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the effectiveness of Scn protection. Significantly more mycobacteria inhabit epi-
thelial cells without Scn than inhabit wild-type epithelial cells expressing Scn in
response to the infection. The protection comes as the secreted Scn is internalized
and then co-localizes with the mycobacteria to inhibit growth [
44
]. Scn activity
prevents mycobacteria from infecting epithelial cells.
In addition to epithelial cells, alveolar macrophages also produce Scn in
response to mycobacterial infection [
6
,
35
,
44
]. The effect of Scn in macrophages
remains unclear and is highly dependent on the species of mycobacteria. Murine
macrophages infected with
Mycobacterium bovis
-bacillus Calmette-Guerin (BCG)
permitted similar bacterial growth with or without Scn production [
6
,
44
], but
the intracellular
M. tuberculosis
was significantly decreased [
6
].
M. tuberculosis
infects an equal number of macrophages whether or not Scn is present, but when
Scn is present, fewer bacteria inhabit each macrophage. The bacteria in the wild-
type macrophage are elongated and filamentous, indicating that they are growth
arrested [
6
].
To protect against an intracellular pathogen, Scn must enter the macrophage
to interact with the mycobacteria. Wild-type Scn is always secreted, but it reent-
ers the cell by endocytosis. In the case of
M. tuberculosis
protection mentioned
above, a cytosolic mutant of human Scn lacking the secretion sequence and the
wild type protein equally protect a macrophage cell line against
M. tuberculosis
infection [
6
]. However,
M. avium
uses the intracellular trafficking system of bone
marrow-derived macrophages to avoid Scn. Once inside the cell, the
M. avium
places the phagosome in the endocytic recycling compartments which intersect
with the ferric transferrin recycling pathway. Endocytosed Scn progress to the
lysosomal pathway and cannot interact with the
M. avium
[
35
]. This species of
Mycobacterium
effectively use the intracellular environment to overcome the host
defense and accumulate iron for growth and further infection. Additional work
will be helpful to better define the activity of Scn in macrophages during a myco-
bacterial infection and justify the differences observed between
M. tuberculosis
,
M. avium
, and BCG.
4.5 Concluding Remarks
The battle for iron between humans and pathogens is ancient in development and
current in impact on human health. Humans have developed Scn to defend against
siderophore-mediated iron acquisition, and some pathogens have responded by
making stealth siderophores to avoid Scn recognition. The response by pathogenic
mycobacteria appears to be at an intermediate stage. Hydroxamate iron-binding
units of carboxymycobactin and mycobactin limit the affinity of Scn, but the aro-
matic hydroxyphenyl-oxazoline subunit provides an effective handle for Scn rec-
ognition. Some alkyl chain lengths prevent Scn binding, while others allow it.
Depending on the species, mycobacteria evade Scn protection in alveolar mac-
rophages but are vulnerable in epithelial cells. The intracellular trafficking and
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