Accession Number:

ADA459045

Title:

Characterization and Function of the Inflammatory Response to Infection by a Gastrointestinal Nematode Parasite: New Insights into Protective Th2 Responses

Descriptive Note:

Doctoral thesis

Corporate Author:

UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF MICROBIOLOGY AND IMMUNOLOGY

Personal Author(s):

Report Date:

2006-01-01

Pagination or Media Count:

114.0

Abstract:

Effective immune responses to infectious diseases involve appropriate primary and secondary reactions mediating host protection. Th2 effector mechanisms leading to host-protection remain elusive. Using an infectious model employing a nematode parasite, Heligmosomoides polygyrus, we characterized the immune cell infiltrate surrounding invasive larval parasites in the small intestinal muscosa and submucosa hostparasite interface during early stages of a secondary infection. A primary is chronic, with established adult parasites detectable up to four months post infection, where as the parasites are naturally cleared from the intestinal lumen by 14 days follow challenge. This distinction between primary and secondary H. polygyrus infections allows a clear readout of protective immunity, making this infectious model useful for examining protective secondary Th2 responses. A distinct and highly reproducible leukocyte architecture developed by the fourth day post challenge, which included CD4 T cells surrounding the parasite. Additionally, laser capture microdissected LCM samples from the hostparasite interface featured upregulated Th2 cytokine mRNAs relative to untreated intestinal tissue. This localized inflammatory response differed during primary infection, as CD4 T cells did not infiltrate the hostparasite interface, and there were no increases in cytokine expression. These findings were extended to show that the peripheral inflammation during the memory Th2 response at the hostparasite interface is essential for host-protection leading to worm expulsion. Memory CD4 T cells that express Th2 cytokines rapidly accumulate around the invading parasite and induce the alternative activation of macrophages. Alternatively activated macrophages metabolize the amino acid, arginine, by the enzyme arginase-1. Our findings demonstrate that macrophages and arginase contribute to the natural clearance of a secondary H. polygyrus infection.

Subject Categories:

  • Medicine and Medical Research
  • Microbiology

Distribution Statement:

APPROVED FOR PUBLIC RELEASE