Defining the immunological basis of infection susceptibility in cerebral ischaemia and its relevance in injury

UoM administered thesis: Phd

  • Authors:
  • Siddharth Krishnan

Abstract

Ischaemic stroke results from the occlusion of vessels in cerebrovasculature, causing the loss of blood flow which deprives the brain of oxygen and glucose, leading to the death of neurones and glia. In addition to the induction of functional deficits, stroke also leads to infectious complications such as pneumonia and urinary tract infections (UTI) in the acute phase that hinder optimal recovery and increase morbidity and mortality. By employing established immunological tools, high-dimensional analyses and transcriptomics we aimed to determine the basis of increased infection susceptibility post-stroke. Specifically, we investigated the effects of stroke on systemic immunity in a clinical setting and using a model of experimental stroke. We also sought to understand the relevance of the immune response to injury in the context of stroke. In a clinical setting, we demonstrated that stroke could impair T cell priming by disrupting the balance of monocyte subsets, altering classical monocyte surface phenotype (increased CD14 and decreased HLA-DR) whilst simultaneously decreasing the frequencies of non-classical monocytes and dendritic cell subsets in the circulation. By using an infection-free model of experimental stroke, we illustrated that stroke elicited tissue-specific alterations in systemic immunity and dissociated the effects of infection on systemic immunity from those imposed by stroke. Critically, we illustrated that experimental stroke also elicited global alterations to the surface phenotype of classical Ly6Chi monocytes 72 h post-injury by conferring them with a CD62LhiCX3CR1lowMHCIIlow status, reminiscent of the HLA-DRlow phenotype observed clinically. We determined the functional consequence of alterations in the surface phenotype of classical monocytes in the context of stroke by taking a reductionist approach and used a model of incisional skin wounding. We showed that a surgical skin wound can educate Ly6Chi monocytes which are identified by decreased CX3CR1 expression and that this occurred prior to their egress from the bone marrow through complex alterations in myelopoiesis, affecting only direct monocyte progenitors via signals from the sympathetic nervous system (SNS). Moreover, CX3C1lowLy6Chi monocytes were transcriptionally distinct from CX3CR1hi counterparts with a diminished capacity to respond to interferon signalling and activated a transcriptional programme that could predispose them to an alternatively activated state as they transitioned from the bone marrow and into circulation. Taken together, our work presents a new paradigm in which stroke could functionally educate Ly6Chi monocytes for repair prior to tissue entry through neurogenic input from the SNS which could preclude them from taking on anti-microbial functions. Whether this ability in itself constitutes immune suppression remains to be determined. Regardless, further research on how neuronal signals modulate immune function in health and disease could open new avenues for targeted therapies.

Details

Original languageEnglish
Awarding Institution
Supervisors/Advisors
Award date31 Dec 2018