Malaria Immunology Notes

Innate Immunity

• Involves myeloid cells (such as macrophages and dendritic cells) and epithelial cells.

• Activation begins upon recognition of pathogens through Pathogen Recognition Receptors (PRRs), leading to a rapid response.

• Engagement of PRRs on immune cells triggers intracellular signaling pathways that result in the production and secretion of inflammatory cytokines, such as IL-1, IL-6, and TNF-alpha, which mediate the inflammatory response.

• Natural Killer (NK) cells contribute to innate immunity through direct cytotoxicity against virus-infected or tumor cells and by producing inflammatory cytokines like interferon-gamma to enhance the responses of other immune cells.

Adaptive Immunity

• This immune response is initiated by innate immune cells, specifically dendritic cells (DCs), which act as antigen-presenting cells (APCs).

• DCs capture and process antigens, presenting them on major histocompatibility complex (MHC) molecules to naïve T lymphocytes in the lymph nodes.

• Adaptive immunity primarily involves T lymphocytes (helper T cells and cytotoxic T cells) and B cells, which are responsible for antibody production.

• Immunization

• Vaccines are designed to induce specific immune responses that prepare the body to fight infections.

• Immune responses from vaccines can result in pathology, including local and systemic inflammation, which may present as fever, pain at the injection site, and other reactions.

General Principles of the Innate Immune Response

• Entry of Pathogen

  • The pathogen enters through various routes, such as respiratory, gastrointestinal, or broken skin.

• Recognition

  • Macrophages recognize the pathogen using specific receptors, including Toll-like receptors (TLRs).

• Phagocytosis

  • Macrophages phagocytose the pathogen, engulfing it in vesicles called phagosomes that fuse with lysosomes to degrade the pathogen.

• Cytokine Production

  • Macrophages produce cytokines like IL-8 that recruit other immune cells to the site of infection.

• Neutrophil Activation

  • IL-8 activates neutrophils, promoting their migration to the infection site and enhancing their phagocytic abilities.

• Phagocytosis by Neutrophils

  • Neutrophils also phagocytose and kill pathogens, further amplifying the immune response.

Innate vs. Adaptive Immunity

• Innate Immunity

  • Characterized by a rapid, non-specific response.

  • Recognizes Pathogen-Associated Molecular Patterns (PAMPs) through PRRs, leading to the release of cytokines.

  • Involves the recruitment of various immune cells, such as neutrophils and macrophages.

• Adaptive Immunity

  • Features a slower, antigen-specific response that develops over days to weeks.

  • Involves T and B cells with specific receptors that recognize unique antigens.

  • Produces antibodies that provide long-term immunity following pathogen exposure or vaccination.

Immunization

• Primary Antibody Response

  • Following initial exposure to an antigen, antibody concentration gradually rises, peaking approximately 2 weeks after vaccination.

• Secondary Antibody Response

  • A subsequent exposure leads to a quicker and stronger antibody production, often due to the presence of memory T and B cells.

  • Antibody concentration remains elevated for an extended period, providing enhanced immunity.

  • Effective immunization also promotes the generation of cytotoxic CD8+ T cells that recognize and destroy infected cells.

Parasitism

• The term is derived from the Greek word "Parasitos," meaning "one who eats at another's table."

• This describes a relationship between two different organisms, where the parasite benefits at the expense of the host, which can lead to various diseases.

• Examples of Parasites

  • Intracellular: bacteria, protozoa, viruses.

  • Animals: parasitic worms, insect infestations (ectoparasites).

  • Fungal infections.

  • Social Parasitism: such as brood parasitism seen in some bird species.

  • Extracellular: various bacteria and certain plants.

• Key Characteristics of Parasitism

  • Defined as a non-mutual symbiotic relationship.

  • The parasite benefits at the expense of the host, which often incurs damage or disease.

  • Parasites are generally smaller than their hosts and may not directly kill them as they rely on the host for nutrients and habitat.

  • Common benefits to parasites include obtaining nutrients, heat, habitat, and facilitating transmission.

Protozoal Parasites

• Unicellular eukaryotic organisms characterized by a membrane-bound nucleus.

• They exist as independent cells with distinct structures and functions.

• Protozoa is a historical term that encompasses a diverse grouping of distantly related organisms, retaining its utility despite advancements in classifications.

• Examples

  • Leishmania major (Leishmaniasis).

  • Plasmodium falciparum (Malaria).

  • Trypanosoma brucei (African sleeping sickness).

  • Entamoeba (commensal organism).

  • Classification includes Flagellates, Apicomplexans, and Amoebae.

Size of Protozoal Parasites

• Worm (Ascaris): 300,000 \, ext{μm} (about 5000 times larger than a typical mammalian cell).

• Virus (e.g., Epstein Barr Virus): 0.2 \, ext{μm}.

• Trypanosome: 10-20 \, ext{μm} (extracellular).

• Extracellular Bacteria (e.g., Klebsiella): 2 \, ext{μm}.

• Mammalian Cell: 40 \, ext{μm}.

• L. Major promastigote (extracellular phase): 20 \, ext{μm}.

• L. Major amastigote (intracellular phase): 5 \, ext{μm}.

• Plasmodium falciparum Merozoite: 2 \, ext{μm}.

• Red Blood Cell: 8 \, ext{μm}.

Malaria

• First described by Hippocrates in 500 BC, malaria remains a significant parasitic disease with a high burden globally, especially among children.

• High morbidity and mortality rates are linked to malaria, with chronic infections significantly impacting education and economy.

• In endemic areas, around 50% of children are infected, and chronic infection can reduce school performance by up to 15%.

• A decrease in malaria cases often corresponds with improvements in economic outputs and healthcare interventions.

• Malaria - Plasmodium falciparum

  • This protozoan parasite is the predominant cause of malaria in humans, with a significant majority of cases attributed to this species in Africa.

  • Other related species include P. knowlesi, P. vivax, P. ovale, and P. malariae.

  • Transmission primarily occurs through the bite of infected female Anopheles mosquitoes, making vector control a key strategy in preventing infection.

  • Since 2006, it is estimated that there have been around 247 million human infections due to malaria, predominantly affecting children under 5 years old.

Malaria Life Cycle and Immunology

• The lifecycle of Plasmodium involves complex processes including the hepatic and erythrocytic phases, with symptoms manifesting in cycles characterized by chills, fever, and sweats, correlated with the release of merozoites.

• Targets for intervention include the development of effective vaccines, the use of antimalarial drugs that inhibit parasite metabolism, and vector control strategies to reduce mosquito populations.

• The immune response can contribute to pathology through mechanisms like red blood cell lysis, which can cause anemia and stimulate exaggerated inflammatory responses, leading to tissue damage and complications.

Pathology and Immuno-pathology of P. falciparum

• Diagnosis is often made through blood smear microscopy, which reveals characteristic ring forms of the parasite within red blood cells.

• The mass destruction of red blood cells results in significant morbidity, evidenced by anemia, periodic fevers, and can lead to death if not properly treated.

• Common complications include kidney damage, splenic enlargement, and systemic inflammation due to the immune response attempting to clear infected red blood cells, resulting in vascular dysregulation and the potential for death.

Vascular Immuno-pathology in Malaria

• Various components are involved in the pathology of malaria, including ring forms, merozoites, and hemozoin, leading to lymphocyte and monocyte recruitment causing a cytokine storm that exacerbates the disease.

• Interaction with cellular components like platelets can lead to microhemorrhage and multi-organ involvement impacting vital systems such as the kidney and brain.

Malaria-Induced Inflammation

• Pattern recognition through PAMPs and DAMPs activates innate immune cells, leading to a spectrum of inflammatory responses that may vary from mild to severe disease.

• Genetic heterogeneity and age can also influence the severity and quality of the immune response to the malaria infection.

Consequences of Malaria-Induced Inflammation

• Biomarkers such as PfHRP2 can indicate parasite biomass and correlate with disease severity and poor outcomes in infected individuals.

Pathophysiology of Placental Malaria

• The inflammatory immune response within the placenta can lead to abnormal trophoblast development, impairing gas and nutrient transport, which adversely affects maternal and fetal health.

Adaptive Immunity to Malaria

• Recurrent infections typically result in poor protective immunity; however, some individuals can develop significant immunity over time, prompting ongoing research into vaccine development to enhance this process.

Killing of Infected RBC by Cytotoxic CD8+ T Cells

• The recognition of parasite antigens presented by MHC molecules triggers a cytotoxic response, leading to the release of toxic granules by CD8+ T cells that effectively destroy infected host cells.

Malaria Vaccine Design

• Vaccine strategies target various stages of the parasite's lifecycle, including the liver stage to help prevent initial infections in young children, and the gametocyte stage to interrupt transmission cycles.

• The importance of inducing strong immunity in adult populations through vaccine design continues to be a priority in malaria research.

RTS,S/AS01 (RTS,S) Malaria Vaccine

• First effective malaria vaccine demonstrating significant efficacy after 40 years of development, providing 36% protection against disease and 72% mortality reduction compared to standard seasonal antimalarial drugs.

• This vaccine, a hepatitis B virus-like particle, targets sporozoites and liver stages of the parasite, immobilizing it and preventing hepatocyte infection.

• Collaborative development involved GlaxoSmithKline Biologicals (GSK) and the PATH Malaria Vaccine Initiative (MVI), benefitting from substantial support from the Bill & Melinda Gates Foundation among others.

Liver and Anti-Parasite Vaccines

• The liver serves as a crucial site for the synthesis of proteins involved in the acute phase response, including pentraxins and cytokines that modulate immune responses.

• Additionally, the immune architecture of the liver, comprising various types of immune cells, plays a central role in establishing immunological tolerance and managing infections.

Malaria Vaccine Targets & Development Stages

• Current vaccine research is targeting several critical phases of the malaria lifecycle for potential intervention, with a focus on inhibiting sporozoite and merozoite infections while enhancing CD8+ T cell-mediated responses.

Global Infections: Practical Measures

• Practical strategies to combat malaria include implementing the distribution of mosquito nets, improving nutrition, advancing education regarding transmission and prevention, and utilizing insecticides like DDT.

• Socioeconomic factors such as politics and ethics play significant roles in shaping the effectiveness of these interventions and overall public health outcomes.