This webpage was produced as an assignment for an undergraduate course at Davidson College.
Innate Immune Response to L. pneumophila
The innate immune response against L. pneumophila is obviously necessary to clear the bacteria before an infection can take hold. The unique life cycle of this pathogen presents the scenario that an innate immune response could also help the individual bacteria gain entry to macrophages where they can begin replication. While this is a possibility, in a healthy individual, the vast majority of phagocytosed L. pneumophila are cleared like any other extracellular pathogen (Rathore and Alvarez, 2006). This desired response is initiated by several distinct cytokines and receptors of innate immunity.
A neutrophil, which works with macrophages, dendritic cells, and natural killer cells to immediately clear an infection.
Image in public domain.
IL-4 and TNF-a
Interleukin 4 (IL-4) has been experimentally shown to have a direct role in the control of L. pneumophila infection by reducing the levels of the acute-phase cytokine TNF-a (tumor necrosis factor alpha) (Newton et al., 2000). This cytokine is produced unchecked in extremely high levels when L. pneumophila is detected within the cell. If IL-4 is not subsequently released then many host cells will be killed not by the infection but through shock brought by TNF-a (2000). Therefore, IL-4 is an essential regulatory cytokine in the initial immune response to L. pneumophila.
MyD88 and TLR2
More generally, the innate immune response against these bacteria requires MyD88 and toll-like receptor 2 (TLR2). MyD88, a widely used adapter protein that is necessary in many transduction pathways, is the first step in the production of NFkB. This transcription factor leads to the production of many cytokines that are necessary for the suppression of any bacterial infection (Archer and Roy, 2006). Without MyD88 the recognition of any PAMPs on the surface of L. pneumophila would not lead to a transcriptional response in the nucleus, leaving all the host cells vulnerable to infection. Experiments where hosts are MyD88 deficient increase susceptibility to nearly all pathogenic infections, not just L. pneumophila (2006) .
The activation of MyD88 comes most importantly from the host-surface receptor TLR2. This transmembrane pattern recognition receptor detects a specific molecular pattern on the surface of L. pneumophila, which leads to its phagocytosis, and the production of cytokines to further attack the foreign cells. The pathogen-associated molecular pattern (PAMP) on L. pneumophila that is recognized by the receptor is a lipid A molecule that is a weak agonist for TLR4 but a very strong stimulant for TLR2. Without this primary cell-surface detector of L. pneumophila, host cells would likely be overrun with replicating bacteria before the adaptive immune response has a chance to act to control the infection (Archer and Roy, 2006).
IFN-y and IL-12
Several other cytokines have been shown to play a role in the control of L. pneumophila infection. Interferon gamma (IFN-y) and interleukin 12 (IL-12) have both been shown experimentally to reduce the replication of L. pneumophila when present (Newton et al., 2007). IFN-y is an apparent up-regulator of effectors (other chemokines and cytokines) that stop the intracellular growth of the bacteria. The role of IL-12 is not completely understood, but likely protects host cells from infiltration by the bacteria. These few innate immune strategies against L. pneumophila infection are certainly not the only steps the immune system takes in defense against bacteria, but they are the most obvious and fundamental.
Works Cited
Archer KA and CR Roy. 2006. MyD88-dependent responses involving toll-like receptor 2 are important for protection and clearance of Legionella pneumophila in a mouse model of Legionnaire’s disease. Infection and Immunity 74(6):3325-3333.
Newton C, McHugh S, Widen R, Nakachi N, Klein T, and H Friedman. 2000. Induction of interleukin-4 (IL-4) by Legionella pneumophila infection in BALB/c mice and regulation of tumor necrosis factor alpha, IL-6, and IL-1B. Infection and Immunity 68(9):5234-5240.
Newton CA, Perkins I, Widen RH, Friedman H, and TW Klein. 2007. Role of toll-like receptor 9 in Legionella pneumophila-induced interleukin-12 p40 production in bone marrow-derived dendritic cells and macrophages from permissive and nonpermissive mice. Infection and Immunity 75(1):146-151.
Rathore M and A Alvarez. 2006 May 15. eMedicine: Legionella infection. <http://www.emedicine.com/ped/topic1288.htm>. Accessed 2007 April 29.