Page 451 - Clinical Immunology_ Principles and Practice ( PDFDrive )

430 ParT THrEE Host Defenses to Infectious Agents

in part through TLR2 and possibly TLR4. CpG motifs in the T. pathway, T-cell or macrophage suppressor activity, and PGE 2
cruzi genome have also been shown to activate TLR9. Several production. Within the foci of myocarditis, apoptosis of both
other TLR-independent mechanisms of innate immunity, includ- parasites and host cells occurs. The phagocytosis of these apoptotic
ing the activation of nucleotide-binding oligomerization domain cells by macrophages leads to their acquisition of an M2 phe-
(NOD)–like receptors, have been identified. 20 notype, which enables parasite replication and persistence. The
rapid escape of the parasite from the phagosome into the
Adaptive Immunity cytoplasm through the action of acid-activated porins enables
The innate immune response, through production of IL-12, type the organism to avoid phagolysosomal enzymatic destruction.
I IFNS, and other proinflammatory mediators, is critically linked
to the generation of an effective adaptive immune response. Toxoplasma gondii
Antibodies contribute to immunity within the bloodstream
through opsonization, complement activation, and antibody- Pathogenesis
dependent cellular cytotoxicity. Transmission occurs via the ingestion of oocysts, which are shed
Several lines of evidence establish the importance of T cells in the feces of felines or via tissue cysts present in undercooked
in adaptive immunity to T. cruzi infection. Parasite-specific CD4 meat. Following the oral ingestion of cysts, phagocytes recruited to
and CD8 T cells are activated during infection, and mice lacking the gut lumen facilitate transepithelial migration into the lamina
CD4 or CD8 T cells have impaired parasite control. CD8 T cells propria. These phagocytes have been termed “Trojan Horses,”
with cytotoxic activity against T. cruzi–infected cells have been as they carry the parasite to new, unsuspecting host cells. Host-
identified in infected mice, and these cells confer protection cell invasion starts with loose attachment facilitated by laminin.
21
when passively transferred to naïve mice. In the early stage of Intracellular tachyzoites replicate within a parasitophorous
infection, CD4 T cells are the predominant subset recruited to vacuole (PV) and ultimately leave the cell by using an active
the myocardium, but activated CD8 T cells soon dominate the egress pathway. The released tachyzoites can disseminate to invade
inflammatory process in cardiac tissue. IFN-γ and TNF production virtually any nucleated cell type, but mononuclear phagocytes are
by parasite-specific CD8 T cells is more important than cytolytic the preferred host cells. The toxoplasma SAG proteins mediate
activity in the control of infection. 21 parasite attachment, and the transmembrane adhesins, MIC and
T. cruzi infection leads to a mixed Th1/Th2 cytokine response, AMA1, and RON family proteases play major roles in the myosin
and in general, the Th1/Th2 balance determines resistance or motor-driven process of host-cell invasion. Under pressure from
susceptibility. As noted earlier, IL-12/STAT4-dependent IFN-γ the host immune response, tachyzoite replication is controlled
production by NK cells in early infection, and later by T cells, and tissue cysts, containing slowly replicating bradyzoites, are
is critically important to protection. IL-4 does not appear to formed. The tissue cysts persist as a chronic latent infection
play a major role in susceptibility to T. cruzi infection, but IL-10 as long as the host immune function is intact. If the latently
promotes parasite replication by inhibiting macrophage trypano- infected person is immunosuppressed, reactivation occurs, and
cidal activity. IL-10 also plays a critical role in minimizing tachyzoites are released to infect more cells. Because tissue cysts
inflammation-mediated tissue pathology by regulating the Th1 (bradyzoites) are found in proportionately larger numbers in the
and TNF responses. Polymorphisms in the IL-10 gene that lead brain, reactivation of latent infection in the immunocompromised
to reduced IL-10 production are associated with increased severity host most commonly manifests as encephalitis.
of cardiomyopathy in patients with Chagas disease. Similarly,
TGF-β has been shown to inhibit macrophage trypanocidal Innate Immunity
activity and increase parasitemia and mortality. In addition to Similar to immunity to Plasmodium and Leishmania, IL-12,
these regulatory cytokines, the secretion of prostaglandins and IFN-γ, TNF-α, and NK cells contribute to the control of the
+
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NO, the induction of apoptosis of T and B cells, and the expansion early stages of T. gondii infection. CD8α DCs are the primary
of a myeloid suppressor cell population serve to control the producers of IL-12, which is essential to host resistance. IL-12 is
intensity of the immune response. produced through a MyD88-dependent mechanism, at least in
part, through the interaction of parasite-derived proteins and
Evasion of Host Immunity TLR2 and TLR11, and activation of CCR5. IL-12-dependent
24
A significant part of the pathogenesis following T. cruzi infection activation of NK cells leads to IFN-γ production, which, in turn,
is its dissemination through the bloodstream to many tissues. activates macrophages to limit parasite replication. T cells express-
T. cruzi bloodstream trypomastigotes resist complement lysis ing the γδ receptor and neutrophils are also an early source of
via a complement regulatory protein (GP-160). This parasite IFN-γ and TNF-α. Recruitment of inflammatory macrophages
protein is functionally similar to mammalian decay-accelerating to the site of infection is crucial to control of parasite replica-
factor in that it inhibits C3 convertase formation and activation tion and dissemination. IFN-γ-induced macrophage activation is
of the alternate complement pathway. T. cruzi invades host cells, the key effector mechanism leading to parasite killing. In mice,
in particular cardiomyocytes, by subverting a host plasma the induction of immunity-related GTPases (IRG), which
membrane repair pathway that promotes parasite persistence damage the parasitophorous vacuole membrane and kill T.
and tissue tropism. 22 gondii within the cytosol, is the primary macrophage effector
The establishment of chronic infection by T. cruzi is favored mechanism. The generation of reactive nitrogen and oxygen
by a generalized depression of T-cell responses. A number of intermediates, degradation of tryptophan, and the production
different mechanisms may contribute to this, including low IL-2 of LTs have also been implicated in the control of T. gondii in
production or IL-2 receptor expression; downregulation of human macrophages. However, humans lack the entire IRG family,
components of the T cell–receptor complex; T-cell receptor as well as TLR11, and the mechanism(s) of early IFN-γ–medi-
dysfunction; apoptosis of T cells; defects in the processing and ated macrophage activation and parasite control in humans is
presenting of antigens in the MHC class II (but not the class I) unclear.