Page 452 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 30 Host Defenses to Protozoa 431

microvilli shortening and apical separation that allows the parasite
Adaptive Immunity to penetrate between the epithelial cells and degrade connective
Although serum antibodies can be used in the diagnosis of T. tissue, resulting in ulceration of the mucosa and submucosa (Fig.
gondii infection, the systemic antibody response does not play 30.3). The trophozoites can lyse multiple cell types, including
a role in adaptive immunity. Mucosal IgA, however, does provide neutrophils, which release enzymes that further damage the tissue.
resistance to oral infection with T. gondii cysts. CD4 and CD8 The cytotoxic effects of amebae are mediated by a secreted cysteine
T cells are highly activated during infection and are essential for protease, the Gal/GalNAc lectin, phospholipase A, and contact-
adaptive immunity. As such, patients with defects in T cell– dependent cytolysis, in which an ion channel (amebapore) is
mediated immune responses (e.g., patients with AIDS) are at inserted into the membrane of target cells. E. histolytica can induce
risk for reactivation of latent infection. apoptosis in mammalian cells by a caspase-dependent, TNF-α/
IL-12 from DCs drives the differentiation of T cells into type-1 Fas–independent process. Amebic liver abscesses develop when
CD4 and CD8 T cells that are essential to adaptive immunity. trophozoites erode through the intestinal submucosa, enter the
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CD4 and CD8 T cells act synergistically to prevent cyst reactivation portal circulation, and disseminate to the liver. Comparison of
during chronic latent infection. Parasite-specific cytolytic T cells the transcriptional profiles of virulent and nonvirulent Entamoeba
have been demonstrated; however, CD8 T cells mediate protection species has identified novel virulence factors in E. histolytica. 29
primarily through the generation of IFN-γ. IL-12 drives the
generation of terminally differentiated CD8 effector T cells, which Innate Immunity
express the killer cell lectin-like receptor G1 (KLRG1) and high Adherence of trophozoites to intestinal epithelial cells stimulates
levels of granzyme B and IFN-γ. The combination of IL-7 and the release of a variety of proinflammatory mediators, including
IL-15 is required for T cm -cell differentiation. IL-1α, IL-1β, IL 6, IL-8, and TNF-α, which triggers the recruit-
Antiinflammatory molecules, particularly IL-10 and IL-27 ment of neutrophils and macrophages to the site of invasion.
made by Th1 cells, play an important role in modulating the Following activation by IFN-γ and TNF-α, neutrophils and
adaptive immune response and restricting host tissue damage. 25 macrophages become amebicidal through the release of reactive
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oxygen species and production of nitric oxide, respectively.
Evasion of Host Immunity Invariant natural killer T (iNKT) cells, which comprise about
25
T. gondii escapes early macrophage killing in a number of ways. 30% of hepatic lymphocytes, are stimulated by amebic lipopep-
Virulent parasites are protected by localization to the parasi- tidephosphoglycan (LPPG) to release IFN-γ. Production of IFN-γ
tophorous vacuole, which does not fuse with host cell lysosomes reduces parasite burden and controls abscess formation. 28
(probably because the PV membrane proteins are of parasite
rather than host origin), and so the vacuole is not acidified to Adaptive Immunity
kill the parasite. The infected macrophage is also a suboptimal Secretory IgA responses against E. histolytica have been well
target for T cell–induced immunity because of reduced expression characterized and shown to correlate with protection against
of MHC class II and costimulatory molecules. Infection also infection and disease. For this reason, vaccines designed to
induces the production of counterregulatory molecules, such as generate IgA antibodies against the Gal/Gal/NAc lectin have been
IL-10, TGF-β, lipoxin A4. These not only downregulate a poten- highly efficacious in preventing experimental E. histolytica infec-
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tially pathological host inflammatory response but also inhibit tion in mice and baboons. However, the role of antilectin IgG
Th1 induction and macrophage antimicrobial activity. In addition, is unclear, and protection may be subclass-dependent. Cell-
T. gondii interferes with normal macrophage signaling. For mediated immunity is also critical for host defense against E.
example, infection inhibits DNA binding of signal transducer histolytica. IFN-γ–producing CD4 T cells provide protection
and activator of transcription 1 (STAT1) and NF-κB by interfering through their ability to activate macrophages and neutrophils
with chromatin structure, and promotes antiinflammatory to the parasite. CD8 T cells mediate protection through the
pathways downstream of the suppressor of cytokine synthesis secretion of IL-17, a key player in the secretion of mucin and
proteins. The parasite also has several virulence proteins, including antimicrobial peptides, recruitment of neutrophils, and IgA
ROP5 and ROP16, which bind to the parasitophorous vacuole transport across the epithelial barrier. Impairment of cell-mediated
and reduce accumulation of the IRGs. ROP proteins also activate immunity results in parasite dissemination. Indeed, patients with
host STAT3 and STAT6 driving an M2 macrophage phenotype human immunodeficiency virus infection and coinfected with
that is permissive to infection. 26 E. histolytica have high rates of invasive amebiasis, liver abscesses,
and seroconversion. 29
Entamoeba histolytica Evasion of Host Immunity

Pathogenesis E. histolytica utilizes a number of strategies to circumvent the
E. histolytica causes asymptomatic intestinal colonization, acute immune defenses of the host. It resists complement-mediated
diarrhea, dysentery, colitis, liver abscess, and, rarely, disseminated lysis during hematogenous spread by proteolytic degradation of
disease. Susceptibility to amebiasis is determined by the host’s C3a and C3b. In addition, the Gal/GalNAc lectin binds to C8
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nutritional status, intestinal microflora, genetics, and gender. and C9, preventing assembly of the C5b-9 membrane attack
E. histolytica cysts are ingested through consumption of food or complex. The cytolytic capability of E. histolytica affords protection
water contaminated by feces. After excystation, the trophozoites from neutrophils, macrophages, and eosinophils, unless these
degrade the colonic mucus barrier through secretion of proteases cells are activated. Cytolysis by E. histolytica can occur via necrosis
and glycosidases. The trophozoites adhere to the colonic epithelial and apoptosis. Trophozoites also inhibit the macrophage respira-
cells by a galactose/N-acetylgalactosamine-inhibitable lectin (Gal/ tory burst and the production of IL-1 and TNF-α. A protective
GalNAc), which leads to NF-κB activation and proinflammatory antibody response is subverted by the degradation of IgA and
cytokine release. Epithelial cells with adherent amebae undergo IgG by amebic cysteine proteases and by capping, ingesting, or