Immunity to Protozoa and Worms

Chapter 15 Immunity to Protozoa and Worms




Summary




Parasites stimulate a variety of immune defense mechanisms.


Parasitic infections are often chronic and affect many people. They are generally host specific and most cause chronic infections. Many are spread by invertebrate vectors and have complicated life cycles. Their antigens are often stage specific.


Innate immune responses are the first line of immune defense.


T and B cells are pivotal in the development of immunity. Both CD4 and CD8 T cells are needed for protection from some parasites, and cytokines, chemokines, and their receptors have important roles.


Effector cells such as macrophages, neutrophils, eosinophils, and platelets can kill both protozoa and worms. They secrete cytotoxic molecules such as reactive oxygen radicals and nitric oxide (NO). All are more effective when activated by cytokines. Worm infections are usually associated with an increase in eosinophil number and circulating IgE, which are characteristic of TH2 responses. TH2 cells are necessary for the elimination of intestinal worms.


Parasites have many different escape mechanisms to avoid being eliminated by the immune system. Some exploit the host response for their own development.


Inflammatory responses can be a consequence of eliminating parasitic infections.


Parasitic infections have immunopathological consequences. Parasitic infections are associated with pathology, which can include autoimmunity, splenomegaly, and hepatomegaly. Much immunopathology may be mediated by the adaptive immune response.


Vaccines against human parasites are not yet routinely available.



Parasite infections


Parasitic infections typically stimulate a number of immune defense mechanisms, both antibody and cell mediated, and the responses that are most effective depend upon the particular parasite and the stage of infection. Some of the more important parasitic infections of humans (Fig. 15.1) affect the host in diverse ways. Parasitic protozoa may live:




Parasitic worms that infect humans include trematodes or flukes (e.g. schistosomes), cestodes (e.g. tapeworms), and nematodes or roundworms (e.g. Trichinella spiralis, hookworms, pinworms, Ascaris spp., and the filarial worms).


Tapeworms and adult hookworms inhabit the gut, adult schistosomes live in blood vessels, and some filarial worms live in the lymphatics (Fig. 15.2). It is clear that there is widespread potential for damaging pathological reactions.



Many parasitic worms pass through complicated life cycles, including migration through various parts of the host’s body:



Most protozoa rely upon an insect vector, apart from Toxoplasma and Giardia spp. and amoebae, which are transmitted by ingestion. Thus:




Parasitic infections are often chronic and affect many people


Parasitic infections present a major medical problem, especially in tropical countries (see Fig. 15.1), for example:



Anemia and malnutrition are also associated with parasitic disease.


Over millions of years of evolution, parasites have become well adapted to their hosts and show marked host specificity. For example, the malarial parasites of birds, rodents, or humans can each multiply only in their own particular kind of host.


There are some exceptions to this general rule, for example:



Protozoan parasites and worms are considerably larger than bacteria and viruses (Fig. 15.w1), and have very different strategies for avoiding the host immune response.




Parasites that have complicated life histories may express certain antigens only at a particular stage of development, giving rise to a stage-specific immune response. Thus, the protein coat of the sporozoite (the infective stage of the malarial parasite transmitted by the mosquito) induces the production of antibodies that do not react with the erythrocytic stages. The different stages of the worm T. spiralis also display different surface antigens.


Protozoa that are small enough to live inside human cells have evolved a special mode of entry:



Leishmania can also gain entry to the cell by using the mannose receptor (see Fig. 7.11) on the macrophage surface.



Immune defenses against parasites





Host defense depends upon a number of immunological mechanisms


The development of immunity is a complex process arising from the activation of both adaptive and innate immune responses and the switching on of many different kinds of cell over a period of time. Effects are often local and many cell types secreting different mediators may be present at sites of immune rejection. Moreover, the processes involved in controlling the multiplication of a parasite within an infected individual may differ from those responsible for the ultimate development of resistance to further infection.


In some helminth infections a process of ‘concomitant immunity’ occurs, whereby an initial infection is not eliminated, but becomes established, and the host then acquires resistance to invasion by new parasites, mostly worms, of the same species.


In very general terms, humoral responses are important to eliminate extracellular parasites such as those that live in blood (Fig. 15.4), body fluids, or the gut.



However, the type of response conferring most protection varies with the parasite. For example, antibody, alone or with complement, can damage some extracellular parasites, but is better when acting with an effector cell.


As emphasized above, within a single infection different effector mechanisms act against different developmental stages of parasites. Thus in malaria:




Innate immune responses


The innate and adaptive immune responses are co-evolving to allow mammals to identify and eliminate parasites.


The innate immune system provides the first line of immune defense by detecting the immediate presence and nature of infection.


Many different cells are involved in generating innate responses including phagocytic cells and NK cells. It is also becoming clear that early recognition of parasites by antigen-presenting cells (APCs), for example dendritic cells, determines the phenotype of the adaptive response (Fig. 15.5).



Innate immune recognition relies on pattern recognition receptors (PRRs) that have evolved to recognize pathogen-associated molecular patterns (PAMPs).




Q. Which groups of receptors and soluble molecules recognize PAMPs?


A. Toll-like receptors (see Fig. 6.20), the mannose receptor (see Fig. 7.11) and scavenger receptors (see Fig. 7.10) allow phagocytes to directly recognize pathogens. Ficolins, collectins, and pentraxins act as soluble opsonins by binding to pathogen surfaces (see Fig. 6.w3image).


A unifying feature of these targets is their highly conserved structures, which are invariant between parasites of a given class.


Although many parasites are known to activate the immune system in a non-specific manner shortly after infection, it is only recently that attention has been given to the mechanisms involved.


While major advances are being achieved in the area of microbial recognition by PRRs, a small but growing number of studies show that parasites also possess specific molecular patterns capable of engaging PRRs. Examples of some parasite PAMPs along with their receptors are given in Figure 15.6.





Classical human PRRs also contribute to recognition of parasites


Classical PRRs also play important roles in the innate response to parasite infection (see Fig. 15.6) and include collectins (e.g. MBL), pentraxins (e.g. CRP), C-type lectins (e.g. macrophage mannose receptor, and scavenger receptors (e.g. CD36) – see Chapters 6 and 7. For example, MBL binds mannose-rich LPG from Leishmania, Plasmodium, trypanosomes, and schistosomes; and polymorphisms in the MBL gene are associated with increased susceptibility to severe malaria.




Adaptive immune responses to parasites



T and B cells are pivotal in the development of immunity


In most parasitic infections, protection can be conferred experimentally on normal animals by the transfer of spleen cells, especially T cells, from immune animals.


The T cell requirement is also demonstrable because nude (athymic) or T-deprived mice fail to clear otherwise non-lethal infections of protozoa such as T. cruzi or Plasmodium yoelii, and T cell-deprived rats fail to expel the intestinal worm Nippostrongylus brasiliensis (Fig. 15.7).



Counterintuitively, many parasites require signals from immune cells to thrive – for example, schistosomes fail to develop in the absence of hepatic CD4+ lymphocytes.


B cells also play key roles in regulating and controlling immunity to parasites. For example:




Both CD4 and CD8 T cells are needed for protection from some parasites


The type of T cell responsible for controlling an infection varies with the parasite and the stage of infection, and depends upon the kinds of cytokine they produce. For example, CD4+ and CD8+ T cells protect against different phases of Plasmodium infection:



The action of CD8+ T cells is twofold:




The immune response against T. cruzi depends not only upon CD4+ and CD8+ T cells, but also on NK cells and antibody production; the same is true for the immune response against T. gondii.


CD8+ T cells confer protection in mice depleted of CD4+ T cells, both through their production of IFNγ and because they are cytotoxic for infected macrophages.


NK cells, stimulated by IL-12 secreted by the macrophages, are another source of IFNγ – chronic infections are associated with reduced production of IFNγ.


These observations probably underlie the high incidence of toxoplasmosis in patients with AIDS, who are deficient in CD4+ T cells.


CD4+ T cells are critical for the expulsion of intestinal nematodes and as immunity to T. muris can be transferred to a SCID (severe combined immune deficiency) mouse by the transfer of CD4+ T cells alone there is no evidence for a role of CD8+ T cells.


The cytokines produced by CD4+ T cells can be important in determining the outcome of infection. As TH1 and TH2 cells have contrasting and cross-regulating cytokine profiles, the roles of TH1 or TH2 cells in determining the outcome of parasitic infections have been extensively investigated.


As a result of early studies, predominantly in mouse infections, certain dogmas have arisen suggesting that:



However, this is very much an oversimplification of the true picture, and based on work in animal models that may not fully recapitulate the human immune system.


Although the TH1/TH2 paradigm may be a useful tool in some situations, it is probably more realistic in humans to consider that TH1 and TH2 phenotypes represent the extremes of a continuum of cytokine profiles, and that perhaps it may be more accurate to look at the role of the cytokines themselves in the resolution of infectious disease, particularly as new TH subsets are being discovered, e.g. TH17, TH22, and TH9, and their roles in immunity to parasites investigated.


Regulatory T cells are able to modulate the extremes of both TH2 and TH1 responses.



Cytokines, chemokines, and their receptors have important roles




Cytokines not only act on effector cells to enhance their cytotoxic or cytostatic capabilities, but also act as growth factors to increase cell numbers, while chemokines attract cells to the sites of infection. Thus in malaria, the characteristic enlargement of the spleen is caused by an enormous increase in cell numbers.


Other examples include:



Mucosal mast cells and eosinophils are both important in determining the outcome of some helminth infections and proliferate in response to the products of T cells – IL-3, granulocyte–macrophage colony stimulating factor (GM-CSF), and IL-5 respectively.


However, an increase in cell number can itself harm the host. Thus administration of IL-3 to mice infected with Leishmania major can exacerbate the local infection and increase the dissemination of the parasites, probably through the proliferation of bone marrow precursors of the cells the parasites inhabit.


IL-10 and transforming growth factor-β (TGFβ), the regulatory cytokines (see Chapter 11), downregulate the proinflammatory response and thus minimize pathological damage.


Chemokines are key molecules in recruiting immune cells by chemotaxis, but also act in leukocyte activation, hematopoiesis, inflammation, and antiparasite immunity.


Protozoan parasites have been most studied in the context of chemokines and their diverse roles in the parasite–host relationship. For example, T. gondii possesses cyclophilin-18, which binds to the chemokine receptor CCR5 and induces IL-12 production by dendritic cells.


Jun 18, 2016 | Posted by in IMMUNOLOGY | Comments Off on Immunity to Protozoa and Worms

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