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Immediate IFNγ production determines host compatibility differences between Toxoplasma gondii and Neospora caninum in mice

Coombs, Rachel S. (2021) Immediate IFNγ production determines host compatibility differences between Toxoplasma gondii and Neospora caninum in mice. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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T. gondii parasitizes mammalian hosts indiscriminately and is adapted to survive in rodents which are critical for transmission of Toxoplasma gondii to the definitive feline host via predation. As described in Chapter 1, this relationship has been extensively studied as a model for immune responses to parasites, yet the molecular basis of this unique lack of host specificity is unknown. Neospora caninum provides a natural contrast to T. gondii, in that it is a closely related coccidian parasite of ruminants and canines, but is not naturally transmitted by rodents. In Chapter 2, we compared mouse innate immune responses to N. caninum or T. gondii and found marked difference in cytokine levels and parasite growth kinetics during the first 24 hours post-infection. N. caninum-infected mice produced significantly higher levels of IFNγ as early as 4hpi, but IFNγ was significantly lower in T. gondii-infected mice during the first 24hpi. “Immediate” IFNγ production was not detected in MyD88-/- mice. However, unlike IFNγ-/- mice, MyD88-/- mice survived N. caninum infections. Measures of parasite burden showed MyD88-/- mice were more susceptible to N. caninum infections than WT mice, and control of parasite burden correlated with serum IFNγ production 3-4 days after infection. Immediate IFNγ was partially dependent on the T. gondii mouse profilin receptor TLR11 but ectopic expression of N. caninum profilin in T. gondii had no impact on early IFNγ production or parasite proliferation. Our data indicate that T. gondii is capable of evading host detection during the first hours after infection while N. caninum is not, and this is likely due to early MyD88-dependent recognition of ligands other than profilin. In Chapter 3, we compared innate immune cell populations and determined that the frequency of IFNγ+ peritoneal natural killer T (NKT) cells 4hpi was significantly higher in N. caninum infections compared with T. gondii and uninfected mice. We identified two main populations of NKT cells producing IFNγ: CD3+ NKT and CD4+ NKT cells. In Chapter 4 we describe future work that will determine if T cells are required for immediate IFNγ production, and identify a role for CD1d-restricted NKT cells in this process.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Coombs, Rachel S.rsc30@pitt.edursc30
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBoyle, Jonboylej@pitt.eduboylej
Committee MemberBerman, Andreaajb190@pitt.eduajb190
Committee MemberRebeiz, Markrebeiz@pitt.edurebeiz
Committee MemberHildebrand, Jeffjeffh@pitt.edujeffh
Committee MemberHand, Timothyhandt@pitt.eduhandt
Date: 11 January 2021
Date Type: Publication
Defense Date: 26 August 2020
Approval Date: 11 January 2021
Submission Date: 3 December 2020
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 166
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Biological Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Neospora caninum, Toxoplasma gondii, innate immune response, parasite
Date Deposited: 11 Jan 2021 16:01
Last Modified: 20 Jan 2021 18:26


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