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426 ParT THrEE Host Defenses to Infectious Agents

TABLE 30.1 Worldwide Significance of the Major Protozoal Infections
Parasite Estimated Worldwide Cases (annual Mortality) Clinical Manifestations
Plasmodium spp. 400–490 million (P. falciparum: >2 million deaths/year, Fever with potential complications of severe hemolysis, renal
primarily children) failure, pulmonary edema, cerebral involvement
Leishmania spp. 10–50 million people infected, 1.2 million new cases per Asymptomatic infection; skin ulcers or nodules; destructive
year oropharyngeal lesions; visceral disease with fever,
hepatosplenomegaly, cachexia, pancytopenia
Trypanosoma cruzi 24 million (60 000 deaths) Asymptomatic infection; dysrhythmias or chronic heart failure;
hypertrophy and dilation of the esophagus, colon
Toxoplasma gondii Several hundred million people infected worldwide. Self-limited fever, hepatosplenomegaly; lymphadenopathy and
5–9% of healthy US adults are seropositive encephalitis (reactivation in patients with acquired
immunodeficiency syndrome [AIDS]); congenital infection,
with fetal death, chorioretinitis, meningoencephalitis
Entamoeba histolytica 50 million (100 000 deaths) Asymptomatic infection, diarrhea, dysentery, or liver abscess
Giardia lamblia 200 million (most common in young children and Asymptomatic infection, chronic diarrhea
immunocompromised persons)
Cryptosporidium parvum Prevalence 3–10% in patients with diarrhea in developing Self-limited diarrhea in immunocompetent persons, severe
and C. hominis countries intestinal and biliary disease in patients with AIDS
Trichomonas vaginalis 170 million/year Asymptomatic infection, vaginal discharge, urethritis

Pathogen or KEY CONCEPTS
soluble products
IFN-α/β Immunopathogenesis of Severe Plasmodium
falciparum Malaria
IL-10
TGF-β (-) (+) • Release of malarial antigens stimulates tumor necrosis factor (TNF),
PGE 2 NK cell interleukin (IL)-1, and lymphotoxin production from innate immune
RNI cells.
IL-12 ROI • TNF/leukotriene (LT) induce vascular leakage, hemorrhage, endothelial
IFN-γ
TNF-α (+) TNF-α cell activation with expression of endothelial adhesion molecules,
IL-18 platelet activation and adhesion, and coagulation.
(+) IL-1β (+) NO Macrophage • Inflammatory cytokines amplify severe anemia caused by loss of
Macrophage activated infected red blood cells (RBCs) by inducing dyserythropoiesis and
or dendritic cell for intracellular phagocytosis of uninfected RBCs, which can be coated with parasite
IFN-γ killing antigens.
TNF-α • Lethal outcomes for the fetus of infected women during pregnancy
FIG 30.1 Macrophage, Natural Killer (NK) Cell, and Cytokine are caused by the local immune response induced by placenta-specific
Interactions in the Innate Immune Response to Intracellular parasites.
Protozoa. Exposure of macrophages or dendritic cells to a
pathogen or microbial product can result in the release of
cytokines and inflammatory mediators that may stimulate (+) or Innate Immunity
suppress (−) NK cell activation. Activated NK cells produce Complement-mediated lysis can occur at the sporozoite and
cytokines that can then activate macrophages for intracellular merozoite stages, though parasites have evolved evasive mecha-
killing. It must be recognized that this diagram is oversimplified nisms. While sporozoites rapidly transit from the skin to the
and that these cytokines, most notably interferon (IFN)-α/β, liver, they can activate DCs at the site of inoculation or in the
interleukin (IL)-10, transforming growth factor (TGF)-β, and IL-12, regional lymph node. Early activation of NK cells and IFN-γ
may be produced by other types of cells, such as epithelial cells are associated with better outcomes of infection. Although high
or enterocytes. NO, nitric oxide; RNI, reactive nitrogen intermedi- levels of TNF are associated with severe malaria, physiological
ates; ROI, reactive oxygen intermediates. levels are protective through the activation of macrophages. γδ
+
T-cell receptor (TCR) T cells that respond to phosphorylated
nonpeptide antigens on live parasites have been demonstrated.
factor (TNF) production, which have a role in severe and cerebral DCs initially induce a strong adaptive immune response to the
malaria, act to limit the inflammatory response. erythrocytic stage, which is tempered during prolonged infection.
Severe malaria includes severe anemia, respiratory distress,
placental malaria, and cerebral malaria, with the latter causing Adaptive Immunity
up to 90% of deaths. In cerebral malaria, a combination of Partial immunity to Plasmodium spp. infection is acquired slowly
6
inflammation, cytoadhesion of parasites, and leukocytes, and following repeated exposure in endemic areas. In areas of intense
vascular pathology leads to coma. Cytokines and endothelial cell perennial P. falciparum transmission, the density of parasitemia,
production of nitric oxide (NO) contribute to inflammatory morbidity, and the incidence of cerebral malaria and malaria-
lesions in the brain. Patients may die as a result of severe edema related deaths are highest in the early childhood years, declining
and swelling of the brainstem. Severe anemia is the result of a thereafter. Naturally acquired immunity to repeated infections
combination of destruction of infected and uninfected RBCs develops in young adults, with the exception of the morbidity
and dyserythropoiesis. Both destruction of uninfected RBCs and associated with placental infections.
malformation of RBCs in bone marrow are increased by inflam- Adaptive immunity to the preerythrocytic stage is primarily
matory cytokines, as is the damage in placental malaria. mediated through major histocompatibility complex (MHC)