Dissertation
Toll-like receptor 2 (TLR2) and cathelicidin-related anti-microbial peptide (CRAMP) as critical regulators of immune responses in neonatal IAV infection
Doctor of Philosophy (Ph.D.), Drexel University
Oct 2024
DOI:
https://doi.org/10.17918/00010758
Abstract
Respiratory viral infections are a leading cause of morbidity and mortality in infants, particularly preterm neonates, due to their immunological immaturity and distinct immune responses. To determine developmental factors in the neonatal susceptibility to infection, we established a 3-day old neonatal mouse influenza A virus (IAV) model. Pretreatment with intranasal Lactobacillus rhamnosus GG (LGG) prior to IAV infection significantly improved neonatal survival by activating the innate immune system via pattern recognition receptors (PRRs), with Toll-like receptor 2 (TLR2) playing a key role. TLR2-deficient (TLR2-/-) neonates demonstrated enhanced survival; a finding mirrored in conditional myeloid-specific TLR2 knockouts. Analysis of bronchoalveolar lavage fluid showed reduced pro-inflammatory cytokines, chemokines and cellular infiltrate in the conditional knockout model. Additionally, neutrophil depletion and anti-TLR2 antibody treatment in wild-type neonates further improved survival, highlighting the harmful impact of TLR2-driven inflammation during IAV infection. LGG treatment also led to the downregulation of cathelicidin-related antimicrobial peptide (CRAMP), a critical immune effector protein. CRAMP-deficient neonates showed better survival, suggesting that CRAMP amplifies the innate immune response and contributes to increased mortality as the infection progresses in WT neonates. These findings underscore the crucial roles of TLR2 and CRAMP in shaping immune responses during IAV infection in neonates. Targeting TLR2 and modulating CRAMP levels may offer promising therapeutic strategies to protect this vulnerable population from respiratory viral infections.
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Details
- Title
- Toll-like receptor 2 (TLR2) and cathelicidin-related anti-microbial peptide (CRAMP) as critical regulators of immune responses in neonatal IAV infection
- Creators
- Abhishek S. Rao
- Contributors
- Michele Kutzler (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiii, 187 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991021970901204721