Immune System Evasion

Generally, M. leprae manages to avoid the immune system through its unique lifecycle: by replicating exclusively inside of macrophages and Schwann cells, most phagocytes and antigen-presenting cells do not encounter the pathogen. This lack of meeting causes a paucity of immune response – hence, M. leprae stays mainly silent.

(3 - Janeway et al, 2005 Figure1-26)
           
However, even when an immune response has begun, M. leprae can often avoid complete clearance by the immune system. By causing a predominantly Th2 cell response, M. leprae is able to avoid direct interaction with the immune system by preventing the cells that might recognize infected host cells from being activated in the first place (3). While a predominantly Th2 cell response only occurs in a fraction of leprosy cases, it is enough to provide a significant evasion system for the pathogen. These cases provide such an ineffective immune response that the bacterium is actually able to proliferate significantly more, and usually results in death (3).
           
In tuberculoid leprosy, immune system evasion tactics are more specific, and less effective. Specifically, M. leprae has developed a mechanism to prevent host cell apoptosis by affecting a number of apoptosis-linked mRNA’s (2,4).

 

Apoptosis Prevention:
M. leprae is able to upregulate the host macrophage’s production of Mcl-1, an anti-apoptotic gene (2). In addition, M. leprae downregulates the cell’s expression of the pro-apoptotic genes Bak and Bad (2). When activated, Bad forms heterodimers with Bcl-x and Bcl-2 – thus switching their roles from apoptosis preventors to activators (2). A prevalence of Bad in the cell therefore makes it more prone to apoptosis.

A good summary of this trend can be found here.

Like M. tuberculosis (which is a mycobacterium similar to M. leprae that causes tuberculosis), M. leprae is also able to prevent host macrophage apoptosis in vitro (4). While this may not be the case in vivo, it is an interesting point that the bacterium is able at least in vitro to affect the sensitivity of the host cell to apoptosis. The mycobacteria find a way to increase expression of Fas-ligand and decrease expression of the Fas receptor on the surface of the macrophages (4). This allows the macrophage to protect itself against killing by CD8+ T-cells (3). Fas ligand is usually only expressed by the CD8+ cell itself and recognizes the Fas receptor on infected cells (3). Therefore, the host macrophages’ increase of Fas-ligand expression serves to hide it from recognition by the CD8+ T-cell. By this mechanism, M. leprae may (in vivo) be able to evade immune system recognition by CD8+ T-cells, thereby avoiding the results of a Th1 predominant response (2).

 

Induction of anergy:
Similarly, M. leprae infection of dendritic cells causes them to be poor inducers of T-cell activation in vitro (1). In addition, the study suggested that infected DC’s that have not fully matured can induce an anergic state in the DC where it activates regulatory T-cells instead of CD4+ or CD8+ cells and therefore suppresses any previously activated specific immune response (1). Again, this study was only conducted in vitro, and it is still questionable as to whether the trend could be replicated in vivo.

 

Sources:
1. Hanekom, W. A., Mendillo, M., Manca, C., Haslett, P., Siddiqui, M., Barry, C., Kaplan, G. 2003. Mycobacterium tuberculosis inhibits maturation of human monocyte-derived dendritic cells in vitro. JID. 188:257-66.

2. Hasan, Z., Ashraf, M., Tayyebi, A., Hussain, R. 2006. M. leprae inhibits apoptosis in THP-1 cells by downregulation of Bad and Bak and upregulation of Mcl-1 gene expression. BMC Micro. 6:78.

3. Janeway, C., Travers, P., Walport, M., Shlomchik M. Immuno Biology: the immune system in health and disease. 6th Ed. 2005. New York: Garland Science Publishing.

4. Mustafa, T., Bjune, G., Jonsson, R., Hernandez Panno, R., Nilsen, R. 2001. Increased expression of Fas ligand in human tuberculosis and leprosy lesions: a potential novel mechanism of immune evasion in mycobacterial infection. Scand J Immunol. 54:630-639.

 

Copyright Alex Greer 2007

For questions/comments, please contact Immunology professor Dr. Sofia Sarafova at Davidson College.