Mycobacterium tuberculosis and Immune Evasion

Many of you have likely heard of tuberculosis (TB), a potentially lethal, infectious disease caused by intracellular bacterium called Mycobacterium tuberculosis. Although this bacterium usually attacks the lungs, it can also affect other parts of the body including the brain, the spine, or the kidneys. Tuberculosis germs are spread through the air, particularly when an infected person coughs, sneezes, or vocalizes. Symptoms of tuberculosis include weakness, a chronic cough, night sweats, fever, and weight loss. Tuberculosis is one of the world’s deadliest diseases. In 2012, there were 1.3 million tuberculosis related deaths worldwide (World Health Organization 2013). In fact, one-third of the world’s population is infected (Centers for Disease Control and Prevention 2013).

It is important to distinguish between two tuberculosis conditions: latent TB and active TB (also known as TB disease). Latent TB is defined by the presence of a TB infection, but the bacteria remain in the body remain inactive and do not cause symptoms. This is because the immune system acts to “wall off” the bacteria using a cellular structure called a granuloma which forms around the invaders. Active TB occurs when the immune system cannot prevent the TB bacteria from multiplying in the body. A person with active TB will be contagious and exhibit symptoms. People most susceptible to developing active TB disease are those who have been recently infected by TB bacteria or those with medical conditions that weaken the immune system such as HIV infection, tobacco use, or diabetes mellitus. Specifically, 90% of infected patients will have latent TB, while only 10% will progress to disease (World Health Organization 2013). TB is generally curable with antimicrobial drugs, but in many underdeveloped nations, access to such health care is unattainable. If untreated, 50% of active TB disease cases are fatal (World Health Organization 2013). Additionally, resistance to the medicines is increasing. This is evidenced by the emergence of multi-drug resistant TB, which is the result of bacteria that do not respond to standard anti-TB drugs (Centers for Disease Control and Prevention 2013).

Clearly, TB is a relevant concern in today’s world. An October 2013 study by Heuer et al. (http://www.biomedcentral.com/1471-2172/14/48) examined the effects of two Mycobacterium tuberculosis antigens on human dendritic cell maturation and how this affects immune response. This study was investigating the viability of these antigens as vaccine candidates, while also examining how these antigens may be involved in immune reaction or immune evasion. Antigens are entities (in this case, an element of the Mycobacterium tuberculosis) that can bind to the antigen receptor of a T or B cell (leukocytes that mediate adaptive immunity). Dendritic cells are phagocytic leukocytes that process antigen material and function as antigen presenting cells. Specifically, infection of these dendritic cells by Mycobacterium tuberculosis leads to the downregulation of the expression of MHC class I and II and CD1 (cell surface proteins which present antigens to T cells). Therefore, if there are less of these antigen presentation molecules, antigens will not be effectively presented to T cells and NKT cells so effective immune responses won’t be promoted. This suboptimal immune response is considered to be a cause of susceptibility to Mycobacterium tuberculosis.

A novel way to fight an old foe: expression of TCRs on macrophages in granulomatous responses

Tuberculosis is caused by the bacteria Mycobacterium tuberculosis, and is characterized by an infection of the bronchi (a part of the lungs) in which macrophages (a type of white blood cell) are unable to digest the bacteria. As a result, macrophages release cytokines, small proteins, that attract T lymphocytes, which kill cells by releasing "killer proteins" and create a granuloma (a collection of immune cells surrounding infected tissue) (Knechel 2009). Tuberculosis poses a threat to the health of the world: in 2007, there were approximately 1.77 million deaths from tuberculosis—the second highest death rate of any infectious disease (Glaziou et al. 2009). It is also a highly mutative pathogen: cases of extreme-multidrug resistant tuberculosis are common, and the treatment responses are usually poor, while the mortality rates are high (Telzak et al 1995).

A recent study by Beham et al. published in PLoS pathogens examined how T-cell receptors (TCRs), which recognize a protein-complex on other cells, on macrophages affect the formation of tuberculous granulomas. To begin the study, the researchers had to establish that monocytes, precursors to macrophages, and macrophages do in fact express T-cell receptors. To do this the researchers used antibodies, proteins that target specific molecules, targeted to TCRα/TCRβ and MHC-II (this is the protein complex recognized by TCRs). From this experiment, they were able to establish that approximately 5% of monocytes expressed TCRαβ (a type of TCR). Although the presence of TCRs in monocytes appeared to be promising, the researchers continued by testing monocyte-derived macrophages from three donors. These monocytes were activated using IFNγ and IL-4, both cytokines that are responsible for initiating inflammation. The researchers found that 5% of the naïve macrophages expressed TCRs, while 9% IL-4 of and 11% of IFNγ activated macrophages expressed TCRs.