MyD88-dependent changes in the pulmonary transcriptome after infection withChlamydia pneumoniae

Abstract

, an intracellular bacterium, causes pneumonia in humans and mice. Toll-like receptors and the key adaptor molecule myeloid differentiation factor-88 (MyD88) play a critical role in inducing immunity against this microorganism and are crucial for survival. To explore the influence of MyD88 on induction of immune responses in vivo on a genome-wide level, wildtype (WT) or MyD88 Ϫ/Ϫ mice were infected with C. pneumoniae on anesthesia, and the pulmonary transcriptome was analyzed 3 days later by microarrays. We found that the infection caused pulmonary cellular infiltration in WT but not MyD88 Ϫ/Ϫ mice. Furthermore, it induced the transcription of 360 genes and repressed 18 genes in WT mice. Of these, 221 genes were not or weakly induced in lungs of MyD88 Ϫ/Ϫ mice. This cluster contains primarily genes encoding for chemokines and cytokines like MIP-1␣, MIP-2, MIP-1␥, MCP-1, TNF, and KC and other immune effector molecules like immunoresponsive gene-1 and TLR2. Arginase was highly induced after C. pneumoniae infection and was MyD88 dependent. Genes induced by interferons were abundant in a cluster of 102 genes that were only partially MyD88 dependent. Also, lcn2 (lipocalin-2) and timp1 were represented within this cluster. Interestingly, a set of 37 genes including sprr1a was induced more strongly in MyD88 Ϫ/Ϫ mice, and most of them are involved in the regulation of cellular replication. In summary, ex vivo analysis of the pulmonary transcriptome on infection with C. pneumoniae demonstrated a major impact of MyD88 on inflammatory responses but not on interferon-type responses and identified MyD88-independent genes involved in cellular replication.

Lipocalin 2 Is Required for Pulmonary Host Defense against Klebsiella Infection

“…Previous studies have shown a role for this protein in other infections such as Salmonella (42, 43), Chlamydia (44), and Mycobacterium tuberculosis (45, 46) and have similarly attributed the induction of lipocalin 2 to TLR-dependent signaling and subsequent T cell activation pathways. Indeed, we have recently confirmed the ability of Th17 cytokines, IL-17 and IL-22 to induce Lcn2 and inhibit Klebsiella in an in vitro model (18).…”

Arginase 1: An Unexpected Mediator of Pulmonary Capillary Barrier Dysfunction in Models of Acute Lung Injury

“…Reduction of NO production upon incomplete iNOS inhibition abolishes susceptibility of C57BL/6 mice to Chlamydia -induced disease. Thus, the quantity of NO released by infected macrophages seems to define pathogenic versus protective macrophage responses to chlamydial infection (17). …”

Ironing Out the Wrinkles in Host Defense: Interactions between Iron Homeostasis and Innate Immunity

“…However, in the never-ending battle for iron between pathogen and host, the immune system counters by producing siderocalin (also known as lipocalin 2 and neutrophil gelatinase-associated lipocalin, NGAL), a protein that is upregulated as part of the acute-phase response to infection, and that binds specifically to some siderophores to disrupt pathogen iron acquisition [52,53] . Siderocalin is secreted by neutrophils, macrophages and other cell types following infection by a number of different organisms, and in some cases Toll-like receptors (TLRs) have been shown to be involved in this response [42,[54][55][56][57] . Siderocalin knockout mice have compromised immunity to pathogenic E. coli and to M. tuberculosis , displaying elevated tissue bacterial numbers and decreased survival following infection with these organisms [54,58,59] .…”