Research Report 2010 2011 - Helmholtz-Zentrum für ...

42 RESEARCH REVIEWS | Mycobacterial Phagosomes and Innate Immunity
Mycobacterial Phagosomes and Innate Immunity
AUTHOR | Dr. Maximiliano G. Gutierrez | Junior Research Group Phagosome Biology | mgg08@helmholtz-hzi.de
Although potential pathogens are encountered routinely, only on rare occasion they do cause diseases. The vast majority of
pathogenic agents are eliminated rapidly by innate defenses operating in our bodies.
In 1882, Ilya Metchnikoff in a revealing experiment observed phagocytes surrounding and attempting to avidly eat a splinter he had
introduced into a transparent starfi sh larva. At that time, he postulated that phagocytes are critical part of the host immune
defense and elaborate the theory of phagocytosis and the evolutionary perspective from eating for nutrition to eating for defense.
In 1908, in recognition of his work on immunity, he was awarded the Nobel Prize in Physiology or Medicine, jointly with Paul
Ehrlich. Metchnikoff’s theory identifi ed and established the basis of our current knowledge of phagocytosis and the innate immune
response (reviewed in Tauber, 2003).
Phagocytosis Phagocytosis is the process by which professional
and non-professional phagocytes and other cells
ingest particles whose size exceeds 1 μm. The resulting
intracellular vacuoles, termed phagosomes, go through
dynamic changes that modify the composition of both their
limiting membrane and their contents, by a sequence that
resembles the progression of the endocytic pathway. This
process is referred to as phagosome maturation, and confers
the vacuole with degradative properties, which are central
to its microbicidal function, representing the first line of defense
against infection that vertebrates possess (Haas, 2007).
Phagosome maturation and immunity Advances in the
understanding of phagosome biology have been possible by
the use of the latex bead system. This model was originally
introduced by Weisman and Korn in the late 1960s and rediscovered
in the early 1990s (Desjardins et al, 1994). Latex
beads are a versatile system for both in vitro and in vivo
analyses of many phagosomal functions. This system allows
an easy approach to understand the very complex process
of phagocytosis (Figure 1). Because the latex floats in
sucrose gradients, latex bead phagosomes are much simpler
to isolate in pure fractions in order to analyse their content
(Figure 2). Much of what we understand today about phagocytosis
and phagosome biology in cellular systems has
been obtained from studies from many groups that use the
latex-bead phagosome system (Desjardins & Griffiths, 2003).
Moreover, it is possible to coat these beads with different
proteins or with specific ligands, which selectively bind to
cellular receptors to study the impact during internalisation.
Recently, it has been shown that particular substrates can
also be coupled to the beads to monitor enzymatic activity
in real-time (Yates et al, 2005).
By ingesting microbial pathogens, phagocytic cells achieve
two essential immune functions orchestrated by the phagosome.
First, phagosomes initiate microbial elimination, in
part by directing ingested microbial pathogens to lysosomes
in a process known as phagosome maturation pathway.
Second, phagocytic cells make use of phagocytic pathway
to direct processed protein and lipid antigens to the Major
Histocompatibility Complex (MHC) class I, MHC class II
and CD1 positive compartments. This loading and exposure
of antigens on plasma membrane allows the development
of a more customised adaptative immune response. Thus,
phagosomes play a dual role: as an innate immune effector
and as a bridge between the innate and acquired immune
system (Figure 3). Actually, phagosome maturation allows
the shaping of a cellular compartment where killing,
degradation and antigen processing take place in a very
organised manner (Jutras & Desjardins, 2005). The study of
phagosome biology is evolving rapidly and reflects recent
advances in a broad range of disciplines including cell biology,
proteomics, and immunology. A better understanding
of the mechanisms of phagosome formation and maturation
and its interactions with intracellular compartments will
Fig. 1. Phagocytosis of latex beds. RAW 264.7 macrophages
expressing Rab34-GFP (green) ingesting avidly IgG-coated
latex beads (red). Nucleus is shown in blue. This process
mimics the IgG-opsonised bacteria that also enter macrophages
via Fcγ receptors (FcγRs). A. Beads at different stages
of internalisation. B. 3D diagram of the localisation of Rab34
on the phagosomal membrane. Photo: HZI, Kasmapour