Alhallaf, Rafid Abdulwahid (2018) Regulation of immunity and inflammation during parasitic helminth infection by inflammasomes. PhD thesis, James Cook University.

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Abstract

More than 1.5 billion people, or 24% of the world's population, are infected with helminths worldwide. Infections are highly epidemic in tropical and subtropical areas, with the greatest numbers occurring in sub-Saharan Africa, the Americas, China and East Asia. Helminths are strongly immunomodulatory, which has facilitated their ability to resist attack by their host's immune system, which has made attempts to vaccinate against parasitic helminths an enormous challenge. In order to develop a vaccine, we need to understand more about the nature of the protective immune response against helminths, and how helminths have evolved to control the host immune system to enable their survival.

Inflammasomes are important for immunity against invading microbial pathogens such as bacteria, viruses and protozoa by promoting the maturation and secretion of inflammatory cytokines such as IL-18 and IL-1β and resultant Type 1-mediated immunity. However, the roles for inflammasomes in Type 2 immunity to parasitic helminths are less well studied. Therefore, this dissertation has focused on studying the roles of distinct inflammasome activation pathways (NLR Family Pyrin Domain Containing (NLRP3 and NLRP1) in immunity and inflammation following infections with multiple species of gastrointestinal helminth. Firstly, we show that intestinal whipworm infection, Trichuris muris, and its excretory/secretory proteins can promote NLRP3-dependent IL-18 and IL-1β secretion in vivo and in vitro, in concert with signals from bacteria. Critically, we have identified a novel mechanism by which NLRP3-dependent IL-18 suppresses innate and adaptive immune responses to T. muris, resulting in immunopathology and more persistent infections. This suggest that worm-mediated NLRP3 inflammasome activation is one potential mechanism of how parasitic worms may enhance their survival in their host. We next assessed whether NLRP3 plays a similar or different role in regulation of immunity to a different species of parasite helminth, Nippostrongylus brasiliensis, a model of hookworm that infects both the lung and intestine. Similar to results we observed with whipworm infections, N. brasiliensis infections promoted NLRP3-dependent increases in IL-18 and IL-1β levels in the lungs and gut and ablation of NLRP3 resulted in increased anti-parasitic immunity in the lung. NLRP3-deficient mice displayed marked increases in neutrophil recruitment to the lung, a cell type that is potently toxic to parasite larvae. Thus we demonstrate that NLRP3 may restrain anti-parasitic neutrophil responses within the lung. Lastly, we investigated for the first time the role for a distinct inflammasome regulator, NLRP1, in immunity to a parasitic helminth. We found that NLRP1 does suppress immunity to both T. muris and N. brasiliensis infection in a similar way to NLRP3, however NLRP3 appears to play a greater role in regulating innate immunity to N. brasiliensis, in particular.

Together these data provide novel insights into the activating and regulatory pathways of both the innate and adaptive immune systems following gastro-intestinal helminth infections. By understanding the precise mechanism of how inflammasomes regulate immunity and inflammation following helminth infection, it may help inform the development of novel vac vaccines against human infections.

Item ID:	57435
Item Type:	Thesis (PhD)
Keywords:	helminths, tropics, immunity, inflammasomes, whipworms, Trichuris muris, hookworms
Related URLs:	https://researchonline.jcu.edu.au/56690/
Copyright Information:	Copyright © 2018 Rafid Abdulwahid Alhallaf
Additional Information:	Publications arising from this thesis are available from the Related URLs field. The publications are: Chapter 2: Alhallaf, Rafid, Agha, Zainab, Miller, Catherine M., Robertson, Avril A.B., Sotillo-Gallego, Javier, Croese, John, Cooper, Matthew A., Masters, Seth L., Kupz, Andreas, Smith, Nicholas C., Loukas, Alex, and Giacomin, Paul R. (2018) The NLRP3 inflammasome suppresses protective immunity to gastrointestinal helminth infection. Cell Reports, 23 (4). pp. 1085-1098.
Date Deposited:	13 Mar 2019 22:23
FoR Codes:	06 BIOLOGICAL SCIENCES > 0605 Microbiology > 060599 Microbiology not elsewhere classified @ 33% 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110799 Immunology not elsewhere classified @ 34% 11 MEDICAL AND HEALTH SCIENCES > 1103 Clinical Sciences > 110399 Clinical Sciences not elsewhere classified @ 33%
SEO Codes:	97 EXPANDING KNOWLEDGE > 970111 Expanding Knowledge in the Medical and Health Sciences @ 50% 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920199 Clinical Health (Organs, Diseases and Abnormal Conditions) not elsewhere classified @ 50%
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