Immunity
Immune antagonism may explain negative associations between parasites susceptible to similar immune responses or environments.C.hepaticum shows negative associations with S.dispersa , which may be due to Th1-type responses exhibited during earlyC.hepaticum infection (Kim, Joo, & Chung, 2007) negatively impacting Sarcocystis sp. infection.
Immune antagonism may also explain the negative association betweenT.muris and S.obvelata . Similar associations are observed in mice artificially infected with the pinworm Aspiculuris teraptera , which suffered reduced T. muris burdens (Keeling, 1961). The steady increase in T. muris prevalence associated with age and high prevalence of low-level infection in this population may be indicators of T. muris establishing chronic infections, which are characterised by immunosuppression of protective Th2 responses and polarisation to a Th1 environment in infection models (Artis, Potten, Else, Finkelman, & Grencis, 1999; Else, Hültner, & Grencis, 1992). This is in contrast to T. muris infections observed in other wild rodents, in which burdens increase with age (Behnke, Lewis, Zain, & Gilbert, 1999), and Trichuris distributions observed in humans, in which burdens spike during early life, then decrease to a steady low level (Bundy, Cooper, Thompson, Didier, & Simmons, 1987; Faulkner et al., 2002; Needham et al., 1992). S. obvelata prevalence shows no significant association with age, indicating that parasite clearance and possible reinfection could be the norm. Induction of Th2 responses byS. obvelata could disrupt the immunosuppressive environment established by T. muris , negatively impacting its abundance (Moreau & Chauvin, 2010).
Immune facilitation or suppression may contribute to the positive association between C.hepaticum and Bartonella sp.Polarisation to a Th2 environment observed during some stages of theC.hepaticum life cycle (Kim et al., 2007) could reduce protective immunity to microparasites, which are typically characterised by Th1-type responses (Arvand, Ignatius, Regnath, Hahn, & Mielke, 2001; Kabeya et al., 2007; Karem, Dubois, McGill, & Regnery, 1999). A positive association between C. hepaticum and Bartonella elizabethae was reported in the brown rat (Rattus norvegicus ), though this was based upon an unusual increase in pathology observed in one coinfected individual (Kamani, Akanbi, Baneth, Morrick, & Harrus, 2013).
Peripheral impacts of immunomodulation could be playing a role in the association between C.hepaticum and T.muris . Jackson et al (2009) found positive associations between C. hepaticum and the intestinal nematode Heligmosomoides polygyrus in wild wood miceApodemus sylvaticus, associated with reduced innate immune responses. In rats artificially infected with C.hepaticum , Th1/2 polarisation is observed, with IL-5 (Th2) increasing as the worms matured, and IFNγ (Th1) peaking during egg deposition (Kim et al., 2007). Systemic polarisation to a Th1 environment during C. hepaticum egg deposition could improve survival of T. muris . Moon et al (2017) observed a protective immune response to infection against C. hepaticum and a similar hepatic nematodeClonorchis sinensis in laboratory rats, characterised by eosinophilia and lymphocyte proliferation. The interaction observed in this population may, therefore, alternatively be mediated by an immunosuppressive effect on the part of T. muris , favouringC. hepaticum survival. (Kim et al., 2007).
Associations observed with ectoparasites are less well defined in this population, and less well characterised from laboratory models. Inflammation in the skin may contribute to protection against parasitic arthropods (Moats, Baxter, Pate, & Watson, 2016), and the dermal tissue has been recognised as a site of important immune activity (Kupper, 1990). Th2-type responses have been detected in response to ectoparasite infection (Burgess et al., 2010; Wikel & Alarcon-Chaidez, 2001), which may polarise away from the Th1-type response observed in earlyC.hepaticum infection, and contribute to a positive association between C.hepaticum and mite burden. (Kim et al., 2007).
Pre-existing immune environments within the host, determined by factors other than infection and not accounted for in this study, such as genetics, predispose individuals to susceptibility to or protection against infection. Cross-reactivity between antigens of different nematode species has been observed in both mice and humans (Lillywhite, Bundy, Didier, Cooper, & Bianco, 1991; Nieuwenhuizen et al., 2013; Roach, Wakelin, Else, & Bundy, 1988), and so modulations to the immune environment caused by one helminth may impact the survival of other species.