This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 2007-0413OCv1 39/4/431    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sampaio, E. P. Articles by Holland, S. M. Search for Related Content PubMed PubMed Citation Articles by Sampaio, E. P. Articles by Holland, S. M.

Mycobacterium abscessus and M. avium Trigger Toll-Like Receptor 2 and Distinct Cytokine Response in Human Cells

¹ Laboratory of Clinical Infectious Diseases, ³ Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases; and ⁴ Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland; and ² Leprosy Laboratory, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil

Corresponding author: Dr. Elizabeth Pereira Sampaio, M.D., Ph.D., Laboratory of Clinical Infectious Diseases, Immunopathogenesis Section, National Institutes of Health, NIAID, CRC B3-4141 MSC 1684, Bethesda, MD 20892-1684. E-mail: sampaioe{at}niaid.nih.gov

Mycobacterium avium (MAV) and M. abscessus (MAB) are ubiquitous environmental organisms increasingly recognized to cause chronic lung disease in patients with apparently normal immune function. Little is yet known about their human pathophysiology. Our objective was to examine cytokine and chemokine responses (protein and gene expression) and signaling pathways triggered by reference and clinical isolates of MAB and MAV in human peripheral blood mononuclear cells, monocytes, and murine bone marrow–derived macrophages in vitro. MAB-induced TNF- production was higher than that induced by MAV. IFN-, IL-1β, and the chemokines macrophage inflammatory protein-1 and regulated on activation, normal T cell expressed and secreted were equally up-regulated. Differences between MAB and MAV do not require replication and are heat stable. We found no differential effect due to rough or smooth colonies within the same species. Similar to MAV, MAB triggered mitogen-activated protein kinase (MAPK) signaling and nuclear factor-B translocation. Induction of TNF- was dependent on MAPK pathways, since pre-incubation of cells with signaling inhibitors led to more than 85% reduction in cytokine secretion. MAB also triggered a Toll-like receptor 2 (TLR2)-mediated response that led to TNF- production by human monocytes. Accordingly, stimulation of murine TLR2- or myeloid differentiation factor 88–deficient bone marrow–derived macrophages did not elicit TNF-, reinforcing a critical role for TLR2 in MAB-induced cell activation. We concluded that MAB signals human cells through MAPK and TLR2 pathways and triggers more pronounced pro-inflammatory cytokines and chemokines than MAV.

Key Words: tumor necrosis factor- • M. abscessus • M. avium • chemokines • Toll-like receptor 2

CLINICAL RELEVANCE This article demonstrates for the first time fundamental differences in the innate immunogenicity between Mycobacterium abscessus and M. avium in human cells, which may play roles in clinical prevalence and disease manifestations, and may impact treatment.