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18. Immune Responses to Infectious diseases.pdf
- 1. Immune Response to Infectious Diseases MM.Mirambo, PhD Microbiology/Immunology Department Weill Bugando School of Medicine ©2018
- 2. Objectives At the end of this lecture you should be able to understand: ◼ How the immune system control/eliminate different types pathogens ◼ Innate and adaptive immune mechanisms against different groups of pathogens ◼ Different mechanisms where by different groups of pathogens evade/escape immune system
- 3. The Immune System ◼ The principal function of the immune system is to protect the host against pathogenic microbes
- 4. Pathogens & Disease ◼ Pathogens are defined as microbes capable of causing host damage ◼ When host damage reaches a certain threshold, it can manifest itself as a disease ◼ The evolution of an infectious disease in an individual involves complex interactions between the pathogen and the host
- 5. General Features of Immunity to Pathogens ▪ Defense against pathogens is mediated by both innate and adaptive immunity ▪ The innate immune response to pathogens plays an important role in determining the nature of the adaptive immune response ▪ The immune response is capable of responding in distinct and specialized ways to different pathogens in order to combat these infectious agents most effectively
- 6. General Features… ▪ The survival and pathogenicity of pathogens in a host are critically influenced by their ability to evade or resist protective immunity ◼ Tissue injury and disease are consequence of infections ◼ May be caused by the host response to the pathogen and its products rather than the pathogen itself
- 7. Main agents that cause diseases
- 8. Viruses ◼ Obligatory intercellular pathogens ◼ Replicate within cells ◼ Use synthetic machineries of the host cell ◼ Infect a variety of cell populations
- 9. Immune response ◼ Host defenses against viral infection aim to first slow viral replication and then eradicate infection ◼ Neutralization of virus ◼ Production of interferons ◼ Destruction of infected cells
- 10. Innate Immune Response to Viruses Interferons Antiviral proteins, or glycoproteins produced by several types of cells in response to viral infection ◼ INFα by leucocytes ◼ INFβ by fibroblasts ◼ INFγ by natural killers (NK) cells
- 11. Innate Immune Response to Viruses… ◼ Viral infection directly stimulates the production of interferons (INF) eg.IFNα and IFNβ that inhibit viral replication ◼ Activate genes that interfere with replications ◼ Inteferons also stimulate the production of MHC class I molecules ◼ Natural killer (NK) cells lyse a wide variety of virally infected cells
- 12. Opsonization Opsonizing antibodies may enhance phagocytic clearance of viral particles
- 13. Specific Immune Response to Viruses Humoral mediated immune responses ▪ Most viruses express surface receptor molecules that enable them to initiate infection by binding to host cell molecules ▪ If antibody is produced to the viral receptor, it can block infection altogether by preventing binding of viral particles to host cell ▪ Opsonization enhance phagocytic defenses
- 14. Specific Immune Response to Viruses… ◼ IgA in mucus secretions plays an important role in host defense against viruses by blocking viral attachment to mucosal epithelial cells ◼ Neutralizing antibodies bind to envelope or capsid proteins and prevent viral attachment and entry into host cells ◼ IgG appears to be the most active isotype against viruses
- 15. Specific Immune Response to Viruses… ◼ Cell-mediated immune responses ◼ Most important in host defense, once a viral infection is established ◼ CD8+ T cells and CD4+ T cells are the main components of cell mediated antiviral defense ◼ Activation of MQ by cytokines produced by Th cells
- 16. CTL activating macrophage function
- 17. Tissue Injury ◼ In some cases, infections with non-cytopathic viruses, CTLs may be responsible for tissue damage to the host ◼ Some viruses are known to contain amino acid sequences that are also present in host self cells, leading to an immune response to self components ◼ A persistent infection → circulating immune complexes composed of viral antigens and specific antibodies → deposition in the blood vessels → systemic vasculitis
- 18. Evasion of Immune Mechanisms by Viruses ◼ Viruses have evolved numerous mechanisms for evading host immunity ◼ Despite their restricted genome size, a number of viruses have been found to encode proteins that interfere at various levels with specific or innate host defenses
- 19. Evasion of Immune Mechanisms by Viruses… ▪ By secreting a protein that binds the c4b complement component ▪ Inhibiting the classical complement pathway or by binding to the c3b complement component ▪ Inhibiting both the classical and alternative pathway
- 20. Evasion of Immune Mechanisms by Viruses… ◼ Viruses can also escape immune attack by changing their antigens ◼ A large number of viruses evade the immune response by causing generalized immunosuppression
- 21. Bacteria ◼ Immunity to bacterial infection is achieved by means of antibody unless the bacteria are capable of intracellular growth ◼ Two types of bacteria infection • Extracellular eg: B.anthracis, H.influenza, Mycoplasma spp,V.cholerae,S.aureus, S.pyogenes etc. • Intracellular eg: Ricketsia spp, Mycobacterium spp, L.pneumophilla,L.monocytogenes,Brucella spp,Shigella spp etc.
- 22. Extracellular Bacteria ◼ Replicating outside of the host cells ◼ They cause disease by two principle mechanisms ◼ They induce inflammation. ◼ Many of these bacteria produce toxins ◼ Endotoxins ◼ Exotoxins ◼ The immune responses aimed at ◼ Eliminating the bacteria ◼ Neutralizing the effects of their toxins
- 23. ◼ Phagocytosis by neutrophils, monocytes, and the tissue macrophages ◼ Lectin pathway of complement system ◼ Antimicrobial peptides eg: defensins, cathepsins, cathelecidins and protegrins ◼ Acute phase proteins e.g. C reactive proteins Innate Immunity Extracellular Bacteria
- 24. Inflammation following infections induce production of acute phase proteins from the liver ◼ Neutrophills, MQ, → IL6, IL8,TNFα → sepsis ◼ C-reactive protein → neonatal sepsis
- 25. Three Types of Effector Mechanisms ◼ IgG antibodies opsonize bacteria and enhance phagocytosis ◼ Antibodies neutralize bacterial toxins ◼ IgM and IgG antibodies activate the complement system
- 26. ◼ Humoral immunity ◼ Strong IgM responses are caused by polysaccharides ◼ Antibodies i.e. IgM and IgG against ◼ Bacteria surface antigens ◼ Toxins Specific Immunity to Extracellular Bacteria
- 27. Tissue Injury ◼ Principal injuries of host responses to extracellular bacteria are: ◼ Inflammation ◼ Septic shock
- 29. Evasion of Immune Mechanisms by Extracellular Bacteria ◼ Genetic variation of the surface antigen is one of the mechanisms used by bacteria to evade specific immunity ◼ Inactivate antibodies ◼ Escape phagocytosis ◼ Capsule ◼ The capsule of many gram-negative and gram positive bacteria contain one or more sialic acid residues that inhibit complement activation
- 30. Intracellular Bacteria ◼ Survive and even replicate within phagocytes where they are inaccessible to circulating antibodies ◼ Elimination requires immune responses different from the responses against extracellular bacteria
- 31. Intracellular pathogens exploit distinct niches within the host cells Why do pathogens use the intracellular niches? ◼ Protection against humoral immune response (antibodies, complement) ◼ Abuse of the default uptake by phagocytosis to enter macrophage ◼ Access to specific nutrients
- 32. ◼ During the innate immune response to intracellular bacteria phagocytes ingest and attempt to destroy ◼ Innate immunity is often ineffective in controlling colonization by and spread of these microorganisms Innate Immunity to Intracellular Bacteria
- 33. Innate Immunity to Intracellular Bacteria… ◼ NK cells produce IFN-γ, which in turn activates macrophages and promotes killing of phagocytosed bacteria ◼ NK cell provide an early defense against intracellular bacteria, prior to the development of specific immunity
- 34. Innate Immunity to Intracellular Bacteria… ◼ Intracellular bacteria are resistant to degradation within phagocytes ◼ Intracellular bacteria also activate NK cells, either directly or by stimulating macrophages production of IL-12, a powerful NK cell – activating cytokine
- 35. Specific Immunity to Intracellular Bacteria ◼ Cell-mediated immunity ◼ There are two types of cell-mediated reactions: ◼ Killing of phagocytosed intracellular bacteria as a result of macrophage activation by T cell – derived cytokines, particularly IFN-y ◼ Lysis of infected cells by CTLs
- 36. Tissue Injury ◼ Tissue damage can be caused by macrophage activation that occurs in response to intracellular bacteria ◼ The macrophages and other immune components such as neutrophills, fibroblasts, collagen may accumulate and results in the formation of a granuloma
- 37. Granuloma
- 38. Evasion of Immune Mechanisms by Intracellular Bacteria ◼ Intracellular bacteria’s ability to resist elimination by phagocytes is an important mechanism for survival and evasion of the immune response ◼ Some intracellular bacteria do this by: ◼ inhibiting phagolysosome fusion ◼ while others escape from phagosome
- 39. L.monocytogenes-immune escape/evasion by hemolysin & actin filaments
- 41. Fungi ◼ Fungal infections are eukaryotes that tend to cause serious infections primarily in individuals with impaired immunity
- 42. ◼ The principal mediator of innate immunity against fungi is the neutrophills ◼ Neutrophils liberate fungicidal substances, such as reactive oxygen species and lysosome enzymes ◼ They also phagocytose fungi for intracellular killing ◼ Lectin pathway of complement system Innate Immunity to Fungi
- 43. Specific Immunity to Fungi ◼ Cell-mediated specific immunity is the major defense against fungal infections ◼ Fungi that are intracellular are eliminated by the same cellular mechanisms that are effective against intracellular bacteria
- 44. Evasion of Immune Mechanisms by Fungi ◼ Since individuals with healthy immune systems are not susceptible to opportunistic fungal infections, very little is known about the ability of fungi to evade host immunity
- 45. Parasites Features of parasitic diseases ◼ In infectious disease terminology, “parasitic infection” refers to infection with animal parasites, such as protozoa, helminthes, and ectoparasites ▪ 30% of the world population suffer from parasitic diseases ▪ Malaria affects >100m people worldwide & responsible for about 1-2m deaths annually
- 46. Parasites… ▪ Most pathogens go through complex life cycles (human & other vertebrates, intermediate hosts e.g. flies, ticks snails etc) ▪ Humans are only part of the complex life cycle of parasites
- 47. ◼ Most of parasites cause chronic infections because of weak innate immunity & ability of parasites to evade & resist adaptive immune responses ◼ Parasites in human host are usually resistant to complement ◼ Macrophages can phagocytose protozoa, but the tegument of helminthic parasites makes them resistant to the cytocidal effects of both neutrophils and macrophages Innate Immunity to parasites
- 48. Innate Immunity Parasites ▪ Phagocytes secrete microbiacidal substances to kill microbes that are too large to be phagocytosed ▪ Most of protozoa resist phagocytosis & some replicate within phagocytes ▪ Some secrete surface molecules that are recognized by TLR’s
- 49. Specific Immunity to Parasites ◼ Different parasites elicit quite distinct specific immune responses ◼ Cell-mediated immunity is the principal defense against protozoa that survive within macrophages ◼ Protozoa that replicate inside cells and lyse host cells stimulate specific CTL responses, similar to cytopathic viruses ◼ IgE antibodies and eosinophils mediate defense against many helminthic infections
- 50. Tissue Injury ◼ Tissue injury can be caused when parasites deposited in the liver stimulate CD4+ T cells ◼ Cause macrophages to activate and induce DTH reactions ◼ Resulting in the formation of granulomas
- 53. Immune response to malaria ▪ Complex and stage specific ▪ Immunization with antigens from particular stage protects only vs that particular stage ▪ CD4+ T cells act as effector cells to pre erythrocytic stages ▪ CD8+ T cells play key role in hepatic stages (pre erythrocytic stages) ▪ Direct by killing sporozoites infected hepatocytes ▪ Indirect by secretion of IFNγ & activation of hepatocytes that produce nitric oxide & other agents that kill parasites ▪ CD8 responses also requires cross presentation from dendritic cells Cellular immunity to blood stages: Dc’s MØ, T cells→cytokines
- 54. Antigens produced in different stages Stages Surface antigens Secreted antigens Sporozoites Circumsporozoites (CSP) Thrombospondin-related adhesive protein (TRAP) Liver stages Liver stage antigen 1 (LSA-1) Merozoites Merozoite surface protein 1 (MSP1) Merozoite surface protein 2 (MSP2) Merozoite surface protein 4 (MSP4) Rhoptry-associated protein-1 (RAP-1) Apical membrane antigen 1 (AMA-1) Erythrocyte binding antigen-175 (EBA-175) Serine rich antigen (SERA) Infected RBC Erythrocyte membrane protein 1 (PfEMP1) Gametocytes Pfs 230 Pfs 48/45 Gametes Pfg25/27
- 55. Immune evasion mechanisms ▪ Antigenic variation →difficulties in vaccine development ▪ Sexual blood stages of malaria is an important target for vaccine development ▪ Antibody responses to circumsporozoite is T helper cells dependent
- 57. Toxoplasmosis ▪ Caused by protozoan parasite Toxoplasma gondii ▪ Natural (definitive) hosts: cats & other felines but can infect all worm blooded animals & some cold blooded animals ▪ Human –accidental host ▪ Infection is asymptomatic in most cases & glandular fever sometimes, encephalitis & disseminated infection in HIV/AIDS patients
- 60. Immunity to T.gondii ▪ Free tachyzoites recognised by TLRs ▪ IgM binds to tachyzoites & prevent cell invasion ▪ Triggers Th1 type responses eg IL-12 production ▪ Powerful immune response→slows down but not inhibiting multiplication (bradyzoites)→dormant cyst ▪ Strong Th1 responses →inflanmatory cytokines that may cause potential damage to the host cells eg brain & eyes ▪ Counter inflamatory effects TGFβ & IL-10
- 61. Immune evasion by T.gondii ◼ Infect all nucleated cells including MØ ◼ Inside MØ they form parasitophorous vacuole & multiply by binary fission ◼ Survive by subverting normal protective mechanisms ◼ Inhibits expression of MHC class I & II ◼ Inhibits production of NO, TNF & IL-12 ◼ Inhibits internal cell signals NFкB etc
- 62. Immunity to trypanasomes ▪ African trypanosomiasis T.brucei rhodensience T .brucei gambience ▪ Flagellated unicellular protozoa causing African sleeping sickness in humans ▪ Transmitted by tsetse flies (Glossina spp) between humans and wide range of mammals ▪ T.cruzi (intracellular parasite)common in USA – chagas disease
- 63. Immune evasion by Trypanasome spp ▪ Antigenic variation i.e variant surface glycoprotein (VSG) by different mechanisms i.e DNA rearrangement such as segmental gene conversion, telomere exchange, insitu switch etc. ▪ T brucei genome have at least 1250-1500 VSG genes ▪ Antibodies produced in response to one VSG is not protective vs new VSG
- 64. T.cruzi ◼ Intracellular, cause chagas disease ▪ Innate recognition TLR’s 2 and 9 & other TLR’s ▪ Innate cells i.e. MØ & DC’s, NK, NKT cells ▪ Produce TGFβ homologies ▪ CD8+ T cells via MHC associated peptide epitopes ▪ IL-12 & typeI interferons & other pro inflamatory cytokines ▪ Invade host immune system by inhibiting complement mediated killing by enzymes cleaving complement or production of complement inhibitors ▪ Express a molecule that prevents assembly of the complement cascade
- 65. Immunity to helminths ◼ > 2 billion people are infected with helmiths ◼ Predominance of Th2 immune responses ◼ IL17E promote Th2 cell expansion & parasite expulsion ◼ IL-4,IL5,IL-9, IL-13,IL-21 produced by Th2 cells, eosinophills, mast cells, basophills etc.
- 66. Immunity to helminths… ◼ Secretion of IgE by plasma cells ◼ In S.mansonii infection Th1 responses target large parasites & later Th2 response mediate granuloma formation in response to egg antigens ◼ Eosinophills, MQ, lymphocytes, fibroblasts
- 67. Immune evasion ◼ Some worms secretes certain protein that block immune cells functions eg .hydatid cysts of E.granulosus produce proteases that downregulate Th2 functions ◼ Encodes homologies of TGFβ & IL-10 by S. mansoni eggs ◼ Antigen unresponsiveness by T cells induced by some parasites eg B.malayi infection & S.mansoni
- 68. Immune evasion… ◼ T.solium produces paramyosin that blocks assembly of the complement cascade ◼ Trichinella spiralis transform muscle cell to a specialized nurse cell ◼ Degradation of host chemokines by proteses
- 69. General Immune evasion mechanisms by Parasites ◼ Some parasites survive and replicate inside cells ◼ Others develop cysts that are resistant to immune responses ◼ Helminthic parasites can reside in intestinal lumens and are sheltered from cell-mediated immune responses ◼ Antigen masking is an effective form of immune response evasion by some parasites ◼ Avoid MAC by extending surface proteins e.g. Leishmania spp
- 70. General Immune evasion mechanisms by Parasites… ◼ Parasites can develop a tegument that is resistant to damage by antibodies and complement or CTLs ◼ Some parasites have mechanisms for surface antigen variation ◼ There are two forms of antigenic variation: ◼ Stage specific ◼ Continuous variation of major surface antigens
- 71. Conclusion ▪ If pathogens are able to breach the innate immune system, the specific/adaptive immune system is capable of defending the host against infection by means of humoral and/or cell- mediated immune response ▪ The immune responses to infectious disease are an efficient and effective mechanism against the bombardment of pathogens we face everyday
- 72. Recap ◼ Understand how the immune system control/eliminate different types pathogen ◼ Understand innate and adaptive immune mechanisms against different groups of pathogens ◼ Understand different mechanisms where by different groups of pathogens evade/escape immune system