Siderocalin Combats Mycobacterial Infections - Iron Acquisition by the Genus Mycobacterium - page 55

Although the bacteriostatic role of Scn is one of its most important roles
(because Scn is part of the first line of defense by the human immune system), Scn
is also expressed during both normal and pathological events in humans. Studies
that describe the putative role of Scn in mammalian iron transport also demon-
strate the role and necessary expression of Scn during early embryogenesis [ 11 ,
15 ]. Its expression is controlled in part by the Wnt signaling network, the same
network of proteins which influence embryogenesis, cancer and other physiologi-
cal processes in adults [ 16 - 18 ]. Cytokines, hormones and several growth factors
also influence Scn expression. Scn is most commonly found associated within
neutrophil granules, but can also exist as a monomer, homo-dimer or trimer in
human plasma [ 19 ]. A thorough review of Scn expression can be found elsewhere
and thus need not be reiterated here [ 2 ]. The fact that Scn expression can be influ-
enced by many factors and expressed in many forms may also explain why several
papers in the literature report Scn to be a diagnostic biomarker of both benign and
malignant cases, such as in psoriasis, anemia, renal injury and tumorigenesis [ 2 ].
All of these networks of signaling cascades demonstrate the general expression of
Scn by the human body, perhaps hinting at the possibility of some other function
of Scn yet to be identified.
The tuberculosis pathogen, M. tuberculosis , is the cause of one of the most
deadly infectious diseases in humans. Healthy individuals are able to contain
the bacterium in a latent state, thus preventing a M. tuberculosis infection from
progressing to a disease. This is likely due to several components of the immune
system, including Scn, acting in concert to protect the human host. M. tubercu-
losis commonly targets the mammalian respiratory system via alveolar epithelial
cells, where the bacterium can reside, replicate and cause a variety of symptoms,
including chest pain, fever, and weakness. Furthermore, the bacterium may spread
through the body to other systems such as the gastrointestinal or skeletal systems,
compromising a patient's general health. The tuberculosis pathogen can be deadly
for immunocompromised patients, such as those with human immunodeficiency
virus or those living in poverty without access to proper treatment. Furthermore,
various drug-resistant strains of M. tuberculosis have evolved as a result of incom-
plete or ineffective drug treatments, forcing us to search for additional therapeutic
measures to fight the bacterium.
4.2 Role of Siderophores in Mycobacterial Infections
Pathogenic mycobacteria encounter an iron limited environment when invading a
human host. Host iron concentrations are more than sufficient to support life, but
the iron-binding proteins transferrin, lactoferrin, and ferritin regulate and withhold
the vital resource. Accessing the host iron is critical to the survival of the patho-
gen. Mycobacteria obtain host iron by producing small-molecule iron chelators
known as siderophores that deliver iron to the pathogen. The ability to produce
siderophores directly contributes to mycobacterial virulence [ 20 ].