Page 446 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Host Defenses to Protozoa

Peter C. Melby, Robin Stephens, Sara M. Dann

Protozoal infections are an important cause of morbidity and T cells can be critically important through cytokine production
mortality worldwide (Table 30.1). Protozoan pathogens exact (e.g., Plasmodium spp., T. cruzi, T. gondii) or direct cytotoxic
their major toll in the tropics, but infection by these parasites activity (e.g., Cryptosporidium). For the parasites that have an
remains a significant problem in developed countries because extracellular stage (e.g., Plasmodium spp., Trypanosoma spp.,
of travel to and emigration from developing countries, the Giardia, and Trichomonas), specific antibodies mediate acquired
susceptibility of patients with acquired immunodeficiency immunity.
syndrome (AIDS) to opportunistic protozoans, and episodic Intensive effort has been dedicated to the development of
transmission within communities. effective vaccines for protozoal diseases, but as of 2016, only the
malaria circumsporozoite vaccine (RTS,S) has reached the stage
of clinical use. The reader is referred to a number of excellent
KEY CONCEPTS reviews of the potential vaccine candidates. A discussion of
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Host Defense Against Protozoa the immune responses to some of the individual protozoal
pathogens follows.
• Interaction of the parasite with host cells induces an array of cytokines
that stimulate the innate and adaptive immune responses to eliminate
the pathogen, and/or cytokines that inhibit or downregulate the Plasmodium spp.
antiparasitical responses to enable the initiation of tissue parasitism.
• The outcome of infection is determined by the balance between the Pathogenesis
infection-promoting and the host-protective cytokines and effector Soon after Plasmodium spp. sporozoites are injected into the
cells. Often there is a mixed response, resulting in a persistent bloodstream by the Anopheles mosquito, they invade hepatocytes
infection. and undergo schizogony (asexual reproduction). A dormant form
• A persistently infected host may develop clinical disease if there is a of P. vivax and P. ovale (hypnozoites) can reside within hepatocytes
waning of the immune mechanisms (e.g., in acquired immunodeficiency
syndrome [AIDS]) that are critical to the control of infection. for months and then cause clinical bloodstream infection. Fol-
lowing schizogony, merozoites are released from hepatocytes
into the bloodstream in a membrane-bound structure, known
Protozoan pathogens make up a group of highly diverse as merosomes. The merosomes rupture in blood, and free mero-
organisms that utilize a wide array of mechanisms for pathogenesis zoites invade red blood cells (RBCs) to produce ring-stage para-
and immune evasion. There are numerous host targets for the sites. These parasites mature into trophozoites, which again
intracellular protozoan parasites, including erythrocytes (Plas- undergo schizogony, leading to rupture of the erythrocyte and
modium and Babesia), macrophages (Leishmania and Toxoplasma the release of new invasive merozoites. Merozoites can also develop
gondii), or multiple cell types (Trypanosoma cruzi). The luminal into sexual-stage gametocytes, which can be ingested by a feeding
parasitical protozoan may be extracellular, such as amebae and mosquito to continue the transmission cycle.
the flagellates (Giardia and Trichomonas), or primarily intracel- The clinicopathological features of malaria are caused by
lular, such as the coccidian parasite Cryptosporidium. intraerythrocytic infection and the associated immune response.
The innate and adaptive immune systems respond in diverse The cyclical rupture of erythrocytes is associated with fever. The
ways to the blood and tissue and intestinal protozoan pathogens. induction of a proinflammatory cytokine cascade plays a central
Neutrophils, macrophages, and natural killer (NK) cells are the role in the pathogenesis of P. falciparum malaria and its complica-
effector cells that mediate the innate response against the extracel- tions. Parasite antigens, particularly those having glycophospha-
lular protozoan parasites. The NK cell–activated macrophage tidyl inositol (GPI) membrane anchors, released during the
system is central to the innate response to intracellular parasites rupture and reinvasion of RBCs, activate the innate immune
(Fig. 30.1) (Chapters 3, 17). The innate cytokine response activates response. The production of proinflammatory cytokines (IL-1,
phagocytes and is critical to the induction of the adaptive immune TNF, lymphotoxin, IL-12, and IFN-γ) leads to fever, expression
response via antigen presentation by dendritic cells (DCs). For of endothelial adhesion molecules, and cytoadherence. It is
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the intracellular pathogens (e.g., Leishmania spp., T. cruzi, T. mediated, in part, by TLR2 and is MyD88-dependent. NK cells
gondii), the early production of interleukin-12 (IL-12) and and memory T cells produce early IFN-γ, which contributes to
interferon-γ (IFN-γ) drives the differentiation of T cells to a the production of a pathologically high level of TNF. IL-10- and
protective T-helper 1 (Th1) phenotype. In most cases CD4 T transforming growth factor-β (TGF-β)–mediated downregulation
cells play a primary role in adaptive cellular immunity, but CD8 of the Th1 immune response and leukotriene (LT)/tumor necrosis

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