There are several types of unwanted RNA in the cytoplasm of a cell including viral RNAs, endogenous retroelements, mitochondrial RNAs and mRNAs with processing errors. When a cell detects these RNAs, it can target them for degradation, inhibit their translation or induce signal transduction pathways that activate pro-inflammatory and antiviral gene expression. Global RNA degradation, inhibition of cap-dependent translation and cell death pathways can also be activated. If these RNAs accumulate in the cytoplasm, they lead to several pathologies including autoimmune and neurodegenerative diseases.
Unwanted RNAs are detected by reader proteins that bind a specific molecular pattern. This pattern can be a linear RNA sequence, RNA structure or a combination of these elements. RNA modifications, such as N6-methyladenosine (m6A), can also promote or inhibit binding of reader proteins to RNA. Unwanted RNAs are enriched in dinucleotides (e.g. CpG or UpA), long exons, retained introns, double stranded RNA structures or the absence of RNA modifications (e.g. the 5’ cap structure on mRNAs). The full spectrum of reader proteins that recognise these patterns is unclear and how they recruit effector proteins for RNA decay, translation inhibition or signalling is poorly understood.
The Swanson lab is characterising how reader proteins recognise unwanted RNAs in the cytoplasm and regulate these transcripts, with a focus on viral RNAs and endogenous retroelements. One of the reader proteins that we are studying is zinc finger antiviral protein (ZAP), which restricts several RNA viruses that cause human disease as well as endogenous retroelements. ZAP interacts with other cellular proteins to form the ZAP antiviral system, and we are characterising two additional components of this system: the E3 ubiquitin ligase TRIM25, and the endonuclease KHNYN. In addition, we are studying how m6A RNA modifications modulate gene expression and viral replication. The Swanson lab uses a variety of experimental approaches to answer these questions including molecular biology and virology techniques, transcriptomics, proteomics and microscopy. Overall, we are characterising how cellular proteins recognise specific patterns in viral or cellular RNAs to target them for degradation or inhibit their translation to prevent them from promoting autoimmune or neurodegenerative diseases.
Current PhD student:
Projects

The ZAP antiviral system
In collaboration with Stuart Neil (KCL), Rui Pedro Galão (KCL), Jernej Ule (KCL) and Ian Taylor (Francis Crick Institute) Zinc finger antiviral protein (ZAP) is a cellular protein that inhibits the replication of many viruses. Viral RNA sequences containing clustered CpG dinucleotides are detected by ZAP, which targets these transcripts for decay and inhibits their translation. The frequency of CpG dinucleotides is supressed in many mammalian RNA viruses, potentially to avoid being targeted by ZAP. When CpG dinucleotides are introduced into diverse viruses such as picornaviruses, influenza A virus or HIV, they inhibit viral replication. Introduction of CpG dinucleotides into viral genomes using synthetic biology techniques may be a new way to develop live attenuated virus vaccines, but a full understanding of how ZAP and CpG dinucleotides inhibit viral replication is necessary to develop this approach. We are specifically characterising how ZAP distinguishes target RNAs and recruits effector proteins that mediate RNA decay or translation inhibition. ZAP interacts with several proteins including the E3 ubiquitin ligase TRIM25 and the endonuclease KHNYN to restrict viral replication, though how ZAP interacts with these proteins and how they regulate or mediate ZAP antiviral activity is still unclear. ZAP is downregulated in several types of cancer, and we are studying how it targets and regulates cellular RNAs. These RNAs may have evolved RNA sequences that mimic the molecular pattern of viral RNAs, and we are analysing the RNA sequence pattern that ZAP recognises in them. We are also characterising how ZAP regulates cellular gene expression and retroelement expression in neurons to determine how it may control transcripts that lead to neurodegenerative diseases. We are currently characterising the following questions for the ZAP antiviral system: 1. How do viral and cellular RNA sequences and structures affect ZAP binding? 2. What are the effector proteins recruited by ZAP to inhibit viral and cellular gene expression? 3. How does ZAP bind KHNYN, TRIM25 and other cofactors at atomic level resolution? 4. How do cellular proteins regulate ZAP activity through post-translational modifications? 5. How do ZAP, TRIM25 and KHNYN orthologs and paralogs regulate viral replication and cellular gene expression?

Regulation of viral replication and cellular gene expression by m6A RNA modifications
In collaboration with Michelle Holland (KCL) RNA modifications are critical regulators of gene expression and cellular function. Over 150 different RNA modifications have been detected in cellular RNAs and the function of only a few of these is known. A methyl modification of adenosine, N6-methyladenosine (m6A), is the most abundant internal modification of cellular mRNAs and is also found in viral RNAs. By modulating RNA-protein interactions and RNA structures, it can control cell differentiation and viral replication. It is also implicated in cancer and can regulate tumour progression. However, how it regulates cellular gene expression and viral replication is unclear. We are characterising how m6A modifications modulate influenza virus, HIV and SARS-CoV-2 replication. The specific questions we are studying are: 1. Which cellular mRNAs are modified by m6A, which sites in the mRNA are modified, how frequently are these sites modified, and does this change when a virus infects a cell? 2. Which m6A reader proteins control the antiviral response? 3. Which effector proteins are recruited by these reader proteins and which steps of gene expression do they control? 4. Do m6A modifications regulate the expression of antiviral proteins and does this prevent their overexpression, which could lead to tissue damage?
Publications
Activities

We welcome A-level students to visit the Swanson lab from 1-10 days. Parents and carers can contact Dr Chad Swanson directly. In addition, we participate in the In2ScienceUK programme.
Hearing HIV
Chad Swanson collaborated with composer Benjamin Oliver to create ‘The Virus Within: Hearing HIV’. This was funded and supported by the Medical Research Council (MRC), King’s College London Teaching Centre of Immunology, University of Southampton Music Department and Guy’s Chapel (with special thanks to Revd Jim Craig).
The Virus Within: Hearing HIV is a three-movement composition that musically depicts the biological processes involved in HIV replication and how innovative ‘Shock and Kill’ treatments might provide a cure for HIV. The musical materials undergo conceptually similar processes or transformations that occur at the molecular and cellular level. It was premiered at Guy’s Chapel by Workers Union Ensemble in February 2018. To listen to each movement, click on the titles below.
- ‘Integration’ depicts the reverse transcription of viral RNA into DNA followed by the viral DNA integrating into a person’s genome.
- ‘Gene Expression’ consists of four main sections that musically embody HIV gene expression and protein production in a single cell.
- ‘Shock and Kill’ highlights how research focused on HIV gene regulation can potentially be translated into a cure for HIV.
Projects

The ZAP antiviral system
In collaboration with Stuart Neil (KCL), Rui Pedro Galão (KCL), Jernej Ule (KCL) and Ian Taylor (Francis Crick Institute) Zinc finger antiviral protein (ZAP) is a cellular protein that inhibits the replication of many viruses. Viral RNA sequences containing clustered CpG dinucleotides are detected by ZAP, which targets these transcripts for decay and inhibits their translation. The frequency of CpG dinucleotides is supressed in many mammalian RNA viruses, potentially to avoid being targeted by ZAP. When CpG dinucleotides are introduced into diverse viruses such as picornaviruses, influenza A virus or HIV, they inhibit viral replication. Introduction of CpG dinucleotides into viral genomes using synthetic biology techniques may be a new way to develop live attenuated virus vaccines, but a full understanding of how ZAP and CpG dinucleotides inhibit viral replication is necessary to develop this approach. We are specifically characterising how ZAP distinguishes target RNAs and recruits effector proteins that mediate RNA decay or translation inhibition. ZAP interacts with several proteins including the E3 ubiquitin ligase TRIM25 and the endonuclease KHNYN to restrict viral replication, though how ZAP interacts with these proteins and how they regulate or mediate ZAP antiviral activity is still unclear. ZAP is downregulated in several types of cancer, and we are studying how it targets and regulates cellular RNAs. These RNAs may have evolved RNA sequences that mimic the molecular pattern of viral RNAs, and we are analysing the RNA sequence pattern that ZAP recognises in them. We are also characterising how ZAP regulates cellular gene expression and retroelement expression in neurons to determine how it may control transcripts that lead to neurodegenerative diseases. We are currently characterising the following questions for the ZAP antiviral system: 1. How do viral and cellular RNA sequences and structures affect ZAP binding? 2. What are the effector proteins recruited by ZAP to inhibit viral and cellular gene expression? 3. How does ZAP bind KHNYN, TRIM25 and other cofactors at atomic level resolution? 4. How do cellular proteins regulate ZAP activity through post-translational modifications? 5. How do ZAP, TRIM25 and KHNYN orthologs and paralogs regulate viral replication and cellular gene expression?

Regulation of viral replication and cellular gene expression by m6A RNA modifications
In collaboration with Michelle Holland (KCL) RNA modifications are critical regulators of gene expression and cellular function. Over 150 different RNA modifications have been detected in cellular RNAs and the function of only a few of these is known. A methyl modification of adenosine, N6-methyladenosine (m6A), is the most abundant internal modification of cellular mRNAs and is also found in viral RNAs. By modulating RNA-protein interactions and RNA structures, it can control cell differentiation and viral replication. It is also implicated in cancer and can regulate tumour progression. However, how it regulates cellular gene expression and viral replication is unclear. We are characterising how m6A modifications modulate influenza virus, HIV and SARS-CoV-2 replication. The specific questions we are studying are: 1. Which cellular mRNAs are modified by m6A, which sites in the mRNA are modified, how frequently are these sites modified, and does this change when a virus infects a cell? 2. Which m6A reader proteins control the antiviral response? 3. Which effector proteins are recruited by these reader proteins and which steps of gene expression do they control? 4. Do m6A modifications regulate the expression of antiviral proteins and does this prevent their overexpression, which could lead to tissue damage?
Publications
Activities

We welcome A-level students to visit the Swanson lab from 1-10 days. Parents and carers can contact Dr Chad Swanson directly. In addition, we participate in the In2ScienceUK programme.
Hearing HIV
Chad Swanson collaborated with composer Benjamin Oliver to create ‘The Virus Within: Hearing HIV’. This was funded and supported by the Medical Research Council (MRC), King’s College London Teaching Centre of Immunology, University of Southampton Music Department and Guy’s Chapel (with special thanks to Revd Jim Craig).
The Virus Within: Hearing HIV is a three-movement composition that musically depicts the biological processes involved in HIV replication and how innovative ‘Shock and Kill’ treatments might provide a cure for HIV. The musical materials undergo conceptually similar processes or transformations that occur at the molecular and cellular level. It was premiered at Guy’s Chapel by Workers Union Ensemble in February 2018. To listen to each movement, click on the titles below.
- ‘Integration’ depicts the reverse transcription of viral RNA into DNA followed by the viral DNA integrating into a person’s genome.
- ‘Gene Expression’ consists of four main sections that musically embody HIV gene expression and protein production in a single cell.
- ‘Shock and Kill’ highlights how research focused on HIV gene regulation can potentially be translated into a cure for HIV.