Elucidating the immunomodulatory mechanisms of the KSHV protein vOX2

CD200 is a transmembrane protein with known immunoregulatory activities exerted via its receptor, CD200R. The Kaposi’s sarcoma associated-herpesvirus (KSHV) ORF K14 lytic cycle gene product, vOX2, shares 36% protein identity with cellular CD200. Both vOX2 and CD200 ligate CD200R with similar affinity. The main aim of this project was to determine whether vOX2 and CD200 regulate the function of human leukocytes. Thus, vOX2, CD200 and an inactive KSHV protein KCPmut were fused to the Fc region of human IgG1. vOX2:Fc and CD200:Fc exerted no effect upon isolated neutrophils, but suppressed granulocyte oxidative activity in whole blood by up to 25%. B lymphoblastoid cells were engineered to express full-length vOX2 or CD200 and utilized as antigen-presenting cells for Epstein Barr Virus-specific human T cell clones. vOX2 and CD200 suppressed IFNγ production by up to 50% in seven CD8$^+$ CD200R$^+$ T cell clones and one CD4$^+$ CD200R$^+$ clone. Mechanistically, vOX2 and CD200 suppressed the phosphorylation of ERK1/2, p38 and Akt kinases. This is the first evidence of a role for both cellular CD200 and KSHV vOX2 in negatively modulating antigen-specific T cell activity. The negative regulation of T cells by vOX2 probably contributes to KSHV evasion of antigen-specific T cell responses during lytic replication

Targeted Nasal Vaccination Provides Antibody-Independent Protection Against Staphylococcus aureus

Despite showing promise in preclinical models, anti-Staphylococcus aureus vaccines have failed in clinical trials. To date, approaches have focused on neutralizing/opsonizing antibodies; however, vaccines exclusively inducing cellular immunity have not been studied to formally test whether a cellular-only response can protect against infection. We demonstrate that nasal vaccination with targeted nanoparticles loaded with Staphylococcus aureus antigen protects against acute systemic S. aureus infection in the absence of any antigen-specific antibodies. These findings can help inform future developments in staphylococcal vaccine development and studies into the requirements for protective immunity against S. aureu

Suppression of antigen-specific T cell responses by the Kaposi's sarcoma-associated herpesvirus viral OX2 protein and its cellular orthologue, CD200

Regulating appropriate activation of the immune response in the healthy host despite continual immune surveillance dictates that immune responses must be either self-limiting and therefore negatively regulated following their activation or prevented from developing inappropriately. In the case of antigen-specific T cells, their response is attenuated by several mechanisms, including ligation of CTLA-4 and PD-1. Through the study of the viral OX2 (vOX2) immunoregulator encoded by Kaposi's sarcoma-associated herpesvirus (KSHV), we have identified a T cell-attenuating role both for this protein and for CD200, a cellular orthologue of the viral vOX2 protein. In vitro, antigen-presenting cells (APC) expressing either native vOX2 or CD200 suppressed two functions of cognate antigen-specific T cell clones: gamma interferon (IFN-γ) production and mobilization of CD107a, a cytolytic granule component and measure of target cell killing ability. Mechanistically, vOX2 and CD200 expression on APC suppressed the phosphorylation of ERK1/2 mitogen-activated protein kinase in responding T cells. These data provide the first evidence for a role of both KSHV vOX2 and cellular CD200 in the negative regulation of antigen-specific T cell responses. They suggest that KSHV has evolved to harness the host CD200-based mechanism of attenuation of T cell responses to facilitate virus persistence and dissemination within the infected individual. Moreover, our studies define a new paradigm in immune modulation by viruses: the provision of a negative costimulatory signal to T cells by a virus-encoded orthologue of CD200

Assessing groundwater quality: a global perspective: importance, methods and potential data sources

The paper is prepared in the framework of the World Water Quality Assessment led by UN Environment (UNEP) and was presented at the 2nd annual global meeting of the World Water Quality Alliance 27-28 January 2021