response.

They also have a number of

virulence factors and have the ability to
evade host defenses. Given their ability
to survive in a variety of environments,
these pathogens have a number of
factors that allow them to exist in various
host tissues or on various abiotic
surfaces. Lipopolysaccharides, Adhesion,
and Invasion Both BCC species and S.
maltophilia produce lipopolysaccharides
(LPSs) that are capable of stimulating
cytokine-driven inflammatory responses
and allow for resistance to complement-
mediated bacterial clearance. B.
cenocepacia LPSs can activate immune
cells through Toll-like receptor 4–
mediated signaling.13 Blood
mononuclear cells that have been
activated by BCC LPSs release various
 cytokines including tumor necrosis
factor-α, interleukin-6, and interleukin-
8.14 In S. maltophilia, lipid A has been
shown to stimulate tumor necrosis
factor-α in both blood mononuclear cells
and alveolar macrophages leading to
airway inflammation.15 In addition,
interleukin-8 stimulates recruitment of
polymorphonuclear neutrophils to sites
of infection, further driving a robust
inflammatory response. Divergent Toll-
like receptor/MD2 signaling has been
shown to occur due to changes in the
inner core of BCC LPSs.16 B. cepacia has
been shown to be able to bind to various
epithelial cell receptors such as
cytokeratin 13 (CK13) through an adhesin
that is expressed on cable pili that helps
to anchor bacteria.17,18 Various
 epidemiologic studies have provided
evidence for the importance of cable pili
in establishing colonization as well as
allowing for patientto-patient
transmissibility in the CF lung
milieu.19,20 In one study, chronic
inflammation enhanced CK13 expression
in patients with CF, and in regions that
had high CK13 expression this
corresponded with an enhanced B.
cenocepacia burden.21 BCC species not
only can invade respiratory epithelial
cells but also have been demonstrated to
be able to survive and multiply within
epithelial cells.22–24 Siderophores and
Secreted Enzymes BCC species have a
number of mechanisms for scavenging
iron. BCC species possess at least four
iron-binding siderophores—pyochelin,
ornibactin, cepaciachelin, and cepabactin
—for iron chelation and uptake.25,26
Likewise, S. maltophilia uses catechol-
type iron-binding siderophores,27 and
these siderophores can be both positively
and negatively regulated.28,29 S.
maltophilia produces a variety of
extracellular enzymes including alkaline
serine proteases (at least one encoded by
StmPr1), DNAse, RNase, gelatinase, and
lipases that degrade tissue fat.30–32
Many of these proteases are resistant to
inhibitors such as α1-antitrypsin and α2-
macroglobulin.32 These exoenzymes
allow for tissue necrosis and
hemorrhage.32 Various BCC species
produce proteases, lipases, and
nonhemolytic phospholipase C.33,34
Chronic Infection and Intracellular
 Survival BCC species can invade and
survive in a number of host cells. Once
internalized into respiratory epithelial
cells, growth can occur, and
microcolonies can be seen (Fig. 220.1).22
Intracellular survival helps facilitate
immune evasion. Although
autophagosomes appear to form, BCC
species appear to block the full
autophagocytic pathway in both
epithelial cells and macrophages and use
the endoplasmic reticulum for
multiplication.22,35,36 A number of
mechanisms are thought to play a role in
intracellular survival including blocking
enzyme production, degradation of
enzymes, and melanin pigment–
associated superoxide quenching.37–41
The BCC type III secretion system assists
 in delaying the maturation of bacteria-
containing phagosomes. The failure of B.
cenocepacia to fuse with lysosomes
allows for prolonged survival in patients
with CF.42,43 Although less is known
about the intracellular life cycle of S.
maltophilia, there are data to support
that some strains can survive in human
monocyte-derived dendritic cells.44
Biofilm and Quorum Sensing Biofilms
normally contain aggregates of bacteria
in extrapolymeric substances and can
form on numerous foreign objects, on
avascular necrotic tissue, and in certain
host environments such as the lung
affected by CF. Quorum sensing systems
and the ability to form biofilm are A B C D
FIG. 220.1 Pathogenesis of Burkholderia
cenocepacia. Electron micrographs
 showing invasion of an A549 respiratory
epithelial cell monolayer by B. cepacia
249-2. All four micrographs show the
same epithelial cell monolayer following
a 2-hour incubation with the bacteria. (A)
Initial contact of bacterial cells (B) with
the surface of A549 cells. Thickening is
seen at the site of contact (arrowheads).
(B) Apparent endocytosis of bacteria in
contact with microvilli (MV) at the cell
surface. A single bacterium is present
within each membrane-bound vacuole.
(C) Lower-power view of bacteria present
within the cell cytoplasm. Although
apparently ingested singly, organisms
appear in clumps within the cytoplasm.
(D) Higher-power view of bacteria within
the cytoplasm. The organisms are
enclosed within membrane-bound
 vacuoles (arrows). (Courtesy Dr. A.
Griffith. From Burns JL, Jonas M, Chi EY,
Clark DK, Berger A, Griffith A. Invasion of
respiratory epithelial cells by
Burkholderia (Pseudomonas) cepacia.
Infect Immun. 1996;64:4054–4059.) traits
of both BCC species and S. maltophilia.
28,45–47,48,49 The presence of biofilm
allows for the ability to withstand both
immune cell activity and antibiotic
efficacy. In S. maltophilia, regulation of
biofilm occurs through the production of
diffusible signaling factor, and diffusible
signaling factor mutants show a number
of phenotypes including loss of motility,
increased susceptibility to antibiotics, and
reduced production of proteases.50,51 B.
cenocepacia has been shown to use N-
acyl homoserine lactones and cis-2-
 dodecenoic acid to regulate biofilm.52
EPIDEMIOLOGY AND AT-RISK
POPULATIONS Stenotrophomonas
maltophilia The rate of S. maltophilia
isolation and infections has increased in
multiple regions of the world. There is a
broad environmental range where S.
maltophilia has been isolated, including
from animals.53 It is not clear whether
increased numbers of infections in
vulnerable patient populations are due to
enhanced lifesaving medical advances or
an overall increase in incidence.
However, there has also been an increase
in the isolation