Virus Host Interaction Team

August 12, 2020

Acta Neuropathol Commun​ (2020) 8(1):135.     doi: 10.1186/s40478-020-01011-7.

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Progressive multi-focal leukoencephalopathy (PML) is a potentially fatal encephalitis caused by JC polyomavirus (JCV). PML principally affects people with a compromised immune system, such as patients with multiple sclerosis (MS) receiving treatment with natalizumab. However, intrathecal synthesis of lipid-reactive IgM in MS patients is associated with a markedly lower incidence of natalizumab-associated PML compared to those without this antibody repertoire. Here we demonstrate that a subset of lipid-reactive human and murine IgMs induce a functional anti-viral response that inhibits replication of encephalitic Alpha and Orthobunyaviruses in multi-cellular central nervous system cultures. These lipid-specific IgMs trigger microglia to produce IFN-β in a cGAS-STING-dependent manner, which induces an IFN-α/β-receptor 1-dependent antiviral response in glia and neurons. These data identify lipid-reactive IgM as a mediator of anti-viral activity in the nervous system and provide a rational explanation why intrathecal synthesis of lipid-reactive IgM correlates with a reduced incidence of iatrogenic PML in MS.

August 10, 2020

PLoS Pathogens (2020) 16(8):e1008716.  

doi: 10.1371/journal.ppat.1008716.

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Pandemic influenza A virus (IAV) remains a significant threat to global health. Preparedness relies primarily upon a single class of neuraminidase (NA) targeted antivirals, against which resistance is steadily growing. The M2 proton channel is an alternative clinically proven antiviral target, yet a near-ubiquitous S31N polymorphism in M2 evokes resistance to licensed adamantane drugs. Hence, inhibitors capable of targeting N31 containing M2 (M2-N31) are highly desirable. Rational in silico design and in vitro screens delineated compounds favouring either lumenal or peripheral M2 binding, yielding effective M2-N31 inhibitors in both cases. Hits included adamantanes as well as novel compounds, with some showing low micromolar potency versus pandemic "swine" H1N1 influenza (Eng195) in culture. Interestingly, a published adamantane-based M2-N31 inhibitor rapidly selected a resistant V27A polymorphism (M2-A27/N31), whereas this was not the case for non-adamantane compounds. Nevertheless, combinations of adamantanes and novel compounds achieved synergistic antiviral effects, and the latter synergised with the neuraminidase inhibitor (NAi), Zanamivir. Thus, site-directed drug combinations show potential to rejuvenate M2 as an antiviral target whilst reducing the risk of drug resistance.

July 20, 2020

Journal of General Virology​  (2020)   doi: 10.1099/jgv.0.001472.

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Some free fatty acids derived from milk and vegetable oils are known to have potent antiviral and antibacterial properties. However, therapeutic applications of short- to medium-chain fatty acids are limited by physical characteristics such as immiscibility in aqueous solutions. We evaluated a novel proprietary formulation based on an emulsion of short-chain caprylic acid, ViroSAL, for its ability to inhibit a range of viral infections in vitro and in vivo. In vitro, ViroSAL inhibited the enveloped viruses Epstein-Barr, measles, herpes simplex, Zika and orf parapoxvirus, together with Ebola, Lassa, vesicular stomatitis and severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) pseudoviruses, in a concentration- and time-dependent manner. Evaluation of the components of ViroSAL revealed that caprylic acid was the main antiviral component; however, the ViroSAL formulation significantly inhibited viral entry compared with caprylic acid alone. In vivo, ViroSAL significantly inhibited Zika and Semliki Forest virus replication in mice following the inoculation of these viruses into mosquito bite sites. In agreement with studies investigating other free fatty acids, ViroSAL had no effect on norovirus, a non-enveloped virus, indicating that its mechanism of action may be surfactant disruption of the viral envelope. We have identified a novel antiviral formulation that is of great interest for the prevention and/or treatment of a broad range of enveloped viruses, particularly those of the skin and mucosal surfaces.

February 23, 2018

J Biol Chem. 2018 Feb 23;293(8):3003-3012.

Chemokines are the principal regulators of leukocyte migration and are essential for initiation and maintenance of inflammation. Atypical chemokine receptor 2 (ACKR2) binds and scavenges proinflammatory CC-chemokines, regulates cutaneous T-cell positioning, and limits the spread of inflammation in vivo Altered ACKR2 function has been implicated in several inflammatory disorders, including psoriasis, a common and debilitating T-cell-driven disorder characterized by thick erythematous skin plaques. ACKR2 expression is abnormal in psoriatic skin, with decreased expression correlating with recruitment of T-cells into the epidermis and increased inflammation. However, the molecular mechanisms that govern ACKR2 expression are not known. Here, we identified specific psoriasis-associated microRNAs (miRs) that bind ACKR2, inhibit its expression, and are active in primary cultures of human cutaneous cells. Using both in silico and in vitro approaches, we show that miR-146b and miR-10b directly bind the ACKR2 3'-UTR and reduce expression of ACKR2 transcripts and protein in keratinocytes and lymphatic endothelial cells, respectively. Moreover, we demonstrate that ACKR2 expression is further down-regulated upon cell trauma, an important trigger for the development of new plaques in many psoriasis patients (the Koebner phenomenon). We found that tensile cell stress leads to rapid ACKR2 down-regulation and concurrent miR-146b up-regulation. Together, we provide, for the first time, evidence for epigenetic regulation of an atypical chemokine receptor. We propose a mechanism by which cell trauma and miRs coordinately exacerbate inflammation via down-regulation of ACKR2 expression and provide a putative mechanistic explanation for the Koebner phenomenon in psoriasis.

August 25, 2016

Shams K, Wilson GJ, Singh M, van den Bogaard EH, Le Brocq ML, Holmes S, Schalkwijk J, Burden AD, McKimmie CS, Graham GJ.

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Journal of Investigative Dermatology 

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In this paper Clive helped Dr. Kave Shams to study the role of ACKR2 in psoriasis. The results have important implications for the understanding of the impact of spatial restriction on the spread of inflammatory lesions and highlight systemic ACKR2 induction as a therapeutic strategy in the treatment and prevention of psoriasis and potentially a broad range of other immune-mediated diseases.

The picture shows migration of T cells in the presence of CCL5 and ACKR2-expressing keratinocytes. 

September 13, 2014

Michlmayr, D., McKimmie, C. S*., Pingen, M., Haxton, B., Mansfield K., Johnson N., Fooks A.R., Graham G.J.

*co-corresponding author.   

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Journal of Virology

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This paper by Daniela Michlmayr, in collaboration with Gerry Graham, defines the mechanism by which inflammatory leukocytes enter the virus infected brain.  Blockade of the chemokine pathways involved prevented leukocyte entry and counter-intuitively helped increase survival to an otherwise lethal infection.

Picture shows T cells (brown) infiltrating the meninges

May 01, 2013

McKimmie, C. S., Singh, M. D., Hewit, K., Lopez-Franco, O., Le Brocq, M., Rose-John, S., Lee K.M., Baker A.H., Wheat R., Blackbourn D.J., Nibbs R.J., Graham G.J.

Blood

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This paper demonstrates that the atypical chemokine receptor ACRK2 (formally called D6) prevents inappropriate associations between lymphatic vessels and inflammatory myeloid cells and immature dendritic cells. Interestingly, the HIV associated Karposi sarcoma demonstrates exceptionally high ACKR2 expression, which likely acts to suppresses inflammatory chemokine responses. Pictured is a lymphatic vessel stained in red (podoplanin) and green (ACKR2/D6).

December 01, 2011

Lee, K. M., McKimmie, C. S*., Gilchrist, D. S., Pallas, K. J., Nibbs, R. J., Garside, P., McDonald V., Jenkins C., Ransohoff R., Liu L., Milling S., Cerovic V., Graham G.J.

*co-first author

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Blood

Here we show that the atypical chemokine receptor ACKR2 (D6) acts in vivo to control interactions between stromal lymphatic endothelial cells and inflammatory leukocytes. Without ACKR2, lymphatics can become congested and overloaded with inflammatory leukocytes such as immature dendritic cells and myeloid cells, resulting in edema.  Importantly, this results in a reduced migration of dendritic cells from inflamed sites to the draining lymph node, which may have consequences for the proper initiation of adaptive immune responses. 

Pictured is a lymphatic vessel (yellow) that lacks ACKR2 expression and consequently becomes decorated with inflammatory immature dendritic cells (red and green)

December 01, 2009

McKimmie, C. S., Moore, M., Fraser, A. R., Jamieson, T., Xu, D., Burt, C., Pitman N.I., Nibbs R.J., McInnes I.B., Liew F.Y., Graham G.J.

Blood

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Here we show that systemic administration of an inflammatory TLR2 ligands can counter-intuitively prevent the development of psoriasis-like inflammation in the skin. We demonstrate that TLR2 ligands alter the ability of leukocytes to respond to chemotactic cues that would otherwise guide them to inflamed skin, and instead redirect their migration to lymphoid tissue. Picture shows lymphatic cells and leukocytes in co-culture for display purposes.