Nutritional sensitivity of periparturient immune responses to parasites in mammals

Lead Research Organisation: SRUC
Department Name: Research

Abstract

Because animals, including humans, are often exposed to parasites, they will eventually become resistant to them, i.e. they will develop an effective immunity. However, there are times in the life of animals that this immunity to parasites does not operate effectively. One such time is around giving birth, i.e. during late pregnancy and subsequent lactation, when immunity to parasites often breaks down. This is referred to as the periparturient relaxation of immunity (PPRI). The importance of PPRI has long been known, but why it occurs and how it can be manipulated is still poorly understood. Recent investigations in lactating rats, infected with the gut worm Nippostrongylus brasiliensis, have shown that poor protein nutrition increases worm numbers, which is indicative of increased PPRI. In this proposal, we aim to investigate how rat protein nutrition influences immune responses that are involved in PPRI. We will first test the effects of low vs high levels of protein nutrition on immune responses to N. brasiliensis during lactation at various time points. We need to do this because effects of nutrition on immunity may differ over time, and we need to ensure that for the rest of the proposal we take our measurements at the most appropriate time point. We will then test the effects of six different levels of protein (from low to high) in order to see how protein nutrition affects the immune responses at this time point. Effects of protein nutrition are by definition effects of its building blocks, the amino acids. There are about 20 amino acids, and some are called essential amino acids because they can not be synthesised in the body. Essential amino acids have to be provided by food, and we will focus our investigations on two essential amino acids that are found in high concentrations in the proteins that are associated with immunity to parasites, and on four amino acids that are known to influence immunity in general. The effects of these amino acids on the extent of PPRI will be investigated. Lastly, we will investigate how fast improved protein nutrition can restore immunity. The information derived from these experiments will help to increase our knowledge on how nutrition can affect immunity to parasites, which will be useful to control parasites with minimal use of drugs.

Technical Summary

Recent studies have shown that the periparturient relaxation of immunity (PPRI) to parasites may have a nutritional basis. At times of protein scarcity, an increase in protein supply and/or reduction in protein demand (through reduction in litter size) in Nippostrongylus brasiliensis re-infected lactating rats results in reduced parasite burdens. Here, we will use this model system to assess nutritional sensitivity of immune responses implicated in nutritional manipulation of PPRI. We will first assess effects of host protein nutrition on parasite expulsion and implicated immune responses during lactation. Initially, an array of Th2 responses will be assessed, including globlet cells, mucosal mast cells, eosinophils and globule leukocytes in small intestinal tissues, concentration of RMCP-II and antibodies in mucosal scrapings, and key Th2 cytokine responses. The immune responses identified as being most responsive to protein nutrition will then be assessed through stepwise increases in protein supply from low to high. Such a dose-response design will allow us to define the relationships between protein supply, degree of PPRI and selected immune responses. Since host responses to protein nutrition are by definition responses to amino acids, we will also assess which essential amino acids are implicated in the nutritional manipulation of PPRI. We will focus on two essential amino acids that are found in high concentrations in the proteins associated with immunity to N. brasiliensis, and four amino acids that are known to influence immunity in general. Last, we will assess at which rate immune responses can be restored through improved protein nutrition. This will be done through manipulating protein demand (litter size) rather than protein supply. The outcome of these studies could lead to the use of immunonutrition as a viable non-chemotherapeutical parasite control strategy. This has implications not only for farm animals, but also for human patients.

Publications

10 25 50
 
Description The consistently observed nutritional improvement of periparturient resistance in the Nippostrongylus brasiliensis re-infected lactating rat model correlated with mast cell hyperplasia, indicating that, in contrast to primary infections, mastocytosis plays a key role in expression of immunity during secondary infections.

This program of work has shown that periparturient expression of immunity to parasites is sensitive to protein scarcity and not to energy scarcity, and that humoral immune responses are less sensitive to protein scarcity than mastocytosis.

The essential amino acids leucine and methionine were key amino acids in maintaining periparturient resistance to parasites as induced by improved protein nutrition. This was identified through reducing the concentration of these amino acids in high protein diets
Exploitation Route Our results strongly suggests that mast cells are key mediators in worm expulsion during secondary infection, which contrasts to the commonly held view that these cells do not play a major role. This may therefore be a characteristic of the secondary immunie response, which indicates that the long held view about non-involvement of mast cells in worm expulsion is open for debate. Speculation on underlying reasons may be addressed in novel applications.

Our novel nutritional methodology to assess importance of specific amino acids in the immunoregulation of worm expulsion may now be used to establish the ideal protein composition for optimal immunity to nematode parasites.
Sectors Agriculture, Food and Drink,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Our findings have largely been used within the academic world in further understanding nutrition x immunity interactions. This has been materialized through an research grant (Blue Sky Research Award, Royal College of Veterinary Surgeons), which utilises gut tissue samples from this BBSRC grant. Micro-array experimentation and real time PCR validation have examined nutritional sensitivity of gene expression in host immunity to parasites. This has provided novel targets for further hypothesis driven research to further increase our understanding of the impact of nutrition on host immunity as a means to reduce reliance on chemoprophylaxis, which has resulted in a PhD program for Ms Aya Masuda, funded through the Japan Student Service Organisation (2012-2015). In addition, we have been able to align the work under this grant with the PhD studies of Mr Panagiotis Sakkas, with funding from the Hellenic State Scholarship Foundation (Greece; 2007-2010).
First Year Of Impact 2007
Sector Agriculture, Food and Drink,Healthcare
Impact Types Economic

 
Description Blue Sky Project Award
Amount £19,834 (GBP)
Organisation RCVS Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2008 
End 10/2010