"This web page was produced as an assignment for an undergraduate course at Davidson College."
Innate Immune Response

Introduction to Innate Immunity:

The innate immune system is our bodies’ first line of defense beyond the epithelium. Upon breach of the epithelium, the first things a pathogen encounters are the mechanism of the innate immune system. Some of the key processes in the innate immune system are ingestion by phagocytes, toxic oxygen-derived products, toxic nitrogen oxides, acidification, antimicrobial peptides, and the complement system to name a few. Responsibilites of the innate immune system include containing/eliminating pathogen if possuble and alerting the adaptive immune system through antigen presentation and cytokines (Janeway 2005).

In this picture, a dendritic cell has engulfed some mycabacterium (M) with are residing within vacuoles (CHV).

Photograph from http://www.nimr.mrc.ac.uk/elecmicroscopy/examples/tem/tisscult/

Provided with permission: Copyright image courtesy of National Institute for Medical Research, London 2007

Important Factors of Innate Immunity that Regulate M. tuberculosis

Mycobacterium tuberculosis lives within the cells of the innate immune system; the response of the innate immune system is vital to bacterial containment.

M. tuberculosis is inhaled through the lungs and is typically engulfed by alveolar macrophages. These macrophages secrete proteolytic enzymes and cytokines that exhibit antimycobacterial effects including IL-1 (fever and inflammation), IL-6 (enhances activated B-cell proliferation), IL-10, TNF-alpha (signals production of nitric oxide metabolites), and TGF-beta (Chan 1994). 

In M. tuberculosis infections, the first cells that initially encounter the bacteria are alveolar resident macrophages. After these macrophages ingest the bacteria, dendritic cells also part take in the phagocyctic process. The uptake of these bacteria involves several different receptors on the surface of the phagocytes which recognize and bind either nonopsonized bacteria or surface proteins. Some examples of these receptors include complement receptor 1 (CR1), complement receptor 3 (CR3), mannose receptor, and type A scavenger receptor (van Crevel 2002).

Depending on which receptor helps a phagocyte ingest M. tuberculosis, the specific receptor can play a role in the virulence and immune response. For example, bacteria bound via CR1 have a better chance at survival than bacteria bound via CR3 or CR4 (van Crevel 2002). Some mycobacteria are up taken through the help of surfactant-protein A in the lungs. Mycobacteria ingested in the presence of surfactant-protein A are better able to repress reactive nitrogen intermediates. Additionally, it has been shown that the more virulent strains of tuberculosis enter the phagocytes through the mannose receptor. Phagocytosis through the mannose receptor does not trigger reactive oxygen species, a key method for mycobacterial elimination. It is unknown, why this method of entry appears to be advantageous to mycobacterial survival (van Crevel 2002).


Importance of TLR Signaling

TLR Signaling (TLR2 and TLR4) recognize the cell wall of mycobacterium.

Recognition of M. tuberculosis by macrophages and dendritic cells occurs primarily through lipoarabinomannan (LAM) identification on the mycobacterial cell surfaces by toll like receptors (van Crevel 2002). Specifically, Toll-like receptor 2 (TLR 2) is responsible for recognizing mycobacteria including M. tuberculosis (Texereau 2005). In particular, TLR 2 recognizes or binds the ligand lipoarabinomannan (LAM), which is a major cell wall component of M. tuberculosis. TLR 2 signaling is important to the innate immune response because it turns on transcription factors that play a role in microbial defense including the NFkB pathway and the map kinase pathway (Texereau 2005). In addition to signaling transcription factors, TLR 2 binding to a ligand can signal host cell apoptosis (Quesniaux 2004). 

Other TLR receptors are important in host innate immune defense as well. For example, in a knockout experiment TLR 4 was knocked out and then mice were exposed to M. tuberculosis within 15 weeks the mice die. Similarly, when TLR 2 was knocked out, the mice were not able to produce and efficient adaptive response and dies within 5 months of exposure (Quesniaux 2004). Recognition of M. tuberculosis through TLRs also initiates the production of interleukin 12 (IL-12), which is a inflammatory cytokine that induces the production of INF-gamma (van Crevel 2002).

Activation of macrophages through ingestion and recognition (via TLRs) of mycobacteria cause the production of several cytokines including TNF-alpha, IL-1beta, IL-6, IL-12, INF-gamma, IL-10, TGF-beta and IL-4 (produced by T helper cells). TNF-alpha, a proinflammatory cytokine, plays a role in host response through the help of granuloma formation, further macrophage activation and containment of latent infections. INF-gamma is extremely important for macrophage activation. However not all of the cytokines produces help protective immunity, it appears that IL-10, TGF-beta and IL-4 all seem to counteract protective immunity, in particular, IL-4, which suppresses the production of INF-gamma and macrophage activation (van Crevel 2002). 

Phagocytosis of M. tuberculosis without recognition of the bacterium by TLRs does not lead to activation of the immune system. In order for the immune response to initiate, the bacterium must be recognized by functional TLRs (van Crevel 2002).


Functions of the Machrophages

Machrophages main weapons= oxidative burst, reactive nitrogen intermediates, and phagosome-lysosome fusion

Macrophage elimination mechanisms for M. tuberculosis include the following reactive oxygen intermediates (ROI), reactive nitrogen intermediates (RNI), and phagosome-lysosome fusion. The exact role of ROI and RNI in host defense against this mycobacteria remains under debate. For ROIs, several of the mycobacterial products including LAM may be able to scavenge ROIs; thereby making M. tuberculosis somewhat resistant to killing by ROIs (van Crevel 2002).

Oxidative bursts, phagosome-lysosome fusion, production of reactive nitrogen intermediates, and cytokine production including INF-gamma are all involved in macrophage defense against mycobacterium (Chan 1994). Macrophages produce several cytokines in response to contact with mycobacterium tuberculosis including IL-1 (interleukin), IL-8, IL-10, and TNF (tumor necrosis factor). IL-1, IL-8 and TNF induce an inflammatory response in the host cell (Chan 1994). 

TNF-alpha and INF-gamma appear to have a synergistic effect on mycobacteria from macrophages in murine cell cultures. These two cytokines intiate the production of reactive nitrogen intermediates (RNI) by activating the inducible from of nitric oxide synthase (NOS2).  Patients with active tuberculosis express high levels of NOS2. (Flynn 2001).  In addition, IL-6 and IL-4 also induce antimycobacterial antibody in macrophages (Chan 1994).  The macrophage also combats mycobacterial reproduction by fusion of the vacuole containing the mycobacteria with the lysosome or by decreasing the pH.  If the macrophage can decrease the pH to 5.8, bacterial growth is inhibited, and better yet to a pH of 5.3, bacterial growth is arrested (Russell 2007).

Apoptosis of mycobacterial infected macrophages, which requires TNF-alpha, weakens the viability of intracellular bacteria; however, necrosis does not (van Crevel 2002).

The lysosome is an organelle that plays a key role in degrading foreign protein. Enzymes with in the lysosome reside at low pH. Many foreign proteins are first ingested by a phagosome. Then the phagosome fuses with a lysosome and the degradation of the protein ensues (Chan 1994).

M. tuberculosis infections are intracellular and are therefore not effected by complement mediated killing.  In the event, that the bacterium is extracellular, the bacterium still resists complement mediated killing due to its high lipid concentration in the cell wall (Todar 2005).

Macrophage Response to encounter with mycobacteria

Image provided with permission from: http://www.fz-borstel.de/en/research/ibm/mi/index.htm

Research Center Bostrel, Leibniz- Center for Medicine and Bioscience



This site was created as partial fulfillment of requirments for Biology 307 at Davidson College in the Spring Semster of 2007.

Davidson Home Davidson Biology Home

Questions and comments should be directed to Dr.Sarafova or to the site creator Emily Rivard