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"Understanding the mechanism of increased susceptibility to Mycobacterium tuberculosis infection in helminth coinfected hosts"

by
Jillian Dietzold
Microbiology and Molecular Genetics Program
B.S., 2005, Montclair State University, Montclair, NJ



Thesis Advisor: Padmini Salgame, Ph.D.
Professor
Department of Medicine

Wednesday, August 12, 2015
2:00pm, MSB C600


Abstract

Previously, we reported that Nippostrongylus brasiliensis (Nb), an intestinal helminth, exacerbates Mycobacterium tuberculosis (Mtb) disease in coinfected BALB/c mice through the generation of alternatively activated (M2) macrophages. In order to gain further mechanistic insight, we determined whether host genetic factors contributed to disease exacerbation in coinfected animals. To investigate this possibility, coinfection experiments were performed in C57BL/6 mice. In contrast to the enhanced susceptibility observed in the BALB/c mice, coinfected C57BL/6 mice were able to control Mtb burden that was comparable to mice infected with Mtb alone, despite the induction of a Th2 response. A comparative gene expression analysis between Nb-infected BALB/c and C57BL/6 mice demonstrated that the lung milieu prior to Mtb infection is starkly different between the two genotypes. BALB/c mice exhibited a stronger Th2 response and a gene expression profile consistent with increased iron availability by the macrophages in the lung. Consistent with this, in in vitro experiments we found that M1 Macs have an iron storage phenotype such that there is restricted access to iron by intracellular Mtb whereas in M2 Macs free iron is accessible to intracellular Mtb. Because Mtb requires iron for intracellular growth, these findings implicate dissimilarity in iron handling by M1 and M2 Macs as the operant mechanism leading to enhanced Mtb growth in M2 Macs in coinfected animals. Additionally we found that Mtb residing in M2 macrophages are less susceptible to treatment with antimicrobials. Overall these data provide a better understanding of how helminth coinfections modulate TB disease severity and treatment outcome.


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