Graham, Andrea

Allen, Judith

Fairlie-Clarke, Karen Jane

Biotechnology and Biological Sciences Research Council (BBSRC)

Princeton programme grant

University of Edinburgh

2012-01-18T09:59:30Z

2012-01-18T09:59:30Z

2011-11-24

The socio-economic and geographical distribution of malaria overlaps with that of many parasitic helminths and in these areas co-infections are common. Co-infection with helminths can influence disease outcome causing either exacerbation or amelioration of malaria. Understanding the complex host-parasite interactions that lead to these different disease outcomes is important for the success of control programmes aimed at these parasites. The immune system has evolved diverse types of response (e.g. T-helper 1 (Th1) and T-helper 2 (Th2)) to efficiently combat infection with ‘microparasites’ and helminths respectively. When faced with co-infection however, the need for the host to multitask means it must manage these counter-regulatory responses. In this study a murine model of malaria-hookworm (Plasmodium chabaudi- Nippostrongylus brasiliensis) co-infection was utilised to investigate how changes in T-helper bias affect malaria disease outcome. Antibody isotypes were used as indicators of Th1/Th2 bias and revealed that helminth co-infection reduced the malaria-specific Th1 response. Counter-intuitively this resulted in ‘protection’ from malaria with co-infected mice having reduced peak P. chabaudi parasitaemia and suffering less severe anaemia. In addition to providing a measure of Th1/Th2 bias, analysis of antibody responses revealed the occurrence of cross-reactive antibodies. The potential for these crossreactive antibodies to influence disease outcome was investigated but in this murine model resource-mediated mechanisms of parasite regulation appear to be responsible for the ‘protection’ that co-infection affords. The question of why cross-reactive antibodies are produced has important immunological and ecological implications. Cross-reactive responses may arise through some physiological constraint on the immune mechanisms that usually result in antibody-specificity. However experiments designed to investigate if the specificity of antibodies is constrained by availability of antigen suggest that this is not the case in the model system used here. There is also the possibility that production of cross-reactive antibodies represents an evolutionary optimal strategy for a host faced with unpredictable exposure to a variety of parasites. However a major finding of this study indicates these two taxonomically distinct parasite species share antigens, which in itself is crucial to understanding host-parasite interactions in a co-infection setting. The main findings of this thesis are relevant to co-infection studies in general and the implications for both evolutionary and applied biology are discussed.

http://hdl.handle.net/1842/5727

en

The University of Edinburgh

Hoeve MA, Mylonas KJ, Fairlie-Clarke KJ, Mahajan SM, Allen JE, Graham AL: Plasmodium chabaudi limits early Nippostrongylus brasiliensis-induced pulmonary immune activation and Th2 polarization in co-infected mice. BMC Immunol 2009, 10:60.

Fairlie-Clarke KJ, Shuker DM, Graham AL: Why do adaptive immune responses cross-react?. Evolutionary Applications 2009, 2(1):122-131.

Fairlie-Clarke et al.: Antibody isotype analysis of malaria-nematode co-infection: problems and solutions associated with cross-reactivity. BMC Immunology 2010 11:6.

malaria

parasitic helminths

helminths

microparasites

cross-reactive antibodies

antigens

Th1/Th2

Significance of cross-reactive antibody responses and isotype bias in malaria- helminth co-infection

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy