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Meeting Report - EMBO workshop on Pathogen immunity and signaling 2022, in St Malo, France by Garima Joshi

The first session broadly covered pathogen immunity at organism level.

Andreas Bergthaler highlighted the role of systemic immunometabolism during viral infections. It is important to study metabolism linked to immunity as high energetic costs are associated with mounting an immune response. It has been shown that mice lose weight when infected while becoming anorectic and harboring a condition called wasting of fat, which display a shift from glucose metabolism to lipid. Genetic ablation of lipolysis in adipocytes results in impaired recovery of weight in mice upon LCMV infection, indicating the crucial role of lipolysis in clearing
In another very interesting talk, Maria Mittelbrunn delivered a presentation about the T cell metabolism during aging. Aging can be linked with chronic inflammation. Thymus is the first site of aging and its manipulation on our bodies. T cells from aged mice lose lymphoid homing capacity and also exhibit mitochondrial DNA damage. The research in her team has identified TFAM (mitochondrial transcription factor A) that promotes senescence in dysfunctional T cells. These cells can control organismal fitness as they are capable of accelerating multiple aging-related features, including metabolic, cognitive, physical, and cardiovascular alterations, which together result in premature death.

The second session focused on molecular mechanisms of immune signaling.

Mice with STING deletion are very similar to wild type but these have higher food intake, they consume more
energy and have higher thermogenesis. Therefore, Nadine Laguette’s team hypothesized that STING is an energy regulator in mice. In their research, they show that STING protein regulates metabolic homeostasis through inhibition of the fatty acid desaturase 2 (FADS2) rate-limiting enzyme in polyunsaturated fatty acid (PUFA) desaturation. STING ablation led to an increased FADS2-associated desaturase activity and in turn, accumulation of PUFA derivatives that drive thermogenesis. Their research shows that metabolic alterations in human pathologies can be linked with aberrant STING activation.
Jan Rehwinkel then gave a talk on the involvement of Z-nucleic acids in innate immunity. Pathogenic RNA/DNA are typically characterized by their altered location, nucleotide sequence, secondary structure and chemical modifications. Double-stranded RNA (involved in the replication of certain viruses) can adopt a Z conformation, which is a left-handed double helix with a zigzag-shaped phosphodiester back bone. Adenosine deaminase acting on RNA 1 (ADAR1) contains Z-RNA binding domains known useful in RNA-editing by conversion of adenosines to inosines in RNAs. A to I editing has two major roles: marking endogenous RNAs as “self”, therefore helping the innate immune system to distinguish repeat- and endogenous retrovirus-derived RNAs from invading pathogenic RNAs; and recoding the information of the coding RNAs, leading to the translation of proteins that differ from their genomically encoded versions. Given the embryonic lethality of Adar1p150/p150 mice, Jan’s team developed a a mouse model Adar1mZa/mZa that developed normally and were fertile. They found a spontaneous type I IFN response in Adar1mZa/mZa mice. They identified the activation of MDA5-MAVS pathway responsible for the ISG signature in Adar1mZa/mZa mice.

Lingyin Li explained how important it is to leverage the STING pathways in immunotherapies directed against cancer and viruses. Despite the production of aberrant cytosolic dsDNA, cancer cells produce very little interferon. In this case secreted cGAMP can be used to elicit anti-tumoral immunity via the cGAS-STING pathway. This therapy is now in clinical trial phase I. The identification of cGAMP carriers or transporters is crucial to realize the full potential of such therapies. The speaker’s team has identified SLC46A family of solute carriers as novel cGAMP transporters primarily in in human CD14+ monocytes. They also found that the M1- polarized intratumoral macrophages primarily respond to tumor-derived extracellular cGAMP.

Andreas Pichlmair, an expert of viral sensing, introduced dsRNA-binding TAO kinases (TAOKs) as novel immune regulators of viral nucleic acid-sensing. The main pattern recognition receptors (PRRs) involved in viral sensing are Toll-like receptors (TLRs), cytoplasmic RIG-I-like receptors (RLRs), cGAS, or AIM2-like receptors, leading ultimately to the expression of type-I and type-III (IFN-λ) interferons. Viral RNAs can also bind to proteins that can scavenge genetic material, act as co-receptors of PRRs or even enzymes. Their team performed affinity purifications of 17 different nucleic acids (NAs) in human, mouse and fly. They then identified cross-species-conserved NA interactors that retained antiviral properties throughout species evolution. They found dsRNA-binding TAO kinases with evolutionarily-conserved function in induction of immune response in flies and humans. Inhibition of TAOK2 led to a reduction of ISG expression and increases viral growth of Semliki Forest virus (SFV). Loss of TAOK2 affected IFN-α/β expression but had little effect on pro-inflammatory cytokines like IL-6, IL-8, and TNF in response to SFV. TRIM4, a known enhancer of RIG-I-dependent innate immune responses, was identified as binding partner of TAOK2.

Stem cells are increasingly being adopted in viral studies for their increased resemblance with primary cells. Enzo Z. Poirier presented his work on an alternatively spliced isoform of enzyme dicer called aviD (antiviral Dicer) which protects mammalian stem cells against multiple RNA viruses. AviD functions by cleaving long base-paired viral RNAs to generate small interfering RNAs. These segments guide the dicer to specifically cleave viral RNAs. Sindbis virus (SINV) or with Zika virus (ZIKV) are targets of antiviral RNAi in insects. AviD, but not Dicer, impaired the cleavage of dsRNA originating from these viruses. They corroborated these results in the stem cell model. Additionally, ZIKV titer was found to be higher in brain organoids that were aviD -/- than aviD +/+. Consequently, the higher ZIKV titer also resulted in a decreased area of the brain organoid.

Moritz M Gaidt, through his talk, described a ‘self-guarded’ immune pathway in human monocytes, in which guarding and guarded functions are united in one protein. IFN induction in response to transfected dsDNA depends entirely on STING, TBK1/IKKε or IRF3/7. However, IFN response to HSV-1 infection is not solely dependent on these factors, as the IFNB response does not change much upon knocking down these factors in the case of HSV-1 infected
monocytes. Their team observed an abrogation of IFN response in monocytes infected by ΔICP0 HSV-1. ICP0 is an essential protein for the lytic lifecycle of HSV-1. ICP0 was required for MORC3 (negative regulator of IFN) degradation during HSV-1 infection in monocytes. MORC3-pathway is therefore a novel innate immune sensing pathway that detects the activity of virulence factors from DNA viruses, such as ICP0 from HSV-1. To escape restriction, HSV-1 employs ICP0 to degrade MORC3. The secondary function of MORC3 to repress the MORC3-regulated DNA element (MRE), adjacent to the IFNB1 locus, allows induction of IFN upon viral attack on MORC3.