Submitted to: Infection and Immunity
Publication Type: Peer reviewed journal
Publication Acceptance Date: 7/16/2006
Publication Date: 10/29/2006
Citation: Motiwala, A.S., Janagama, H.K., Paustian, M., Zhu, X., Bannantine, J.P., Kapur, V., Sreevatsan, S. 2006. Comparative Transcriptional Analysis of Human Macrophages Exposed to Animal and Human Isolates of Mycobacterium avium Subspecies paratuberculosis with Diverse Genotypes. Infection and Immunity.74(11):6046-6056. Interpretive Summary: The bacterium Mycobacterium avium subsp. paratuberculosis (M. paratuberculosis) causes Johne’s Disease, an economically important intestinal infection of ruminants such as cattle and sheep. A better understanding of how this bacterium is able to initially infect animals is needed in order do develop better vaccine and treatment options for livestock producers. This study examined the response of macrophage immune cells to M. paratuberculosis isolates obtained from a human, cow, and sheep as well as an isolate of the closely related bacterium Mycobacterium avium subsp. avium (M. avium). The results indicated that many pro-inflammatory genes were activated in response to M. avium and the sheep isolate of M. paratuberculosis, but not the other M. paratuberculosis isolates. This indicates that the genetic differences observed among isolates of this bacterium directly affect the host animal response to infection. Other scientists should find these results useful as they develop future studies designed to understand how M. paratuberculosis is able to infect cattle, sheep, and other animals.
Technical Abstract: Interactions between Mycobacterium avium subsp. paratuberculosis and host macrophages represent critical early events in the pathogenesis of Johne’s disease. We present here a genome-wide characterization of the transcriptional changes within macrophages in responses to different genotypes of M. paratuberculosis isolated from various hosts. We identified several differentially expressed host genes during intracellular stages of infection, including those that are involved in common canonical pathways such as NF-kB, IL-6, MAPK/ERK, JNK signaling and several pro-inflammatory cytokines and chemokine receptors, T helper type 1 (Th1) responses such as CCL5 ligand. The bovine and human isolates of M. paratuberculosis with identical genotypes induced similar global gene expression patterns and differentially regulated genes necessary for cell survival without major alterations in pro-inflammatory genes. In striking contrast, the sheep isolates with diverse genotypes closely resembled an M. avium avium isolate in its global gene expression pattern and significantly up regulated pro-inflammatory genes related to IL-6, T cell receptor, B cell receptor and death receptor signaling within THP-1 cells. Additionally, quantitative RT-PCR analysis of 7 differentially expressed genes in response to diverse genotypes of bovine (n = 2), human (n = 1), sheep (n = 2), and bison (n = 1) showed consistency within infecting genotypes regardless of the source. Bison isolate induced different expression levels compared with bovine or human isolates but followed the common anti inflammatory, anti apoptotic trend. Our data suggests that the macrophage response to M. paratuberculosis isolates from cattle and human sources regardless of genotypes follow a common theme of anti-inflammatory responses an attribute likely associated with successful infection and persistence. However, these expression patterns induced by human and bovine isolates differ significantly from THP-1 cells infected with the sheep M. paratuberculosis strain or the M avium isolate. These data provide a transcriptional basis for a variety of pathophysiological changes observed during early stages of infection by different strains of M. paratuberculosis, a first step in understanding trait-allele association in this economically important disease.