Publication Date

2014-05-15

Availability

Embargoed

Embargo Period

2016-05-14

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Microbiology and Immunology (Medicine)

Date of Defense

2014-04-22

First Committee Member

Rebecca D. Adkins

Second Committee Member

Kurt R. Schesser

Third Committee Member

Wasif N. Khan

Fourth Committee Member

Gregory E. Conner

Fifth Committee Member

Maria T. Abreu

Abstract

It is becoming increasingly apparent that neonates are not immune-compromised, but rather immune-variant. We have described a neonatal model of Yersinia enterocolitica infection in which protective inflammation occurs at the level of the mesenteric lymph nodes (MLN). The expression of pro-inflammatory, but not anti-inflammatory, cytokine genes was markedly induced in the neonatal MLN early after infection. Strikingly, the expression levels in neonates greatly exceeded those seen in infected adults. Elevated pro-inflammatory gene expression was quickly followed by enhanced innate phagocyte recruitment to the MLN of neonates, compared to adults. Neither CD4+ nor B cells were required for inflammation in the neonatal MLN; however, CD4+ and CD8+ cells did increase as well as innate cells as early as 24 hours post-infection. Although MyD88 was shown to be critical in eliciting inflammation in neonates, neither TLR4 nor TLR9 were required. Because Y. enterocolitica contains ligands for multiple TLRs, it is possible that compensation by other TLRs is sufficient to elicit inflammation in the absence of TLR4 or TLR9. Bacterial components were also critical in eliciting high level inflammation in the neonatal MLN. The virulence plasmid of Y. enterocolitica was required for selected pro-inflammatory gene expression and neutrophil recruitment to the neonatal MLN. TNF-alpha protein expression and neutrophil recruitment was markedly enhanced in the neonatal MLN after infection with the delta-yopP strain, while only a modest increase occurred in adults. These models suggest that the level of intestinal inflammation in neonates is critical in determining whether protection or pathology occurs following infection with microbial pathogens.

Keywords

neonates; Yersinia enteroclitica; innate immunity; mesenteric lymph node

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