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CHAPtER 26 Host Defenses to Intracellular Bacteria 385

appreciated. This has already been highlighted by the tendency to increased cell death and are not expressed by the vaccine BCG,
of M. tuberculosis to use its own membrane lipids to exploit which hence does not escape from the phagosome.
host chemotactic pathways to recruit bacterial growth-permissive
macrophages to the site of infection; this process subsequently T LYMPHOCYTES AS SPECIFIC MEDIATORS OF
allows a proliferative head-start before adaptive immunity kicks ACQUIRED RESISTANCE
in and amplifies intracellular defences by the action of cytokines,
such as IFN-γ and TNF-α. Moreover, bacterial killing must be Activated macrophages act as the nonspecific executors, whereas
tempered inside the granuloma to prevent destruction of host T lymphocytes are the specific mediators of acquired resistance
tissue. This is achieved by balancing macrophage phenotypes against intracellular bacteria. The dramatic increase in the
ranging from a phenotype highly bactericidal, termed “classically” incidence of TB and other intracellular bacterial infections in
activated, to a phenotype that is more suppressive of inflamma- patients with AIDS illustrate the central role of T lymphocytes
tion and is associated with wound healing and fibrosis, termed in protection. For instance, 15 million individuals are coinfected
“alternatively” activated. Tipping the balance one way or the with HIV and M. tuberculosis, and HIV increases the risk of
other is detrimental for the host in terms of disease. developing TB by several orders of magnitude resulting in more
Myeloid-derived suppressor cells (MDSCs) represent a certain than 1 million TB cases annually. At the site of microbial growth,
stage of development of myeloid cells (both of monocytic and T lymphocytes not only initiate the most potent defense mecha-
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granulocytic lineage). Although most of our knowledge stems nisms available, they also focus this response to the site of
from their suppressive role in cancer, recent evidence suggests encounter, thus minimizing collateral damage to the host.
that they play a role in control of chronic infections, such as Although protective T-cell responses are multifactorial, they can
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TB. They can be distinguished from canonical MPs and granu- be reduced to a few principal mechanisms (Fig. 26.3).
locytes by means of distinct surface markers. The granulocytic As previously mentioned, T cells inevitably also produce
+
int
hi
MDSCs are CD11b LY6G Gr1 , whereas monocytic MDSCs pathology through cytotoxic antimicrobial defense mechanisms.
+
+
hi
neg
are CD11b LY6G LY6C Gr1 . Moreover, pathogenesis of intracellular bacterial infection is
More recent findings point to host cell reprogramming result- highly influenced by T cells. It is therefore important that the
ing from intracellular infection. During intracellular infection of T-cell response be tightly controlled and downregulated, when
Schwann cells, M. leprae is able to downregulate genes active for necessary. Regulatory mechanisms, including regulatory T cells
the Schwann cell phenotype and upregulate genes that orchestrate (Tregs), are in place to limit immunopathology. 19
differentiation to a “stem cell–like” phenotype. This stem cell–like Protective immunity involves the so-called conventional T-cell
property allows the infected cell to differentiate further to multiple sets, CD4 αβ T cells, and CD8 αβ T cells, as well as unconventional
mesenchymal cell states, such as skeletal cells or smooth muscle T cells, such as γδ T cells, CD1-restricted αβ T cells, and T cells
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cells. This ability to regress and then reprogram an infected cell that recognize antigen in the context of other nonclassic MHC
phenotype could play a role in spreading infection throughout class I molecules, such as mucosal-associated invariant T (MAIT;
the host during leprosy. Chapter 20) cells (see Fig. 26.3). Although these T-cell sets perform
Recently, mesenchymal stem cells (MSCs) were identified as different tasks, substantial redundancy exists. Furthermore, these
an intracellular niche of M. tuberculosis in mice, and the equivalent T-cell populations act in a coordinated way in close interaction
human MSC phenotype could be readily infected in vitro. Because with other leukocytes. Depending on the etiological agent and the
they reside in hypoxic niches and most antimycobacterial therapies stage of disease, the relative contribution of the different T-cell
are inactive in these conditions, it is feasible that MSCs could subsets to acquired resistance may vary. The conventional αβ T
maintain the bacteria during long-term infection and could cells make up more than 90% and γδ T cells less than 10% of all
represent a protective niche from drug therapy. Dormant M. lymphocytes in the blood and peripheral organs of humans and
tuberculosis has also been detected in hematopoietic stem cells mice. However, γδ T cells represent a significant proportion of
(HSCs) in mice and humans. HSCs are pluripotent, giving rise the intraepithelial lymphocytes in mucosal tissues, suggesting a
to both lymphoid and myeloid cell lineages in the blood. Clarifica- particular role at this important port of microbial entry.
tion of the pathophysiological context of carriage of M. tuber-
culosis by both HSCs and MSCs is an exciting prospect. CD4 T Cells
The CD4 T-cell population can be further subdivided into distinct
Escape Into Cytoplasm subsets, according to their pattern of cytokine production and
A successful strategy for survival inside activated macrophages expression of unique transcription factors that control patterns
is egression from the phagosome into the cytoplasm, which has of gene expression (Chapter 16). At least four major subsets
been exploited by L. monocytogenes and the various pathogenic exist, T-helper cell-1 (Th1), Th2, Th17, and Tregs. The first two
Rickettsia spp. (see Fig. 26.2). 35,36 This has the advantage of both subsets were discovered over 20 years ago and have been identified
avoiding the cellular defense mechanisms within the phagosome in both mice and humans: Th1 cells, which overwhelmingly
and providing the bacteria with a nutrient-rich environment. produce IFN-γ and IL-2, and Th2 cells, which produce IL-4,
L. monocytogenes possesses several virulence factors to facilitate -5, and -13. The Th1 subset can also be defined on the basis of
its escape from the phagolysosome, a pore-forming hemolysin the T-bet transcription factor and the signal transducer STAT4,
(listeriolysin [LLO]) that acts together with a metalloproteinase, whereas Th2 classification is consistent with expression of the
a lecithinase, and two phospholipases to efficiently promote the transcription factor GATA-3 and signal transducer STAT5.
rupture of the phagosomal membrane and to spread to other cells. Th17 cells express the retinoid orphan receptor γt (ROR-γt)
M. tuberculosis and M. leprae can also egress from the phagosome transcription factor and the signal transducer STAT3. They produce
into the cytoplasm of macrophages and DCs, a behavior that is the cytokines IL-17, IL-22, and granulocyte macrophage–colony-
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mediated by a mycobacterial protein secretion system ESX-1. stimulating factor (GM-CSF). Cytokines of the IL-17 family are
Bacterial virulence factors secreted by ESX-1 may also contribute strong inducers of granulopoiesis; of proinflammatory mediators,