Defining the molecular pathways governing antiviral Natural Killer Cell Immunity

Natural Killer (NK) cells are important effector cells for control of cytomegalovirus (CMV) infection. Understanding the mechanisms which contribute to antiviral control by NK cells may inform on the development of safe and effective treatments for viral infection such as NK cell-based therapies. The first aim of this thesis was to identify genes required for control of cytomegalovirus replication using an in vivo MCMV infection screen. Several genes of interest which affected acute viral replication control were discovered from the in vivo screen including Fam111a, Fam114a2, Far1, Heatr9, Serpinb9b and Sytl3. The second aim was to examine how gene(s) of interest regulate NK cell functions. The novel gene Synaptotagmin-like 3 (Sytl3) was chosen for further investigation as it was almost exclusively expressed by mouse (and human) NK cells and Sytl3 deficiency led to a significant impairment in MCMV replication control. Members of the sytl family have been implicated in vesicular trafficking events due to their ability to bind Rab27 proteins which are important in secretory pathways (Taruho S. Kuroda et al., 2002). Interestingly, Sytl3 deficient NK cells had reduced degranulation in response to a variety of stimuli and my studies revealed that sytl3 may drive microtubule organising centre (MTOC) polarisation towards the immunological synapse, which is a key step for efficient degranulation. Therefore, this work provides novel insight into NK cell effector function whereby optimal degranulation in response to MCMV (and possibly other stimuli) contributes to the effective control of acute viral infection

A multivariable Mendelian randomization analysis investigating smoking and alcohol consumption in oral and oropharyngeal cancer

The independent effects of smoking and alcohol in head and neck cancer are not clear, given the strong association between these risk factors. Their apparent synergistic effect reported in previous observational studies may also underestimate independent effects. Here we report multivariable Mendelian randomization performed in a two-sample approach using summary data on 6,034 oral/oropharyngeal cases and 6,585 controls from a recent genome-wide association study. Our results demonstrate strong evidence for an independent causal effect of smoking on oral/oropharyngeal cancer (IVW OR 2.6, 95% CI = 1.7, 3.9 per standard deviation increase in lifetime smoking behaviour) and an independent causal effect of alcohol consumption when controlling for smoking (IVW OR 2.1, 95% CI = 1.1, 3.8 per standard deviation increase in drinks consumed per week). This suggests the possibility that the causal effect of alcohol may have been underestimated. However, the extent to which alcohol is modified by smoking requires further investigation

Neutrophilia, lymphopenia and myeloid dysfunction: A living review of the quantitative changes to innate and adaptive immune cells which define COVID-19 pathology

Destabilisation of balanced immune cell numbers and frequencies is a common feature of viral infections. This occurs due to, and further enhances, viral immune evasion and survival. Since the discovery of the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), which manifests in coronavirus disease 2019 (COVID-19), a great number of studies have described the association between this virus and pathologically increased or decreased immune cell counts. In this review, we consider the absolute and relative changes to innate and adaptive immune cell numbers, in COVID-19. In severe disease particularly, neutrophils are increased, which can lead to inflammation and tissue damage. Dysregulation of other granulocytes, basophils, and eosinophils represent an unusual COVID-19 phenomenon. Contrastingly, the impact on the different types of monocytes leans more strongly to an altered phenotype, e.g. HLA-DR expression, rather than numerical changes. However, it is the adaptive immune response which bears the most profound impact of SARS-CoV-2 infection. T cell lymphopenia correlates with increased risk of ICU admission and death; therefore, this parameter is particularly important for clinical decision making. Mild and severe disease differ in the rate of immune cell counts returning to normal levels post disease. Tracking the recovery trajectories of various immune cell counts may also have implications for long-term COVID-19 monitoring. This review represents a snapshot of our current knowledge, showing that much has been achieved in a short period of time. Alterations in counts of distinct immune cells represent an accessible metric to inform patient care decision or predict disease outcomes

The role and uses of antibodies in COVID-19 infections: a living review

Coronavirus disease 2019 has generated a rapidly evolving field of research, with the global scientific community striving for solutions to the current pandemic. Characterizing humoral responses towards SARS-CoV-2, as well as closely related strains, will help determine whether antibodies are central to infection control, and aid the design of therapeutics and vaccine candidates. This review outlines the major aspects of SARS-CoV-2-specific antibody research to date, with a focus on the various prophylactic and therapeutic uses of antibodies to alleviate disease in addition to the potential of cross-reactive therapies and the implications of long-term immunity

T cell phenotypes in COVID-19 - a living review

COVID-19 is characterized by profound lymphopenia in the peripheral blood, and the remaining T cells display altered phenotypes, characterized by a spectrum of activation and exhaustion. However, antigen-specific T cell responses are emerging as a crucial mechanism for both clearance of the virus and as the most likely route to long-lasting immune memory that would protect against re-infection. Therefore, T cell responses are also of considerable interest in vaccine development. Furthermore, persistent alterations in T cell subset composition and function post-infection have important implications for patients’ long-term immune function. In this review, we examine T cell phenotypes, including those of innate T cells, in both peripheral blood and lungs, and consider how key markers of activation and exhaustion correlate with, and may be able to predict, disease severity. We focus on SARS-CoV-2-specific T cells to elucidate markers that may indicate formation of antigen-specific T cell memory. We also examine peripheral T cell phenotypes in recovery and the likelihood of long-lasting immune disruption. Finally, we discuss T cell phenotypes in the lung as important drivers of both virus clearance and tissue damage. As our knowledge of the adaptive immune response to COVID-19 rapidly evolves, it has become clear that while some areas of the T cell response have been investigated in some detail, others, such as the T cell response in children remain largely unexplored. Therefore, this review will also highlight areas where T cell phenotypes require urgent characterisation