHIQ) for critical reading of the manuscript and useful discussions. This project was supported by Griffith University postgraduate scholarships to X.L. and W.H.N. The schematic diagrams were prepared in BioRender.com.


            We declare no competing interests.


            1. Hanson RP. An epizootic of equine encephalomyelitis that occurred in Massachusetts in 1831. Am J Trop Med Hyg. 1957. Vol. 6(5):858–862

            2. Ross RW. The Newala epidemic. III. The virus: isolation, pathogenic properties and relationship to the epidemic. J Hyg (Lond). 1956. Vol. 54(2):177–191

            3. Edwards A. An unusual epidemic. Med J Aust. 1928. Vol. 1:664–665

            4. Barber B, Denholm JT, Spelman D. Ross river virus. Aust Fam Physician. 2009. Vol. 38:586–589

            5. Russell RC. Ross river virus: ecology and distribution. Annu Rev Entomol. 2002. Vol. 47:1–31

            6. Aaskov J. 2015. Explainer: what is Ross River virus and how is it treated?http://theconversation.com/explainer-what-is-ross-river-virus-and-how-is-it-treated-37889Accessed 5 March 2015

            7. Australia’s National Notifiable Diseases Surveillance System. 2015. Number of notifications of Ross River virus infection, Australia, in the period of 1991 to 2014 and year-to-date notifications for 2015,. October ed. Australia’s National Notifiable Diseases Surveillance System (NNDSS).

            8. Feldstein LR, Ellis EM, Rowhani-Rahbar A, Hennessey MJ, Staples JE, Halloran ME, et al.. Estimating the cost of illness and burden of disease associated with the 2014-2015 chikungunya outbreak in the U.S. Virgin Islands. PLoS Negl Trop Dis. 2019. Vol. 13(7):e0007563

            9. Harley D, Sleigh A, Ritchie S. Ross River virus transmission, infection, and disease: a cross-disciplinary review. Clin Microbiol Rev. 2001. Vol. 14(4):909–932

            10. Gonzalez-Navajas JM, Lee J, David M, Raz E. Immunomodulatory functions of type I interferons. Nat Rev Immunol. 2012. Vol. 12(2):125–135

            11. Aguilar PV, Weaver SC, Basler CF. Capsid protein of eastern equine encephalitis virus inhibits host cell gene expression. J Virol. 2007. Vol. 81(8):3866–3876

            12. Breakwell L, Dosenovic P, Karlsson Hedestam GB, D’Amato M, Liljestrom P, Fazakerley J, et al.. Semliki Forest virus nonstructural protein 2 is involved in suppression of the type I interferon response. J Virol. 2007. Vol. 81(16):8677–8684

            13. Frolova EI, Fayzulin RZ, Cook SH, Griffin DE, Rice CM, Frolov I. Roles of nonstructural protein nsP2 and Alpha/Beta interferons in determining the outcome of Sindbis virus infection. J Virol. 2002. Vol. 76(22):11254–11264

            14. Kuhn RJ. Fields Virology. Vol. Volume 1. 5th edition. 2007

            15. Virus Taxonomy. Academic Press C, USA. The Positive Sense Single Stranded RNA Viruses. CA, USA: Virus Taxonomy Academic Press. 2005. p. 739–1128

            16. Raghow RS, Grace TD, Filshie BK, Bartley W, Dalgarno L. Ross River virus replication in cultured mosquito and mammalian cells: virus growth and correlated ultrastructural changes. J Gen Virol. 1973. Vol. 21:109–122

            17. Jose J, Snyder JE, Kuhn RJ. A structural and functional perspective of alphavirus replication and assembly. Future Microbiol. 2009. Vol. 4(7):837–856

            18. Solignat M, Gay B, Higgs S, Briant L, Devaux C. Replication cycle of chikungunya: a re-emerging arbovirus. Virology. 2009. Vol. 393(2):183–197

            19. Kononchik JP, Hernandez R, Brown DT. An alternative pathway for alphavirus entry. Virol J. 2011. Vol. 8:304

            20. Vaney MC, Duquerroy S, Rey FA. Alphavirus structure: activation for entry at the target cell surface. Curr Opin Virol. 2013. Vol. 3(2):151–158

            21. Martinez MG, Snapp EL, Perumal GS, Macaluso FP, Kielian M. Imaging the alphavirus exit pathway. J Virol. 2014. Vol. 88(12):6922–6933

            22. Zhang R, Kim AS, Fox JM, Nair S, Basore K, Klimstra WB, et al.. Mxra8 is a receptor for multiple arthritogenic alphaviruses. Nature. 2018. Vol. 557:570–574

            23. Davis CW, Nguyen HY, Hanna SL, Sanchez MD, Doms RW, Pierson TC. West Nile virus discriminates between DC-SIGN and DC-SIGNR for cellular attachment and infection. J Virol. 2006. Vol. 80:1290–1301

            24. Klimstra WB, Nangle EM, Smith MS, Yurochko AD, Ryman KD. DC-SIGN and L-SIGN can act as attachment receptors for alphaviruses and distinguish between mosquito cell- and mammalian cell-derived viruses. J Virol. 2003. Vol. 77:12022–12032

            25. Holmes AC, Basore K, Fremont DH, Diamond MS. A molecular understanding of alphavirus entry. PLoS Pathog. 2020. Vol. 16(10):e1008876

            26. Kielian M, Chanel-Vos C, Liao M. Alphavirus entry and membrane fusion. Viruses. 2010. Vol. 2(4):796–825

            27. Wengler G. In vitro analysis of factors involved in the disassembly of Sindbis virus cores by 60S ribosomal subunits identifies a possible role of low pH. J Gen Virol. 2002. Vol. 83:2417–2426

            28. Liu X, Poo YS, Alves JC, Almeida RP, Mostafavi H, Tang PCH, Bucala R, et al.. Interleukin-17 contributes to chikungunya virus-induced disease. mBio. 2022. Vol. 13(2):e0028922

            29. Alves EDL, Lopes da FBA. Characterization of the immune response following in vitro mayaro and chikungunya viruses (Alphavirus, Togaviridae) infection of mononuclear cells. Virus Res. 2018. Vol. 256:166–173

            30. Zhou Y. Regulatory T cells and viral infections. Front Biosci. 2008. Vol. 13:1152–1170

            31. Baumgarth N, Choi YS, Rothaeusler K, Yang Y, Herzenberg LA. B cell lineage contributions to antiviral host responses. Curr Top Microbiol Immunol. 2008. Vol. 319:41–61

            32. Lee SH, Miyagi T, Biron CA. Keeping NK cells in highly regulated antiviral warfare. Trends Immunol. 2007. Vol. 28(6):252–259

            33. Suhrbier A, La Linn M. Suppression of antiviral responses by antibody-dependent enhancement of macrophage infection. Trends Immunol. 2003. Vol. 24(4):165–168

            34. Eisenacher K, Steinberg C, Reindl W, Krug A. The role of viral nucleic acid recognition in dendritic cells for innate and adaptive antiviral immunity. Immunobiology. 2007. Vol. 212(9-10):701–714

            35. Chen W, Foo SS, Rulli NE, Taylor A, Sheng KC, Herrero LJ, et al.. Arthritogenic alphaviral infection perturbs osteoblast function and triggers pathologic bone loss. Proc Natl Acad Sci U S A. 2014. Vol. 111(16):6040–6045

            36. Herrero LJ, Nelson M, Srikiatkhachorn A, Gu R, Anantapreecha S, Fingerle-Rowson G, et al.. Critical role for macrophage migration inhibitory factor (MIF) in Ross River virus-induced arthritis and myositis. Proc Natl Acad Sci U S A. 2011. Vol. 108:12048–12053

            37. Mateo L, La Linn M, McColl SR, Cross S, Gardner J, Suhrbier A. An arthrogenic alphavirus induces monocyte chemoattractant protein-1 and interleukin-8. Intervirology. 2000. Vol. 43(1):55–60

            38. Rulli NE, Guglielmotti A, Mangano G, Rolph MS, Apicella C, Zaid A, et al.. Amelioration of alphavirus-induced arthritis and myositis in a mouse model by treatment with bindarit, an inhibitor of monocyte chemotactic proteins. Arthritis Rheum. 2009. Vol. 60(8):2513–2523

            39. Roozendaal R, Carroll MC. Emerging patterns in complement-mediated pathogen recognition. Cell. 2006. Vol. 125(1):29–32

            40. Steer SA, Corbett JA. The role and regulation of COX-2 during viral infection. Viral Immunol. 2003. Vol. 16(4):447–460

            41. Szekanecz Z, Koch AE. Macrophages and their products in rheumatoid arthritis. Curr Opin Rheumatol. 2007. Vol. 19(3):289–295

            42. Baeten D, Kruithof E, De Rycke L, Boots AM, Mielants H, Veys EM, et al.. Infiltration of the synovial membrane with macrophage subsets and polymorphonuclear cells reflects global disease activity in spondyloarthropathy. Arthritis Res Ther. 2005. Vol. 7:R359–R369

            43. Ritchlin C. Psoriatic disease--from skin to bone. Nat Clin Pract Rheumatol. 2007. Vol. 3(12):698–706

            44. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006. Vol. 440(7081):237–241

            45. Deng GM, Nilsson IM, Verdrengh M, Collins LV, Tarkowski A. Intra-articularly localized bacterial DNA containing CpG motifs induces arthritis. Nat Med. 1999. Vol. 5(6):702–705

            46. Glickstein LJ, Coburn JL. Short report: Association of macrophage inflammatory response and cell death after in vitro Borrelia burgdorferi infection with arthritis resistance. Am J Trop Med Hyg. 2006. Vol. 75(5):964–967

            47. Verdrengh M, Tarkowski A. Role of macrophages in Staphylococcus aureus-induced arthritis and sepsis. Arthritis Rheum. 2000. Vol. 43(10):2276–2282

            48. Lidbury BA, Rulli NE, Suhrbier A, Smith PN, McColl SR, Cunningham AL, et al.. Macrophage-derived proinflammatory factors contribute to the development of arthritis and myositis after infection with an arthrogenic alphavirus. J Infect Dis. 2008. Vol. 197(11):1585–1593

            49. Zaid A, Tharmarajah K, Mostafavi H, Freitas JR, Sheng KC, Foo SS, et al.. Modulation of Monocyte-Driven Myositis in Alphavirus Infection Reveals a Role for CX3CR1(+) Macrophages in Tissue Repair. mBio. 2020. Vol. 11(2):e03353–e03419

            50. Sanchez-Arcila JC, Badolato-Correa J, de Souza TMA, Paiva IA, Barbosa LS, Nunes PCG, et al.. Clinical, virological, and immunological profiles of DENV, ZIKV, and/or CHIKV-infected Brazilian patients. Intervirology. 2020. Vol. 63:33–45

            51. Rulli NE, Rolph MS, Srikiatkhachorn A, Anantapreecha S, Guglielmotti A, Mahalingam S. Protection from arthritis and myositis in a mouse model of acute chikungunya virus disease by bindarit, an inhibitor of monocyte chemotactic protein-1 synthesis. J Infect Dis. 2011. Vol. 204(7):1026–1030

            52. Mostafavi H, Tharmarajah K, Vider J, West NP, Freitas JR, Cameron B, et al.. Interleukin-17 contributes to Ross River virus-induced arthritis and myositis. PLoS Pathog. 2022. Vol. 18(2):e1010185

            53. Dhenni R, Yohan B, Alisjahbana B, Lucanus A, Riswari SF, Megawati D, et al.. Comparative cytokine profiling identifies common and unique serum cytokine responses in acute chikungunya and dengue virus infection. BMC Infect Dis. 2021. Vol. 21(1):639

            54. Schwartz O, Albert ML. Biology and pathogenesis of chikungunya virus. Nat Rev Microbiol. 2010. Vol. 8(7):491–500

            55. Salimi H, Cain MD, Jiang X, Roth RA, Beatty WL, Sun C, et al.. Encephalitic alphaviruses exploit caveola-mediated transcytosis at the blood-brain barrier for central nervous system entry. mBio. 2020. 11

            56. Figueiredo CM, da Silva Neris RL, Gavino-Leopoldino D, da Silva MOL, Almeida JS, Dos-Santos JS, et al.. Mayaro virus replication restriction and induction of muscular inflammation in mice are dependent on age, type-I interferon response, and adaptive immunity. Front Microbiol. 2019. Vol. 10:2246

            57. Bengue M, Ferraris P, Barthelemy J, Diagne CT, Hamel R, Liegeois F, et al.. Mayaro virus infects human brain cells and induces a potent antiviral response in human astrocytes. Viruses. 2021. Vol. 13(3):465

            58. Morrison TE, Fraser RJ, Smith PN, Mahalingam S, Heise MT. Complement contributes to inflammatory tissue destruction in a mouse model of Ross River virus-induced disease. J Virol. 2007. Vol. 81(10):5132–5143

            59. Morrison TE, Simmons JD, Heise MT. Complement receptor 3 promotes severe ross river virus-induced disease. J Virol. 2008. Vol. 82(22):11263–11272

            60. Gunn BM, Morrison TE, Whitmore AC, Blevins LK, Hueston L, Fraser RJ, et al.. Mannose binding lectin is required for alphavirus-induced arthritis/myositis. PLoS Pathog. 2012. Vol. 8(3):e1002586

            61. Gunn BM, Jones JE, Shabman RS, Whitmore AC, Sarkar S, Blevins LK, et al.. Ross River virus envelope glycans contribute to disease through activation of the host complement system. Virology. 2018. Vol. 515:250–260

            62. Manimunda SP, Vijayachari P, Uppoor R, Sugunan AP, Singh SS, Rai SK, et al.. Clinical progression of chikungunya fever during acute and chronic arthritic stages and the changes in joint morphology as revealed by imaging. Trans R Soc Trop Med Hyg. 2010. Vol. 104(6):392–399

            63. Chen W, Foo SS, Taylor A, Lulla A, Merits A, Hueston L, et al.. Bindarit, an inhibitor of monocyte chemotactic protein synthesis, protects against bone loss induced by chikungunya virus infection. J Virol. 2015. Vol. 89(1):581–593

            64. Zhou Z, Hamming OJ, Ank N, Paludan SR, Nielsen AL, Hartmann R. Type III interferon (IFN) induces a type I IFN-like response in a restricted subset of cells through signaling pathways involving both the Jak-STAT pathway and the mitogen-activated protein kinases. J Virol. 2007. Vol. 81(14):7749–7758

            65. Anaeigoudari A, Mollaei HR, Arababadi MK, Nosratabadi R. Severe acute respiratory syndrome coronavirus 2: the role of the main components of the innate immune system. Inflammation. 2021. Vol. 44(6):2151–2169

            66. Medzhitov R, Janeway CA Jr. Decoding the patterns of self and nonself by the innate immune system. Science. 2002. Vol. 296(5566):298–300

            67. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, et al.. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol. 2004. Vol. 5(7):730–737

            68. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004. Vol. 4(7):499–511

            69. Arimoto KI, Miyauchi S, Stoner SA, Fan JB, Zhang DE. Negative regulation of type I IFN signaling. J Leukoc Biol. 2018. Vol. 103:1099–1116

            70. Kawai T, Akira S. TLR signaling. Semin Immunol. 2007. Vol. 19(1):24–32

            71. Kang DC, Gopalkrishnan RV, Wu Q, Jankowsky E, Pyle AM, Fisher PB. mda-5: an interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties. Proc Natl Acad Sci U S A. 2002. Vol. 99(2):637–642

            72. Meylan E, Tschopp J. Toll-like receptors and RNA helicases: two parallel ways to trigger antiviral responses. Mol Cell. 2006. Vol. 22(5):561–569

            73. Kovacsovics M, Martinon F, Micheau O, Bodmer JL, Hofmann K, Tschopp J. Overexpression of Helicard, a CARD-containing helicase cleaved during apoptosis, accelerates DNA degradation. Curr Biol. 2002. Vol. 12(10):838–843

            74. Rothenfusser S, Goutagny N, DiPerna G, Gong M, Monks BG, Schoenemeyer A, et al.. The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I. J Immunol. 2005. Vol. 175(8):5260–5268

            75. Yoneyama M, Kikuchi M, Matsumoto K, Imaizumi T, Miyagishi M, Taira K, et al.. Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol. 2005. Vol. 175(6):2851–2858

            76. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010. Vol. 140(6):805–820

            77. Vitour D, Meurs EF. 2007. Regulation of interferon production by RIG-I and LGP2: a lesson in self-control. Sci STKE. 2007. Vol. 2007(384):pe20

            78. Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, et al.. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol. 2005. Vol. 6(10):981–988

            79. Baron S, Buckler CE, McCloskey RV, Kirschstein RL. Role of interferon during viremia. I. Production of circulating interferon. J Immunol. 1966. Vol. 96(1):12–16

            80. Bradish CJ, Allner K, Maber HB. Infection, interaction and the expression of virulence by defined strains of Semliki forest virus. J Gen Virol. 1972. Vol. 16(3):359–372

            81. Klimstra WB, Ryman KD, Bernard KA, Nguyen KB, Biron CA, Johnston RE. Infection of neonatal mice with sindbis virus results in a systemic inflammatory response syndrome. J Virol. 1999. Vol. 73(12):10387–10398

            82. Ryman KD, Klimstra WB, Nguyen KB, Biron CA, Johnston RE. Alpha/beta interferon protects adult mice from fatal Sindbis virus infection and is an important determinant of cell and tissue tropism. J Virol. 2000. Vol. 74(7):3366–3378

            83. Ryman KD, White LJ, Johnston RE, Klimstra WB. Effects of PKR/RNase L-dependent and alternative antiviral pathways on alphavirus replication and pathogenesis. Viral Immunol. 2002. Vol. 15(1):53–76

            84. Sherman LA, Griffin DE. Pathogenesis of encephalitis induced in newborn mice by virulent and avirulent strains of Sindbis virus. J Virol. 1990. Vol. 64(5):2041–2046

            85. White LJ, Wang JG, Davis NL, Johnston RE. Role of alpha/beta interferon in Venezuelan equine encephalitis virus pathogenesis: effect of an attenuating mutation in the 5′ untranslated region. J Virol. 2001. Vol. 75(8):3706–3718

            86. Neighbours LM, Long K, Whitmore AC, Heise MT. Myd88-dependent toll-like receptor 7 signaling mediates protection from severe Ross River virus-induced disease in mice. J Virol. 2012. Vol. 86(19):10675–10685

            87. Nikonov A, Molder T, Sikut R, Kiiver K, Mannik A, Toots U, et al.. RIG-I and MDA-5 detection of viral RNA-dependent RNA polymerase activity restricts positive-strand RNA virus replication. PLoS Pathog. 2013. Vol. 9(9):e1003610

            88. Olagnier D, Scholte FE, Chiang C, Albulescu IC, Nichols C, He Z, et al.. Inhibition of dengue and chikungunya virus infections by RIG-I-mediated type I interferon-independent stimulation of the innate antiviral response. J Virol. 2014. Vol. 88(8):4180–4194

            89. Scherbik SV, Pulit-Penaloza JA, Basu M, Courtney SC, Brinton MA. Increased early RNA replication by chimeric West Nile virus W956IC leads to IPS-1-mediated activation of NF-kappaB and insufficient virus-mediated counteraction of the resulting canonical type I interferon signaling. J Virol. 2013. Vol. 87(14):7952–7965

            90. Wollish AC, Ferris MT, Blevins LK, Loo YM, Gale M, Heise MT. An attenuating mutation in a neurovirulent Sindbis virus strain interacts with the IPS-1 signaling pathway in vivo. Virology. 2013. Vol. 435(2):269–280

            91. Fros JJ, Liu WJ, Prow NA, Geertsema C, Ligtenberg M, Vanlandingham DL, et al.. Chikungunya virus nonstructural protein 2 inhibits type I/II interferon-stimulated JAK-STAT signaling. J Virol. 2010. Vol. 84(20):10877–10887

            92. Errett JS, Suthar MS, McMillan A, Diamond MS, Gale M. The essential, nonredundant roles of RIG-I and MDA5 in detecting and controlling West Nile virus infection. J Virol. 2013. Vol. 87(21):11416–11425

            93. Rudd PA, Wilson J, Gardner J, Larcher T, Babarit C, Le TT, et al.. Interferon response factors 3 and 7 protect against Chikungunya virus hemorrhagic fever and shock. J Virol. 2012. Vol. 86(18):9888–9898

            94. Her Z, Teng TS, Tan JJ, Teo TH, Kam YW, Lum FM, et al.. Loss of TLR3 aggravates CHIKV replication and pathology due to an altered virus-specific neutralizing antibody response. EMBO Mol Med. 2015. Vol. 7(1):24–41

            95. Liu X, Taylor A, Poo YS, Ng WH, Herrero LJ, Tang PCH, et al.. TIR-Domain-Containing Adapter-Inducing Interferon-beta (TRIF)-Dependent Antiviral Responses Protect Mice against Ross River Virus Disease. mBio. 2022. Vol. 13(1):e0336321

            96. Klimstra WB, Ryman KD. TogavirusesCelluar Signaling and Innate Immune Responses to RNA Virus Infections. Brasier AR, Garcia-Sastre A, Lemon SM. Washington, DC: American Society for Microbiology. 2008

            97. Liu X, Mutso M, Utt A, Lepland A, Herrero LJ, Taylor A, et al.. Decreased virulence of ross river virus harboring a mutation in the first cleavage site of nonstructural polyprotein is caused by a novel mechanism leading to increased production of interferon-inducing RNAs. mBio. 2018. Vol. 9(4):e00044–e00118

            98. Liu X, Mutso M, Cherkashchenko L, Zusinaite E, Herrero LJ, Doggett SL, et al.. Identification of natural molecular determinants of ross river virus type I interferon modulation. J Virol. 2020. Vol. 94(8):e01788–e01819

            99. Prow NA, Tang B, Gardner J, Le TT, Taylor A, Poo YS, et al.. Lower temperatures reduce type I interferon activity and promote alphaviral arthritis. PLoS Pathog. 2017. Vol. 13(12):e1006788

            100. Lane WC, Dunn MD, Gardner CL, Lam LKM, Watson AM, Hartman AL, et al.. The efficacy of the interferon Alpha/Beta response versus arboviruses is temperature dependent. mBio. 2018. Vol. 9(2):e00535–18

            101. Winkler ES, Shrihari S, Hykes BL, Handley SA, Andhey PS, Huang YS, et al.. The intestinal microbiome restricts alphavirus infection and dissemination through a bile acid-type I IFN signaling axis. Cell. 2020. Vol. 182(4):901–918.e18

            102. Ryman KD, Meier KC, Gardner CL, Adegboyega PA, Klimstra WB. Non-pathogenic Sindbis virus causes hemorrhagic fever in the absence of alpha/beta and gamma interferons. Virology. 2007. Vol. 368(2):273–285

            103. Kafai NM, Diamond MS, Fox JM. Distinct cellular tropism and immune responses to alphavirus infection. Annu Rev Immunol. 2022. Vol. 40:615–649

            104. Garcia MA, Gil J, Ventoso I, Guerra S, Domingo E, Rivas C, Esteban M. Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action. Microbiol Mol Biol Rev. 2006. Vol. 70(4):1032–1060

            105. Choy MS, Yusoff P, Lee IC, Newton JC, Goh CW, Page R, et al.. Structural and Functional Analysis of the GADD34:PP1 eIF2alpha Phosphatase. Cell Rep. 2015. Vol. 11(12):1885–1891

            106. Carpentier KS, Morrison TE. Innate immune control of alphavirus infection. Curr Opin Virol. 2018. Vol. 28:53–60

            107. Barry G, Breakwell L, Fragkoudis R, Attarzadeh-Yazdi G, Rodriguez-Andres J, Kohl A, et al.. PKR acts early in infection to suppress Semliki Forest virus production and strongly enhances the type I interferon response. J Gen Virol. 2009. Vol. 90(Pt 6):1382–1391

            108. Clavarino G, Claudio N, Couderc T, Dalet A, Judith D, Camosseto V, et al.. Induction of GADD34 is necessary for dsRNA-dependent interferon-beta production and participates in the control of Chikungunya virus infection. PLoS Pathog. 2012. Vol. 8(5):e1002708

            109. Rebouillat D, Hovanessian AG. The human 2′,5′-oligoadenylate synthetase family: interferon-induced proteins with unique enzymatic properties. J Interferon Cytokine Res. 1999. Vol. 19(4):295–308

            110. Kristiansen H, Scherer CA, McVean M, Iadonato SP, Vends S, Thavachelvam K, et al.. Extracellular 2′-5′ oligoadenylate synthetase stimulates RNase L-independent antiviral activity: a novel mechanism of virus-induced innate immunity. J Virol. 2010. Vol. 84(22):11898–11904

            111. Espert L, Degols G, Gongora C, Blondel D, Williams BR, Silverman RH, et al.. ISG20, a new interferon-induced RNase specific for single-stranded RNA, defines an alternative antiviral pathway against RNA genomic viruses. J Biol Chem. 2003. Vol. 278(18):16151–16158

            112. Wu N, Nguyen XN, Wang L, Appourchaux R, Zhang C, Panthu B, et al.. The interferon stimulated gene 20 protein (ISG20) is an innate defense antiviral factor that discriminates self versus non-self translation. PLoS Pathog. 2019. Vol. 15(10):e1008093

            113. Weiss CM, Trobaugh DW, Sun C, Lucas TM, Diamond MS, Ryman KD, Klimstra WB. The interferon-induced exonuclease ISG20 exerts antiviral activity through upregulation of type I interferon response proteins. mSphere. 2018. Vol. 3(5):e00209–18

            114. Diamond MS, Farzan M. The broad-spectrum antiviral functions of IFIT and IFITM proteins. Nat Rev Immunol. 2013. Vol. 13(1):46–57

            115. Poddar S, Hyde JL, Gorman MJ, Farzan M, Diamond MS. The Interferon-Stimulated Gene IFITM3 Restricts Infection and Pathogenesis of Arthritogenic and Encephalitic Alphaviruses. J Virol. 2016. Vol. 90(19):8780–8794

            116. Kaletsky RL, Francica JR, Agrawal-Gamse C, Bates P. Tetherin-mediated restriction of filovirus budding is antagonized by the Ebola glycoprotein. Proc Natl Acad Sci U S A. 2009. Vol. 106(8):2886–2891

            117. Mahauad-Fernandez WD, Jones PH, Okeoma CM. Critical role for bone marrow stromal antigen 2 in acute Chikungunya virus infection. J Gen Virol. 2014. Vol. 95(Pt 11):2450–2461

            118. Gizzi AS, Grove TL, Arnold JJ, Jose J, Jangra RK, Garforth SJ, et al.. A naturally occurring antiviral ribonucleotide encoded by the human genome. Nature. 2018. Vol. 558:610–614

            119. Teng TS, Foo SS, Simamarta D, Lum FM, Teo TH, Lulla A, et al.. Viperin restricts chikungunya virus replication and pathology. J Clin Invest. 2012. Vol. 122(12):4447–4460

            120. Carissimo G, Teo TH, Chan YH, Lee CY, Lee B, Torres-Ruesta A, et al.. Viperin controls chikungunya virus-specific pathogenic T cell IFNgamma Th1 stimulation in mice. Life Sci Alliance. 2019. Vol. 2(1):e201900298

            121. Suliman BA, Xu D, Williams BR. The promyelocytic leukemia zinc finger protein: two decades of molecular oncology. Front Oncol. 2012. Vol. 2:74

            122. Xu D, Holko M, Sadler AJ, Scott B, Higashiyama S, Berkofsky-Fessler W, et al.. Promyelocytic leukemia zinc finger protein regulates interferon-mediated innate immunity. Immunity. 2009. Vol. 30(6):802–816

            123. Perng YC, Lenschow DJ. ISG15 in antiviral immunity and beyond. Nat Rev Microbiol. 2018. Vol. 16(7):423–439

            124. Lenschow DJ, Lai C, Frias-Staheli N, Giannakopoulos NV, Lutz A, Wolff T, et al.. IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses. Proc Natl Acad Sci U S A. 2007. Vol. 104(4):1371–1376

            125. Werneke SW, Schilte C, Rohatgi A, Monte KJ, Michault A, Arenzana-Seisdedos F, et al.. ISG15 is critical in the control of Chikungunya virus infection independent of UbE1L mediated conjugation. PLoS Pathog. 2011. Vol. 7(10):e1002322

            126. Castaneda-Delgado JE, Bastian-Hernandez Y, Macias-Segura N, Santiago-Algarra D, Castillo-Ortiz JD, Aleman-Navarro AL, et al.. Type I interferon gene response is increased in early and established rheumatoid arthritis and correlates with autoantibody production. Front Immunol. 2017. Vol. 8:285

            127. Roelofs MF, Wenink MH, Brentano F, Abdollahi-Roodsaz S, Oppers-Walgreen B, Barrera P, et al.. Type I interferons might form the link between Toll-like receptor (TLR) 3/7 and TLR4-mediated synovial inflammation in rheumatoid arthritis (RA). Ann Rheum Dis. 2009. Vol. 68(9):1486–1493

            128. Coclet-Ninin J, Dayer JM, Burger D. Interferon-beta not only inhibits interleukin-1beta and tumor necrosis factor-alpha but stimulates interleukin-1 receptor antagonist production in human peripheral blood mononuclear cells. Eur Cytokine Netw. 1997. Vol. 8(4):345–349

            129. Chen W, Foo SS, Li RW, Smith PN, Mahalingam S. Osteoblasts from osteoarthritis patients show enhanced susceptibility to Ross River virus infection associated with delayed type I interferon responses. Virol J. 2014. Vol. 11:189

            130. Navratil V, de Chassey B, Meyniel L, Pradezynski F, Andre P, Rabourdin-Combe C, et al.. System-level comparison of protein-protein interactions between viruses and the human type I interferon system network. J Proteome Res. 2010. Vol. 9(7):3527–3536

            131. Zinzula L, Tramontano E. Strategies of highly pathogenic RNA viruses to block dsRNA detection by RIG-I-like receptors: hide, mask, hit. Antiviral Res. 2013. Vol. 100(3):615–635

            132. Garmashova N, Gorchakov R, Volkova E, Paessler S, Frolova E, Frolov I. The Old World and New World alphaviruses use different virus-specific proteins for induction of transcriptional shutoff. J Virol. 2007. Vol. 81(5):2472–2484

            133. Aguilar PV, Leung LW, Wang E, Weaver SC, Basler CF. A five-amino-acid deletion of the eastern equine encephalitis virus capsid protein attenuates replication in mammalian systems but not in mosquito cells. J Virol. 2008. Vol. 82(14):6972–6983

            134. Rangel MV, Stapleford KA. Alphavirus virulence determinants. Pathogens. 2021. Vol. 10(8):981

            135. Yin J, Gardner CL, Burke CW, Ryman KD, Klimstra WB. Similarities and differences in antagonism of neuron alpha/beta interferon responses by Venezuelan equine encephalitis and Sindbis alphaviruses. J Virol. 2009. Vol. 83(19):10036–10047

            136. Gorchakov R, Frolova E, Sawicki S, Atasheva S, Sawicki D, Frolov I. A new role for ns polyprotein cleavage in Sindbis virus replication. J Virol. 2008. Vol. 82(13):6218–6231

            137. Gorchakov R, Frolova E, Frolov I. Inhibition of transcription and translation in Sindbis virus-infected cells. J Virol. 2005. Vol. 79(15):9397–9409

            138. Akhrymuk I, Kulemzin SV, Frolova EI. Evasion of the innate immune response: the Old World alphavirus nsP2 protein induces rapid degradation of Rpb1, a catalytic subunit of RNA polymerase II. J Virol. 2012. Vol. 86(13):7180–7191

            139. Ishida R, Cole J, Lopez-Orozco J, Fayad N, Felix-Lopez A, Elaish M, et al.. Mayaro virus non-structural protein 2 circumvents the induction of interferon in part by depleting host transcription initiation factor IIE subunit 2. Cells. 2021. Vol. 10(12):3510

            140. Shabman RS, Morrison TE, Moore C, White L, Suthar MS, Hueston L, et al.. Differential induction of type I interferon responses in myeloid dendritic cells by mosquito and mammalian-cell-derived alphaviruses. J Virol. 2007. Vol. 81(1):237–247

            141. Simmons JD, White LJ, Morrison TE, Montgomery SA, Whitmore AC, Johnston RE, et al.. Venezuelan equine encephalitis virus disrupts STAT1 signaling by distinct mechanisms independent of host shutoff. J Virol. 2009. Vol. 83(20):10571–10581

            142. Morrison J, Laurent-Rolle M, Maestre AM, Rajsbaum R, Pisanelli G, Simon V, et al.. Dengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling. PLoS Pathog. 2013. Vol. 9(3):e1003265

            143. Bae S, Lee JY, Myoung J. Chikungunya Virus-Encoded nsP2, E2 and E1 strongly antagonize the interferon-beta signaling pathway. J Microbiol Biotechnol. 2019. Vol. 29(11):1852–1859

            144. Cruz CC, Suthar MS, Montgomery SA, Shabman R, Simmons J, Johnston RE, et al.. Modulation of type I IFN induction by a virulence determinant within the alphavirus nsP1 protein. Virology. 2010. Vol. 399:1–10

            Author and article information

            Compuscript (Shannon, Ireland )
            09 September 2022
            : 2
            : 1
            [1 ]Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia
            [2 ]Global Virus Network (GVN) Centre of Excellence in Arboviruses, Griffith University, Gold Coast, Queensland, Australia
            [3 ]School of Medical Sciences, Griffith University, Gold Coast, Queensland, Australia
            Author notes
            *Corresponding author: E-mail: Xiang.liu@ 123456griffith.edu.au (XL)

            Edited by: Huanyu Wang, Institute of Viral Diseases, China CDC

            Reviewed by: Reviewer 1: Jinglin Wang, Yunnan Tropical and Subtropical Animal Viral Disease Laboratory

            Reviewer 2 chose to be anonymous.

            Copyright © 2022 The Authors.

            This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY) 4.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.

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            Review Article

            Parasitology,Animal science & Zoology,Molecular biology,Public health,Microbiology & Virology,Infectious disease & Microbiology
            antagonism,alphavirus,innate immune response,Type I IFN


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