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T cell plasticity and co-infections in mycobacterial diseases.

Monin Aldama, Leticia (2015) T cell plasticity and co-infections in mycobacterial diseases. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The genus Mycobacterium comprises a variety of organisms, of which only a few are pathogenic, causing diseases of varying nature and severity. Despite this diversity, it is well established that CD4+ T helper type 1 (Th1) cells are instrumental in generating effective anti- mycobacterial immune responses. In addition, Th17 cells are required for mucosal vaccine recall responses. In this work, we studied T cell plasticity and how cytokine defects or co-infections that skew the immune response to a predominantly Th2 or Th17 type, can affect the outcome of primary and recall responses to mycobacterial infections. We explored the plasticity of Mycobacterium tuberculosis (Mtb)-specific Th responses, showing that Mtb-specific Th1 and Th17 cells can acquire the cytokine secretion patterns of other Th subsets. In a vaccination setting, where Mtb-specific Th17 cells are required for protection, we studied the requirements for Mtb control following Th17 transfer. Firstly, we found that upon re-exposure to Mtb antigen, Th17 cells were plastic and required external signaling via IL-23 and CXCR5 expression for protection. Surprisingly, IFN-γ−deficient Th17 cells conferred enhanced protection against Mtb. Together, our data suggest that optimizing vaccine strategies to boost CXCR5 and IL-23 expression, while limiting IFN-γ production, may enhance vaccine efficacy. In countries with poorly developed infrastructure, Mtb is often co-endemic with helminth infections. Thus, using a model helminth organism (Schistosoma mansoni), we assessed whether helminth co-infection or antigens impact T cell plasticity during Mtb infection. Our data show that helminth infection enhances arginase expression in macrophages within the lung, reduces Th1 responses and diminishes Mtb control. Importantly, antihelminthic treatment of co-infected mice was sufficient for restoring T cell responses and reducing inflammation, suggesting that T cell modulation is reversible. In addition, we determined the effect of Aspergillus fumigatus co-infection on Mycobacterium abscessus (Mabs), which is an emerging pathogen in cystic fibrosis.
Interestingly, we found that A.fumigatus alleviated Mabs-induced lung pathology in a mouse model. Future studies will establish if modulation of Th1 and Th17 commitment toward a regulatory phenotype underlies the decreased inflammation. Together, our results provide novel information on the dynamic interplay between host genetics, competing host responses to parasitic and fungal antigens and Mtb co-infection.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Monin Aldama, Leticialem83@pitt.eduLEM83
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKhader, Shabaana
Committee CoChairKolls, Jay K.jay.kolls@chp.eduJKK23
Committee MemberRay, Anuradharaya@pitt.eduRAYA
Committee MemberBomberger, Jennifer M.jbomb@pitt.eduJBOMB
Committee MemberOury, Tim Dtdoury@pitt.eduTDOURY
Date: 18 August 2015
Date Type: Publication
Defense Date: 29 June 2015
Approval Date: 18 August 2015
Submission Date: 17 July 2015
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 177
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Immunology, Tuberculosis, Schistosoma, Mycobacteria, co-infection
Date Deposited: 18 Aug 2015 12:11
Last Modified: 19 Dec 2016 14:42


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