Disease relevance of VISA

• Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus [1].
• Legionella pneumophila Induces IFNbeta in Lung Epithelial Cells via IPS-1 and IRF3, Which Also Control Bacterial Replication [2].
• In conclusion, we demonstrated a critical involvement of RIG-I, IPS-1 and IRF3 in influenza A virus infection of epithelial cells [3].
• We report the first instance in Australia of treatment failure due to a strain of methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to vancomycin--heteroresistant vancomycin-intermediate S. aureus (hVISA) [4].
• These clinical markers of hVISA bacteremia may help focus diagnostic efforts and treatment [5].

Psychiatry related information on VISA

• Using transcranial magnetic stimulation (TMS), we investigated the functional role of the hIPS by examining two effects from the domain of numerical cognition: in magnitude comparison tasks response latencies are inversely related to the numerical distance between two numbers [6].

High impact information on VISA

• Epistasis experiments show that MAVS is required for the phosphorylation of IRF 3 and IkappaB and functions downstream of RIG-I, an intracellular receptor for viral RNA [7].
• Conversely, overexpression of MAVS induces the expression of IFN-beta through activation of NF-kappaB and IRF 3, thus boosting antiviral immunity [7].
• The transmembrane domain targets MAVS to the mitochondria, implicating a new role of mitochondria in innate immunity [7].
• Silencing of MAVS expression through RNA interference abolishes the activation of NF-kappaB and IRF 3 by viruses, thereby permitting viral replication [7].
• In this issue, it is shown that the mitochondrial antiviral signaling protein is critical for intracellular detection signaling, but is dispensable for the activation of innate immunity via Toll-like receptors [8].

Chemical compound and disease context of VISA

• Cardif is targeted and inactivated by NS3-4A, a serine protease from hepatitis C virus known to block interferon-beta production [1].
• Four independent studies have identified a novel CARD-containing protein, variously called IPS-1, MAVS, VISA and Cardif, which is an essential signaling adaptor of the host defense mediating CARD-CARD interactions with retinoic acid inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDAS), sensors of virus infection [9].

Biological context of VISA

• Gene silencing and overexpression experiments demonstrated that RIG-I, its adapter interferon-beta promoter stimulator 1 (IPS-1) and interferon-regulated factor 3 (IRF3) were involved in influenza A virus-mediated production of the antiviral IFNbeta [3].
• Recently, the adapter molecule that links RIG-I sensing of incoming viral RNA to downstream signaling and gene activation events was characterized by four different groups; MAVS/IPS-1-1/VISA/Cardif contains an amino-terminal CARD domain and a carboxyl-terminal mitochondrial transmembrane sequence that localizes to the mitochondrial membrane [10].
• This study describes the molecular cloning of the full length human myo-inositol 1-phosphate synthase (hIPS) cDNA, tissue distribution of its mRNA and characterizes its gene expression in cultured HepG2 cells [11].
• This up-regulation is prevented by mevalonic acid, farnesol, and geranylgeraniol, suggesting a G-protein mediated signal transduction mechanism in the regulation of hIPS gene expression. hIPS mRNA expression is 50% suppressed by 10mM lithium ion in these cells [11].
• While the biochemical and phenotypic features including a thickened cell wall of hVISA and VISA are well known, the genetic basis of these phenotypes remains unknown [12].

Anatomical context of VISA

• In conclusion, we demonstrated a critical role of IPS-1, IRF3, and IFNbeta in Legionella infection of lung epithelium [2].
• NS3/4A binds to and colocalizes with MAVS in the mitochondrial membrane, and it can cleave MAVS directly in vitro [13].
• Human testis, ovary, heart, placenta, and pancreas express relatively high level of hIPS mRNA, while blood leukocyte, thymus, skeletal muscle, and colon express low or marginal amount of the mRNA [11].

Associations of VISA with chemical compounds

• Mutation of the critical cysteine 508 to alanine was sufficient to maintain mitochondrial localization of MAVS/IPS-1/VISA/Cardif and IKKepsilon in the presence of NS3-4A [10].
• Neither 5mM myo-inositol nor the three hormones: estrogen, thyroid hormone, and insulin altered hIPS mRNA expression in these cells [11].
• In the presence of glucose, hIPS mRNA level increases 2- to 4-fold in HepG2 cells. hIPS mRNA is also up-regulated 2- to 3-fold by 2.5 microM lovastain [11].
• On the other hand, infections caused by S. aureus with intermediate resistance to glycopeptides (VISA), or heterogeneously expressed intermediate level glycopeptide resistance (hVISA), are more common [12].
• New antibiotics such as linezolid and quinupristin/dalfopristin have good antistaphylococcal activity but are very expensive and should be reserved for patients who fail on or are intolerant of conventional therapy or who have highly resistant strains such as hVISA (heterogenous vancomycin-intermediate S aureus) [14].

Physical interactions of VISA

• Results indicate that LGP2 can inhibit antiviral signaling independently of dsRNA or virus infection intermediates by engaging in a protein complex with IPS-1 [15].

Other interactions of VISA

• TBK1 and IKKi protein kinases were required for the IPS-1-mediated interferon induction [16].
• Experiments suggest that LGP2 can compete with the kinase IKKi (also known as IKKepsilon) for a common interaction site on IPS-1 [15].
• In resting cells, RIG-I is maintained as a monomer in an autoinhibited state, but during virus infection and RNA binding it undergoes a conformation shift that promotes self-association and CARD interactions with the IPS-1 adaptor protein to signal IFN regulatory factor 3- and NF-kappaB-responsive genes [17].
• Finally, bacterial multiplication assays in small interfering RNA-treated cells indicated that IPS-1, IRF3, and IFNbeta were essential for the control of intracellular replication of L. pneumophila in lung epithelial cells [2].

Analytical, diagnostic and therapeutic context of VISA

• Clinicians and diagnostic laboratories need to be aware of VISA and hVISA as a clinical problem, and consider aggressive surgical debridement and non-glycopeptide-based therapy where infections with such strains are suspected or proven [18].

References