Recommended
More Related Content
Similar to 18. Immune Responses to Infectious diseases.pdf
Similar to 18. Immune Responses to Infectious diseases.pdf (20)
Recently uploaded
Recently uploaded (20)
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