Page 400 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHAPtER 26 Host Defenses to Intracellular Bacteria 381

interact with host molecules. However, receptors, such as SR-A, that induce innate immune mechanisms and, subsequently, the
MARCO, CD36, LOX-1, and SREC, can bind a wide array of mobilization of the adaptive immune response. These include
bacterial molecules, such as lipids, CpG DNA, and proteins cytokines that act both locally and systemically and are important
(see Table 26.2 for binding specificities). SR-A is important for mediators of protection against intracellular bacteria via specific
clearance of extracellular bacteria from the spleen and liver. signaling through engagement of host cell surface receptors. Such
MARCO expressed on alveolar macrophages is implicated in engagement mobilizes both critical mechanisms of host protection
clearance of pneumococcal bacteria preventing pneumonia. and orchestration of adaptive immune responses.
C-type lectins are similarly membrane-expressed and include
DC-specific intercellular adhesion molecule–grabbing nonintegrin Macrophage Training by Epigenetic Mechanisms
(DC-SIGN); mannose receptor; dectin-1; dectin-2, which chiefly Following infection with, for example, M. tuberculosis, macro-
recognize fungal components; and MINCLE, which recognizes phages express elevated effector mechanisms over long periods.
trehalose dimycolate (TDM), the cord factor of M. tuberculosis. More recent findings have revealed that this is caused, at least
It has been suggested that scavenger receptors and C-type in part, by epigenetic changes that are induced in MPs during
lectins are required to bind and internalize the bacillus, whereas infection. Similar training can also occur after vaccination with
it is primarily the TLRs that discriminate between the pathogens live vaccines. Moreover, BCG vaccination was shown to induce
and initiate the necessary intracellular signaling events. It should, changes in methylation patterns of the NOD2 gene in humans.
however, be noted that intracellular signaling events can also be These epigenetic changes led to increased production of proin-
triggered by other interactions, such as ligand binding to mac- flammatory cytokines by MPs, namely, TNF and IL-1β, a tendency
rophage mannose receptor (MMR), dectin 1, or DC-SIGN. Far that persisted for 3 months after vaccination. Furthermore, this
from a one-ligand, one-receptor binary mechanism of sensing enhanced innate immunity led to increased resistance not only
and signaling, PRRs often collaborate to produce multiprotein against M. tuberculosis but also against other bacterial pathogens.
complexes. CD14, MD2, and TLR4 collaborate for LPS sensing Indeed, it has been speculated that epigenetic alterations in MPs
and signaling. Similarly, MARCO and TLR2 synergize to recognize following vaccination are responsible for the nonspecific reduction
TDM. To allow signaling, these complexes interact with adaptor of mortality in BCG-vaccinated infants in resource-poor regions
proteins containing immunoreceptor tyrosine-based activation of the world. 23
motif (ITAM)-like or Toll/interleukin-1 receptor (TIR) domain
motifs. TLR signaling occurs via the adaptor proteins MyD88,
TIRAP/Mal, and Trif. These molecules then orchestrate a down- Cytokines as Mediators of Defense Against
stream signaling cascade, which culminates in induced patterns Intracellular Bacteria
of gene transcription that mediate innate and, ultimately, adaptive We have already mentioned that a range of cytokines are induced
immune mechanisms that aim at combating the intracellular by the signaling mechanisms that result from engagement of
bacteria. PRRs. These serve by both enhancing intracellular mechanisms
The cellular cytoplasm is monitored for presence of molecules of bacterial killing and mobilizing adaptive immune responses,
of bacterial origin by a further group of PRRs, the nucleotide representing the next layer of host defense. Because these responses
oligomerization domain protein-like receptors (NLRs). These allow an amplification of the initial innate immune responses,
molecules are characterized by presence of a nucleotide-binding they must be carefully regulated by the host to prevent extensive
domain and leucine-rich repeat motifs. Molecules from this tissue pathology. In fact, we might view the development of a
group recognizing bacterial components are nucleotide-binding granuloma as the sequela of a balance between bacterial killing
oligomerization domain (NOD)–containing proteins NOD1 and mechanisms and the need to restrict tissue pathology orchestrated
NOD2, NOD-like receptor P1 (NLRP1), NLRP3, and Naip5. Other by adaptive immunity. At the onset of infection, initial cytokine
cytosolic PRRs include the absent in melanoma-2-like receptor secretion occurs in the cell type that initially encounters intracel-
(ALR) family, cyclic guanosine monophosphate–adenosine lular bacteria and on initiation of signaling cascades by PRRs.
monophosphate (cGMP-AMP) synthase (cGAS), and stimulator These small molecules can act locally and systemically to directly
of interferon (IFN) genes (STING), all of which can be activated instruct cells, to produce antibacterial molecules, to combat
by bacterial DNA (see Table 26.2). intracellular infection, and to both increase numbers of immune
Engagement of NLRs and ALRs leads to activation of the cells and direct the composition of the cellular infiltrate that
multiprotein complex called the inflammasome, leading to cleavage will ultimately attempt to resolve intracellular bacterial infection.
of pro-IL-1β and pro-IL-18 to produce their active forms. In Cytokines are ultimately produced by multiple cell types, including
addition, activation of the NLRs, NOD1, and NOD2 results in adaptive T cells, B cells, unconventional T cells, MPs, DCs, PMNs,
inflammatory cytokine secretion. Certain PRRs are also receptive and even epithelial and endothelial cells. We will first consider
to certain endogenous “danger” signals produced by tissues the hierarchy by which these cytokines act in the control of
undergoing stress, damage, or cell death. These signals are trig- intracellular bacterial infection and the antibacterial mechanisms
gered by self-proteins, named danger-associated molecular patterns they regulate. We will then return to the generation and regulation
(DAMPs), include endogenous heat shock proteins, host of the cells that produce them.
nucleotides, and the chromatin component HMGB1. Therefore
PRRs mediate signals not only emanating from intracellular IFN-γ, TNF-α, IL-12, and IL-18
bacteria but also from host cells damaged by the infection process. By far, the cytokine with the clearest demonstrable potency
Understanding how PAMP and DAMP PRR signaling meshes against intracellular bacteria is IFN-γ. Extensive studies on the
to produce a coherent disease-specific output remains an exciting activation of antibacterial effector functions in macrophages have
challenge for future research. revealed a central role for IFN-γ. Accordingly, IFN-γ neutralization
As already alluded to, the culmination of PRR collaborative with antibodies, or deletion of the IFN-γ gene by homologous
sensing and signaling is the induction of inflammatory genes recombination, markedly exacerbates infectious diseases, such as