Strategies of Infectious Pathogens: Immune Responses & Evasion Tactics

1. Immune Responses to Infectious Disease Immunology

2. The Importance of Barriers to Infection and the Innate Response • the epithelial surfaces of the skin and the lining of the gut • chemicals that are useful in preventing infection { gastric enzymes lowers the pH of the stomach ; antibacterial peptides.} • Normal commensal flora present at mucosal surfaces can competitively inhibit the binding of pathogens to host cells.

3. Pathogens use variety of strategies to escape immune system

4. Some pathogens reduce their own antigenicity either by growing within host cells, where they are sequestered from immune attack, or by shedding their membrane antigens. • Other pathogen strategies include camouflage (expressing molecules with amino acid sequences similar to those of host cell membrane molecules or acquiring a covering of host membrane molecules); • suppressing the immune response selectively or directing it toward a pathway that is ineffective at fighting the infection; • and continual variation in surface antigens

5. Viral Infections • Viruses are small segments of nucleic acid with a protein or lipoprotein coat • require host resources for their replication. • Typically, a virus enters a cell via a cell-surface receptor for which it has affinity

6. Viral Infections survival strategies available to viruses: • Long latency period before severe illness • HIV • Efficient transmission during short illness • Influenza • Life cycle in other host, vectors may also include nonhuman hosts, providing them with additional reservoirs. • West nile

7. The innate immune response to viral infection primarily begins • recognition of Pathogen Associated Molecular Patterns (PAMPs) and leads to the generation of antiviral effectors. For example, Double- Stranded RNA (dsRNA) molecules and other virus-specific structures are detected by one of several PAMP receptors, inducing • the expression of type I interferons (IFN-α and IFN- β ) • the assembly of intracellular inflammasome complexes, • and the activation of NK cells.

9. Viral Infections • Activation of NK cells: • The binding of type I interferon to NK cells induces lytic activity, killing virally infected cells, • NK is enhanced by IL-12, a cytokine that is produced by dendritic cells very early in the response to viral infection. • Induction of interferons • Bind to IFN receptor • Activate JAK-STAT pathway • Induces transcription of genes of host cell • Enzyme that degrades viral RNA

11. Can be neutralized by antibodies • interferingwith their ability to attach to host cells:For example, influenza virus binds to sialic acid residues in cell membrane glycoproteins and glycolipids, rhinovirus binds to (ICAMs) • antibodies may block viral penetration by binding to epitopes that are necessary to mediate fusion of the viral envelope with the plasma membrane. • If the induced antibody is of a complement-activating isotype, lysisof enveloped virions can ensue. • Antibody can also agglutinate viral particles and function as an opsonizing agent to facilitate Fc-receptor-mediated phagocytosis of the free virions

12. If viral DNA is integrated into host, cell-mediated immune mechanisms are most important in host defense (both CD8+ T C cells and CD4+ T H 1 cells)

15. Viral Infections • Viruses Employ Several Different Strategies to Evade Host Defense Mechanisms • Block or inhibit production of interferons ; hepatitis C virus inhibit the action of PKR • Inhibition of antigen presentation ;Herpes Simplex Virus (HSV) produces an immediate-early protein Inhibit TAP which blocks antigen delivery to class I MHC molecules • Evade complement ; vaccinia virus, secret a protein that binds to the C4b complement component, inhibiting the classical complement pathway. • Cause general immunosuppression ; EBV, CMV, and HIV direct viral infection of lymphocytes or macrophages (HIV) … or EBV produces a protein that is homologous to IL-10suppress TH1. • constantly changing their surface antigens.The influenza virus is a prime example

17. Bacterial Infections • Immunity to Bacteria mainly achieved by antibodies • Unless bacteria is capable of intracellular growth ;(DTH) has an important role • Depending on NO. of organisms entering and Virulence, different levels of host defense enlisted • If inoculum size and virulence is low, phagocytes may be able to eliminate the bacteria • Larger inocula or organisms with greater virulence tend to induce antigen-specific adaptive immune responses

18. Bacterial Infections • 4 steps: • Attachment to host cells • Proliferation • Invasion of host tissue • Toxin-induced damage to host cells • Host defenses act at each of these sites, some bacteria have developed ways to avoid

19. Immune responses can contribute to bacterial pathogenesis • Overproduction of cytokines • Septic shock, food poisoning, toxic shock (1) cell wall endotoxins of some gram negative bacteria activate macrophages, resulting in release of high levels of IL-1 and TNF-α , which can cause septic shock. (2) In staphylococcal food poisoning and toxic shock syndrome,exotoxins produced by the pathogens function as super antigens, which can activate all T cells that express T-cell receptors with a particular V β domain. The resulting systemic production of cytokines by activated T H cells is over whelming, causing many of the symptoms of these diseases.

20. Immune Responses to Extracellular and Intracellular Bacteria Can Differ • Extracellular ; The humoral immune response is the main protective response against extracellular bacteria. removal of the bacteria and inactivation of toxins • Ab.+Ag on B.+C3b opsonin phagocytosis and thus clearance of the bacterium. • G-ve + C .activation directly to lysis of the organism. • Ab. activate C3a+C5a anaphylatoxins local mast-cell degranulation extravasation of lymphocytes and neutrophils from the blood into tissue spaces. • Ab.+B. toxin neutralization & phagocytosed by MQ

22. Intracellular bacteria • intracellular bacteria can activate NK cells, which in turn provide an early defense against these organisms. • Intracellular bacterial infections tend to induce a cell-mediated immune response, specifically DTH. • In this response, cytokines secreted by CD4+T cells are important—most notably IFN- γ , which activates macrophages to kill ingested pathogens more effectively.

27. N. gonorrhoeae avoid the damaging effects of antibody. • First, it fails to evoke a large antibody response, • Second, the organism secretes an IgA protease to destroy antibody. • Third, blebs of membrane are released, and these appear to adsorb and so deplete local antibody levels. • Finally, the organism uses three strategies to alter its antigenic composition: • (i) the LPS may be sialylated, so that it more closely resembles mammalian oligosaccharides and promotes rapid removal of complement; • (ii) the organism can undergo phase variation, so that it expresses an alternative set of surface molecules; • (iii) the gene encoding pilin, the subunits of the pilus, undergoes homologous recombination to generate variants.  • N. gonorrhoeae also impairs T cell activation by engaging a co-inhibitory receptor on the lymphocyte surface.

29. Parasitic Disease • Protozoan and helminthic organsims • major difference between these types of parasites is that : [the protozoans are unicellular eukaryotes that usually live and multiply within host cells for at least part of their life cycle, whereas helminths are multicellular organisms that can be quite large and have the ability to live and reproduce outside their human host].

31. Parasitic Disease • Malaria – Plasmodium, protozoan • Complex life cycle • three distinct cycles • Sporogonic cycle (mosquito) • Exo-erythrocytic cycle • Erytrocytic cycle • malaria symptoms caused by excessive production of cytokines ; TNF-α

32. Mechanisms of Immunity Pre-erythrocytic cycle targets are free sporocytes and infected hepatocytes Requires mainly CD8+effector cells producing interferon-γ Need the help of CD4+ T cells Antibodies to sporozoites are thought to have a lesser function Kill parasites in infected hepatocytes Antibodies to sporocyte neutralize sprozoites and/or block invasion of hepatocytes IFN-γ and CD8+ T, NK, NKT, and T cells kill intrahepatic parasites 1 2 Langhorne et al., 2008

33. Mechanisms of Immunity Erythrocytic cycle targets are free merozoites or intraerythrocytic parasites (Schizont) Humoral responses are the key to blood stage immunity (protective antibody response) Antibodies to merozoites opsonize merozites for uptake and/or inhibit invasion of RBCs Antibodies to block infection of RBCs by merozoites Antibody-dependent cellular killing mediated by cytophilic antibodies Block adhesion of infected RBCs to endothelium Neutralize parasite toxins and prevent the induction of excessive inflammation 4 3 Langhorne et al., 2008

34. Mechanisms of Immunity Erythrocytic cycle targets are free gametocytes Humoral responses are the key to blood stage immunity (protective antibody response) Antibodies prevent sequestration and maturation of gametocytes Antibody and complement mediate lysis of gametocytes and prevent further development 6 5 Langhorne et al., 2008

35. factors may contribute to low levels of immune response to Plasmodium • The maturational changes of the surface molecules, resulting in continual changes in the antigens seen by the immune system. • The intracellular phases of the life cycle reduce the degree of immune activation and allow the organism to multiply shielded from attack. • The most accessible stage, the sporozoite, circulates in the blood for such a short time before infecting hepatocytes (approx. 30 minutes) • Even when an antibody response does develop to sporozoites, Plasmodium overcomes that response by sloughing off the surface antigens • The development of drug resistance by Plasmodium

36. Parasitic Infections (Schistosomiasis) • Helminthes dominated by T H -2-like mediators • IgE plays big role (top) with high titers, localized increases in degranulating mast cells, and an influx of eosinophils.These cells can then bind the antibody-coated parasite using their Fc receptors for IgE or IgG, inducing degranulation and death to the parasite via antibody- Dependent Cell-mediated Cytotoxicity (ADCC). One eosinophil mediator, called basic protein, toxic to helminths. • T H 1 response • characterized by IFN- γ and macrophage accumulation (bottom) effective for inducing protective immunity

37. Immune reaction in helminthes • activation of TH2 cells, production of IgE antibodies and activation of eosinophils. •  TH2 subset of effector cells, secrete IL-4 and IL-5. • IL-4 stimulates the production of IgE, binds to the Fcε receptor of eosinophils and mast cells, • IL-5 stimulates the development of eosinophils and activates eosinophils to release their granule contents, which destroy the helminths. • The combined actions of mast cells and eosinophils also contribute to expulsion of the parasites from the intestine due to IL-4–dependent mechanisms that do not require IgE, such as increased peristalsis.

38. Adaptive immune responses to parasites can also contribute to tissue injury. • Some parasites and their products by induction of granulomatous responses with concomitant fibrosis. • Schistosoma mansoni eggs deposited in the liver stimulate CD4+ T cells,  activate macrophages and induce DTH reactions result in the formation of granulomas around the eggs. • Such TH2-induced granulomas serve to contain the schistosome eggs, but severe fibrosis associated with this chronic cell-mediated immune response leads to  cirrhosis, disruption of venous blood flow in the liver, and portal hypertension.

39. several unique mechanisms that protect them from immune defenses. These include: • decreasing the expression of antigens on their outer membrane and • enclosing themselves in a glycolipid-and-glycoprotein coat derived from the host, masking the presence of their own antigens. Among the antigens observed on the adult worm are the host’s own ABO blood-group and histocompatibility antigens! The immune response is, of course, diminished by this covering made of the host’s self antigens, which must contribute to the lifelong persistence of these organisms.

40. Fungal Infections • Most fungal infections of healthy individuals resolve rapidly • Barriers of innate immunity control most fungi • Barrier • Commensal organisms • Phagocytosis • Mannose-binding protein recognizes(PRRs) some major fungal pathogens PAMPs (β-glucans , mannans & chitin)

41. Innate Immunity to Fungi • The principal mediators of innate immunity against fungi are neutrophils and macrophages. • Phagocytes and dendritic cells sense fungal organisms by TLRs and lectin-like receptors called dectins. • Neutrophils presumably liberate fungicidal substances, such as reactive oxygen species and lysosomalenzymes, and phagocytose fungi for intracellular killing. • Virulent strains of Cryptococcus neoformansinhibit the production of cytokines such as TNF and IL-12 by macrophages and stimulate production of IL-10, thus inhibiting macrophage activation.

42. Adaptive immunity to fungi • Intracellular fungal infection • Cell-mediated immunity is the major mechanism of adaptive immunity against fungal infections. • Histoplasmacapsulatum, a facultative intracellular parasite that lives in macrophages, is eliminated by the same cellular mechanisms that are effective against intracellular bacteria. • CD4+ and CD8+ T cells cooperate to eliminate the yeast forms, which tend to colonize the lungs and brain in immunodeficient hosts. • TH1 responses are protective in intracellular fungal infections, such as histoplasmosis, but these responses may elicit granulomatous inflammation, which is an important cause of host tissue injury in these infections.

43. Many extracellular fungi elicit strong TH17 responses, which are driven in part by the activation of dendritic cells by fungal glucans binding to dectin-1, a receptor for this fungal polysaccharide. • Dendritic cells activated via this lectin receptor produce TH17-inducing cytokines, such as IL-6 and IL-23. • The TH17 cells stimulate inflammation, and the recruited neutrophils and monocytes destroy the fungi. • Individuals with defective TH17 responses are susceptible to chronic mucocutaneousCandida infections. • Fungi also elicit specific antibody responses that may be of protective value.

45. Like other microbes, fungi have evolved mechanisms to evade the innate immune response.: • These include production of a capsule, as in the case of C. neoformans, which blocks PRR binding. • Another evasion strategy employed by this organism involves fungi-induced expulsion عمليّة طرد from macrophages that does not kill host cells and therefore avoids inflammation.