Understanding the relationship between host tolerance-resistance to multiple pathogen challenge

Abstract

A host has only two distinctive defence strategies that it can employ when it encounters a pathogen invasion. The first strategy, resistance, is the ability to clear the pathogen. The second strategy, tolerance, is the ability to limit the pathogen's impact on host fitness. Therefore, the relationship between host defence strategies is subjected to correlational selection, which should support combinations of resistance and tolerance (high resistance-low tolerance, low resistance-high tolerance, or immediate values for both).

Although several studies have generated significant knowledge on animal resistance and tolerance, these were limited to single pathogen infection when naturally host is infected with multiple pathogen infection. Therefore, this PhD aimed to investigate further the relationship between resistance and tolerance in a mice model harbouring multiple pathogen challenges.

This thesis focuses on the helminth-virus model using Heligmosomoides bakeri and Theiler’s Murine Encephalomyelitis Virus (TMEV) to create the co-infection. Chapter 2 is focusing on quantifying the impact of the order of co-infection (H-V or V-H) on the resistance and tolerance of susceptible mice infected with the two pathogens. The data showed that co-infection (Co-inf) in H-V as opposed to V-H order, resulted in mice showing a more resistant and tolerant phenotype compared to those infected with a single parasite infection (H. bakeri-only). Chapter 3 characterises the phenotypic variation in the resistance to the two pathogens during the H-V co-infection in mice from different genotypes. The data demonstrated that Co-inf improved susceptible mice's resistance response but reduced intermediate mice's resistance response. During this experimental study, parameters such as performance and carcass weight were recorded to estimate tolerance in Chapter 4. In line with the resistance against H. bakeri, tolerance against H. bakeri follows similar directions. It was found that Co-inf enhanced the tolerance response against nematode infection in the susceptible mice but suppressed the tolerance response of the intermediate mice. On the other hand, Co-inf reduced the tolerance against virus infection in the susceptible and resistant mice but increased the tolerance of the intermediate strain. Chapter 5 investigates the underlying gene expression and immune mechanisms of the genetically different mice during co-infection, showing that not only did Co-inf modify Th1-Th2 balance but also influenced Tregs, resulting in different phenotypic responses. The data from this thesis, discussed all together in Chapter 6, suggest that the order of co-infection and the genetic background of the host are essential in quantifying host defence strategies to multiple pathogen infection.