Articulo linfo

Antimicrobial mechanisms of
phagocytes and bacterial evasion
strategies
Ronald S. Flannagan*, Gabriela Cosío* and Sergio Grinstein
Abstract | Professional phagocytes have a vast and sophisticated arsenal of microbicidal
features. They are capable of ingesting and destroying invading organisms, and can present
microbial antigens on their surface, eliciting acquired immune responses. Tosurvive this
hostile response, certain bacterial species have developed evasive strategies that often
involve the secretion of effectors to co-opt the cellular machinery of the host. In this Review,
we present an overview of the antimicrobial defences of the host cell, with emphasis on
macrophages, for which phagocytosis has been studied most extensively. In addition, using
Mycobacteriumtuberculosis, Listeria monocytogenes, Legionella pneumophila and Coxiella
burnetii as examples, we describe some of the evasive strategies used by bacteria.
The identity of the guanine nucleotide exchange factors
(GEFs) that are responsible for Rac and Cdc42
activation are the subject of debate5,6. By contrast, it is
generally agreed that downstream effectors, such as
wiskott–Aldrich syndromeprotein7, which in turn
interacts with and activates actin-related protein 2/3
(Arp2/3), are actively involved in actin polymerization
during FcγR-initiated phagocytosis8. In the case of CR3-
mediated phagocytosis, the diaphanous-related formin
Dia1 (also known as DIAPH1) is thought to initiate
actin filament nucleation and elongation4,9.
Phosphoinositides also provide an important contributionto actin remodelling during phagocytosis. Both
phosphatidylinositol-4,5-bisphosphate and phosphatidylinositol-
3,4,5-trisphosphate accumulate at sites of
particle engagement and are instrumental in timing
the onset and termination of actin assembly. whereas
phosphatidylinositol-4,5-bisphosphate is essential
for the initial polymerization that drives pseudopod
formation, its conversion tophosphatidylinositol-
3,4,5-trisphosphate seems to be required for pseudopod
extension and phagosomal closure10, at least in
part by recruitment of myosin X11. The metabolism
of other phospholipids by phospholipases A and D is
also necessary for successful completion of phagocytosis12,13,
although the precise products and mechanisms
involved have not been fully resolved.
During phagocytosisof large or multiple particles,
a considerable amount of membrane is internalized,
and the cell needs to compensate for the loss of surface
area. Paradoxically, capacitance measurements have
shown that the plasmalemmal surface in fact increases
during phagocytosis14. This has been attributed to focal
exocytosis of endomembranes at sites of phagocytosis.
Recycling15 and late endosomes16 arethought to be
the main contributors, but even lysosomes have been
reported to fuse when the demand for membrane is
excessive17,18. Rab and ADP-ribosylation factor (Arf)
GTPases are thought to be important in directing
and tethering the endomembrane organelles to form
phagosomes19,20, whereas SNARE proteins (soluble nSFattachment
protein receptor proteins), including vesicleassociatedmembrane protein 3 (vAMP3)15 and vAMP7
(REF. 16) underpin the fusion reaction.
Phagosome maturation
Maturation starts immediately after, and possibly even
before, phagosome sealing. After scission from the surface
membrane, the phagosome undergoes sequential
fusion with early endosomes, late endosomes and lysosomes21.
whether complete fusion of the incoming membranes
with the pre-existingvacuole or ‘kiss and run’
events are involved remains unclear and a combination
of both may occur. Regardless, remodelling of the membrane
of the phagosome is accompanied by acute changes
in the composition of its lumen, which becomes a highly
acidic, oxidative and degradative milieu. The steps leading
to the formation of the phagolysosome, which is the
terminal stage of the maturation...