🪱Parasitology Unit 8 – Immune Responses to Parasitic Infections

Key Parasites and Their Characteristics

• Protozoan parasites (Plasmodium, Toxoplasma, Trypanosoma) are single-celled eukaryotic organisms that can cause severe diseases in humans
  • Plasmodium species cause malaria, a potentially life-threatening disease transmitted by mosquitoes
  • Toxoplasma gondii is an intracellular parasite that can cause toxoplasmosis, particularly dangerous for pregnant women and immunocompromised individuals
• Helminthic parasites (roundworms, tapeworms, flukes) are multicellular organisms that often have complex life cycles involving multiple hosts
  • Schistosoma species are blood flukes that cause schistosomiasis, a chronic disease affecting millions worldwide
  • Taenia solium is a tapeworm that can cause cysticercosis, a condition where larvae invade various tissues, including the brain
• Many parasites have specialized structures (hooks, suckers, adhesion proteins) that enable them to attach to and invade host tissues
• Parasites often exhibit antigenic variation, a process by which they alter their surface proteins to evade host immune recognition
• Some parasites (Trypanosoma cruzi) can enter and survive within host cells, providing protection from immune responses

Immune System Basics

• The immune system consists of two main branches: innate immunity and adaptive immunity
  • Innate immunity provides rapid, non-specific defense against pathogens
  • Adaptive immunity is slower to develop but provides specific, long-lasting protection
• Key cells of the innate immune system include macrophages, dendritic cells, neutrophils, and natural killer cells
  • Macrophages are phagocytic cells that engulf and destroy pathogens and infected cells
  • Dendritic cells are antigen-presenting cells that link innate and adaptive immunity by activating T cells
• Lymphocytes (T cells and B cells) are the main components of the adaptive immune system
  • T cells are involved in cell-mediated immunity and help coordinate the overall immune response
  • B cells produce antibodies, which are key mediators of humoral immunity
• Cytokines are signaling molecules that regulate and coordinate immune responses
  • Pro-inflammatory cytokines (IL-1, IL-6, TNF-α) promote inflammation and activate immune cells
  • Anti-inflammatory cytokines (IL-10, TGF-β) help control and resolve immune responses

Parasite Recognition by the Immune System

• Pattern recognition receptors (PRRs) on immune cells detect pathogen-associated molecular patterns (PAMPs) present on parasites
  • Toll-like receptors (TLRs) recognize various PAMPs, including parasite surface molecules and DNA
  • C-type lectin receptors (CLRs) bind to carbohydrate structures on parasite surfaces
• Antigen-presenting cells (APCs), such as dendritic cells and macrophages, process and present parasite antigens to T cells
  • Major histocompatibility complex (MHC) molecules on APCs display parasite peptides to T cells
  • MHC class I presents peptides to CD8+ T cells, while MHC class II presents peptides to CD4+ T cells
• B cells recognize parasite antigens through their B cell receptors (BCRs) and can differentiate into antibody-secreting plasma cells
• Antibodies can bind to parasite surface antigens, leading to neutralization, opsonization, or complement activation
• Some parasites (Schistosoma) can induce the production of specific antibody isotypes (IgE) that contribute to protective immunity

Innate Immune Responses

• Innate immune responses are the first line of defense against parasitic infections
• Complement system activation leads to parasite lysis, opsonization, and recruitment of immune cells
  • Alternative pathway is activated by parasite surface molecules and amplifies the complement cascade
  • Lectin pathway is triggered by the binding of mannose-binding lectin (MBL) to parasite carbohydrates
• Phagocytic cells (macrophages, neutrophils) engulf and destroy parasites through the production of reactive oxygen species (ROS) and nitric oxide (NO)
• Natural killer (NK) cells recognize and kill parasite-infected cells through the release of cytotoxic granules containing perforin and granzymes
• Innate lymphoid cells (ILCs) secrete cytokines that help shape the adaptive immune response and contribute to parasite clearance
• Mast cells and eosinophils release granules containing toxic mediators that can damage parasites and promote inflammation
  • Eosinophils are particularly important in the defense against helminthic parasites

Adaptive Immune Responses

• T cells play a central role in the adaptive immune response to parasitic infections
  • CD4+ T helper (Th) cells secrete cytokines that activate and coordinate other immune cells
    • Th1 cells produce IFN-γ, which activates macrophages and promotes cell-mediated immunity
    • Th2 cells secrete IL-4, IL-5, and IL-13, which stimulate B cell antibody production and eosinophil recruitment
  • CD8+ cytotoxic T lymphocytes (CTLs) directly kill parasite-infected cells through the release of cytotoxic granules
• B cells differentiate into plasma cells that secrete parasite-specific antibodies
  • IgG antibodies opsonize parasites, enhancing phagocytosis and complement activation
  • IgE antibodies bind to Fc receptors on mast cells and eosinophils, triggering the release of toxic mediators
  • IgA antibodies in mucosal secretions can prevent parasite attachment and invasion
• Memory T and B cells develop following initial exposure to parasites, providing long-lasting protection against reinfection
• The balance between Th1 and Th2 responses is crucial in determining the outcome of parasitic infections
  • Some parasites (Leishmania) can subvert the immune response by promoting a Th2-biased environment

Evasion Strategies of Parasites

• Parasites have evolved various mechanisms to evade or manipulate host immune responses
• Antigenic variation allows parasites to alter their surface proteins, making it difficult for the immune system to recognize and eliminate them
  • Trypanosoma brucei, the causative agent of African sleeping sickness, undergoes rapid antigenic variation of its variant surface glycoprotein (VSG) coat
• Some parasites (Plasmodium) can sequester themselves in specific tissues (brain, placenta) to avoid detection by the immune system
• Parasites can modulate host immune responses by secreting immunomodulatory molecules
  • Schistosoma mansoni secretes a protein (Sm16) that inhibits the production of pro-inflammatory cytokines by macrophages
  • Toxoplasma gondii produces a kinase (ROP16) that suppresses IL-12 production, favoring a Th2-biased response
• Parasites can exploit host immune regulatory mechanisms, such as the induction of regulatory T cells (Tregs) or the production of anti-inflammatory cytokines (IL-10, TGF-β)
• Some parasites (Leishmania) can survive and replicate within host macrophages by inhibiting phagosome-lysosome fusion or by resisting the toxic effects of ROS and NO

Immunopathology in Parasitic Infections

• While immune responses are essential for parasite control, they can also contribute to tissue damage and disease pathology
• Excessive Th1 responses can lead to severe inflammation and organ damage
  • In Chagas disease, caused by Trypanosoma cruzi, chronic inflammation can result in cardiomyopathy and digestive tract disorders
  • In cerebral malaria, caused by Plasmodium falciparum, excessive inflammation can lead to brain swelling and neurological complications
• Th2-mediated responses, particularly those involving IgE and eosinophils, can cause allergic-type reactions and tissue damage
  • In schistosomiasis, egg deposition in the liver can trigger granuloma formation and fibrosis, leading to portal hypertension
  • In lymphatic filariasis, caused by Wuchereria bancrofti and Brugia species, chronic inflammation can result in lymphedema and elephantiasis
• Autoimmune reactions can occur when parasite antigens cross-react with host proteins (molecular mimicry)
  • In Chagas disease, T. cruzi antigens can induce autoantibodies that target heart muscle proteins, contributing to cardiac damage
• Immunosuppression induced by parasites can increase susceptibility to secondary infections or reactivation of latent infections (e.g., tuberculosis, HIV)

Implications for Diagnosis and Treatment

• Understanding the immune response to parasitic infections is crucial for developing effective diagnostic tools and treatments
• Serological tests detect parasite-specific antibodies in the host's blood, indicating current or past infection
  • Enzyme-linked immunosorbent assay (ELISA) and indirect fluorescent antibody test (IFAT) are commonly used serological methods
  • Rapid diagnostic tests (RDTs) based on antigen detection are available for some parasitic diseases (malaria, leishmaniasis)
• Molecular techniques, such as polymerase chain reaction (PCR), can detect parasite DNA in clinical samples, providing high sensitivity and specificity
• Antiparasitic drugs target specific stages of the parasite life cycle or essential metabolic pathways
  • Artemisinin-based combination therapies (ACTs) are the first-line treatment for uncomplicated P. falciparum malaria
  • Praziquantel is the drug of choice for treating schistosomiasis by causing parasite tegument damage and paralysis
• Vaccines aim to induce protective immune responses against parasites
  • The RTS,S/AS01 vaccine provides partial protection against P. falciparum malaria in young children
  • Vaccine development for other parasitic diseases (leishmaniasis, Chagas disease) is an active area of research
• Immunotherapeutic approaches, such as the use of monoclonal antibodies or cytokine-based therapies, are being explored to modulate the immune response and improve parasite clearance
• Combining antiparasitic drugs with immunomodulatory agents may enhance treatment efficacy and reduce the risk of drug resistance