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Sharma, Parul (2019) The mechanism of age-related immunity in cattle. PhD thesis, University of Nottingham.

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Abstract

The present study attempted a cellular and transcriptomatic approach to investigate the age-related immune response in cattle during intra-cellular protozoan infection. Neospora caninum is an obligate intracellular protozoan parasite that causes abortion and negative economic impacts in cattle worldwide. It is important to understand the protective immune mechanisms in response to N. caninum infection and develop an effective and safe vaccine for cattle. There are limited studies available that directly address the age-related immune difference during N. caninum. The immune response during N. caninum infection is Th1 based and mediated by high expression of pro-inflammatory cytokines; most importantly interleukin 12 (IL-12), interferon gamma (IFN-γ) and nitric oxide (NO) by immune cells predominantly macrophages. Monocytes are pivotal due to the link they form between the innate and adaptive immune response and are one of the first immune cells encountered by intra-cellular parasites during infection.

This study investigating the leukocytes profile of neonates (2 week old) and adult cattle (2-3 year old) by flow cytometry. Data shown suggests that neonates had a significant higher percentage of CD14+ monocytes with higher expression of CD80 cell surface markers. Additionally, these data demonstrated an age-related alteration in granulocytes, T and B cell populations across neonates and adult cattle. The monocyte function was compared between young (6 month old) and adult cattle in response to lipopolysaccharide (LPS), IFN-γ, a combination of both and aluminium hydroxide (Alum). These data confirmed monocytes from young cattle have a higher level of secretion of IL-6, IL-1β and tumor necrosis factor alpha (TNF-α) and caspase 1 activity than adult derived monocytes.

Furthermore, this study attempted to resolve if this age-related difference was maintained in the context of an in vitro infection with N. caninum infection. The number of parasitized monocytes was determined after infection or co-culture with autologous natural killer (NK) cells. CD80 expression was determined as a marker of cellular activation by flow cytometry.

These results reveal monocytes from adult cattle harbour a higher number of parasites compared to neonates; additionally, a greater reduction of parasitaemia was observed in neonates with a higher level of cytokines IL-1β and IL-6 during N. caninum infection. However, NK cells from neonates and adult did not display much difference in cytotoxic activity, measured through perforin and granzyme B production after co-culture with N. caninum infected monocytes.

To complement this gene array analysis was also performed which suggests that during infection, neonates have 535 significantly upregulated genes (>2 fold) compared to adults that showed only 23 upregulated genes (>2 fold). Interestingly, only two genes were common in both groups. Further, common biological pathways that involved in the immune response were evaluated and both age groups showed changes in the upregulation of tyrosine phosphorylation of STAT protein and JAK-STAT cascade pathways. These results also indicate a greater magnitude of immune response and a more complex network of upregulated genes in neonates. Overall these comparisons show that there is a fundamental difference in the immune response of neonates and adult cattle during steady-state and in the response to intra-cellular parasite infection in neonatal monocyte led inflammatory responses.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Egan, Sharon Flynn, Robin Emes, Richard
Keywords:	Intra-cellular protozoan infection; Protective immune mechanisms; Inflammatory responses; N. caninum
Subjects:	S Agriculture > SF Animal culture
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Veterinary Medicine and Science
Item ID:	53836
Depositing User:	SHARMA, PARUL
Date Deposited:	19 Jul 2019 04:40
Last Modified:	07 May 2020 12:00
URI:	https://eprints.nottingham.ac.uk/id/eprint/53836

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