Selected publications

• Cooney Rachel, Baker Jonathan, Brain Oliver, Pichulik T, Danis B, Ferguson DJP, Campbell BJ, Jewell DP, and Simmons Alison (2009) NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nature Medicine.

• Hodges Ashleigh, Sharrocks Katherine, Edelmann Mariola, Baban Dilair, Moris Arnaud, Schwartz Olivier, Drakesmith Hal, Davies Kay, Kessler Benedikt, McMichael Andrew, and Simmons Alison (2007) Activation of the lectin DC-SIGN induces an immature dendritic cell phenotype triggering Rho-GTPase activity required for HIV-1 replication. Nat Immunol, 8(6):569-77.

• Simmons Alison, Gangadharan Bevin, Hodges Ashleigh, Sharrocks Katherine, Prabhakar Sripadi, Garcia Angel, Dwek Raymond, Zitzmann Nicole, and McMichael Andrew (2005) Nef-mediated lipid raft exclusion of UbcH7 inhibits Cbl activity in T cells to positively regulate signaling. Immunity, 23(6):621-34.

• Cebere Inese, Dorrell Lucy, McShane Helen, Simmons Alison, McCormack Sheena, Schmidt Claudia, Smith Carol, Brooks Mary, Roberts Joanna E, Darwin Simon C, Fast Patricia E, Conlon Christopher, Rowland-Jones Sarah, McMichael Andrew J, and Hanke Tomas (2006) Phase I clinical trial safety of DNA- and modified virus Ankara-vectored human immunodeficiency virus type 1 (HIV-1) vaccines administered alone and in a prime-boost regime to healthy HIV-1-uninfected volunteers. Vaccine, 24(4):417-25.

• Simmons A, Aluvihare V, and McMichael A (2001) Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators. Immunity, 14(6):763-77.

Dr Alison Simmons

Research Overview

We are interested in defining molecular aspects of innate immune recognition that govern the nature of the subsequent adaptive immune response normally, or in infectious or inflammatory disease. Specifically we are interested in how innate immune receptors decode information from ligands they encounter, be it self-antigen, commensals or pathogens and translate this to a correctly targeted immune response.

HIV-1

Early events in HIV-1 infection

We are examining the earliest events in HIV-1 infection to understand how HIV-1 gains an initial foothold in the immune cells it encounters and subverts their function to allow persistent infection and latency. Dendritic cells (DCs) are one of the first cells HIV-1 encounters at mucosal surfaces during sexual transmission. HIV-1 enters DCs via the pathogen recognition receptor and C-type lectin DC-SIGN and triggers a signaling path that mimics that of DC-SIGN, involving activation of the Rho guanine nucleotide exchange factor Leukemia associated Rho GEF (LARG) or ARHGEF12. This process is required for successful HIV-1 infection of DCs and affects the efficiency of formation of the infectious synapse between DCs and T cells. The signaling path activated by DC-SIGN in DCs contrasts with that induced by other PRRs in that DCs retain an immature phenotype, failing to upregulate co-stimulatory molecules and anti-viral response genes, or inflammatory cytokines but preferentially inducing IL-10. 
Current work involves defining how HIV-1 subverts DC function via this signal in more detail including examination of the effect of microRNAs differentially expressed on HIV-1 infection of DCs, proteomic analysis of subcellular compartments hijacked by HIV-1 within DCs and further dissection of HIV-1 signaling within monocte derived DCs or gut tissue DC subsets.

HIV-1 infection in the gut

The gastrointestinal tract has been estimated to house the bulk of lymphoid tissue in the body and in recent years it has been shown the bulk of HIV-1 replication, persistence and CD4+ T cell depletion occurs in the gut of HIV-1 infected subjects. CD4+ T cells play a critical role in HIV-1 infection as they are both infected by HIV-1 but are required to mount an effective antiviral response. CD4+ T cells in the gut undergo depletion from the earliest stages of disease but the mechanisms by which this occurs is unclear. We are analyzing subsets of gut mucosal cells using large scale gene expression profiling and proteomic techniques to understand how the general activation stage of these cells might contribute to HIV-1 mediated CD4+ T cell depletion at this site.

Function of individual HIV-1 genes

Other work in the lab involves dissecting the function of HIV-1 genes in particular Nef and more recently Integrase. We are using proteomic techniques combined with subcellular fractionation to define Integrase function within the HIV-1 preintegration complex during HIV-1 infection of primary CD4+ T cells.

IBD/Crohn’s disease

Function of CD susceptibility genes

Crohns disease is an inflammatory disease of the gastrointestinal tract involving a dysregulated immune response to the gut microbiota. Twin studies, amongst others, indicate CD involves a genetic component and the nature of this is a subject of intense study.  GWAS and linkage studies have revealed candidate susceptibility genes for CD that account for a proportion of the genetic risk. The most strongly associated of these is NOD2, an intracellular PRR expressed in monocyte lineage, intestinal epithelial cells and Paneth cells.  NOD2 variants associated with CD are mutated in the ligand recognition domain. NOD2 recognizes both MDP, an integral component of bacterial cell walls and single stranded RNA. We have found NOD2 activation induces autophagy in DCs in a manner requiring another CD susceptibility gene ATG16L1. CD NOD2 variants fail to induce autophagy on MDP stimulation, which affects their ability to handle bacteria correctly and present antigen.
Currently we are exploring the molecular nature of NOD2 signaling and cross-talk with other PRRs using microarray profiling and a new method of phosphoproteomics developed in the lab and in collaboration with Dr Benedikt Kessler.  NOD2 appears to control signaling thresholds of other PRRs and regulates a series of positive and negative regulators of inflammation whose expression is largely abrogated in the presence of mutant NOD2. The effect of this on inflammatory responses and maintanance of mucosal integrity is being explored.

Microbiome and immune system cross-talk

We are undertaking molecular analysis of microbiomes of healthy individuals or CD patients to identify changes in microbiome gene expression in different contexts. These changes are being studied for their effect on PRR signaling thresholds and inflammatory changes in gut mucosal cells.

Molecular stratification of the Oxford IBD cohort

We have developed a method of high throughput susceptibility genotyping of IBD patients (in collaboration with Oxford Gene Technology) for their full complement of known susceptibility variants that is currently being used to stratify the Oxford CD cohort to guide identification of new molecular biomarkers within subsets of patients for use in pharmacogenetic studies.