Lecture 20_ Immune Disorders and Antimicrobial Therapy.pdf

Immune Disorders and Antimicrobial Therapy Chapter 28 of Brock Biology of Microorganisms, 16th Ed. Farhan R. Chowdhury PhD Candidate Findlay lab [email protected] The immune system is incredibly complex The more complex a system becomes, the more things can go wrong. Disorders of...

Immune Disorders and Antimicrobial Therapy Chapter 28 of Brock Biology of Microorganisms, 16th Ed. Farhan R. Chowdhury PhD Candidate Findlay lab [email protected] The immune system is incredibly complex The more complex a system becomes, the more things can go wrong. Disorders of the immune system: ● Hypersensitivity: ○ ○ ○ ○ Allergies/Immediate hypersensitivity/Type I Cytotoxic/Type II Immune complex/Type III Delayed-type hypersensitivity/Type IV ● Autoimmunity 2 Hypersensitivity: Immediate hypersensitivity/Type I Vasodilation, Smooth muscle constriction 3 Hypersensitivity: Immediate hypersensitivity/Type I Symptomatic treatment: ● Mild symptoms: antihistamines (OTC/prescription) ● Severe symptoms: epinephrine Long term: ● Desensitization: Small, increasing doses of allergen shifts Ig interaction from IgE to IgA and IgG. IgA and IgG compete with IgE for allergen binding, reducing allergy. 4 Delayed-type hypersensitivity (DTH)/Type IV ● Maximal response/reaction in 24-48 h. ○ Erythema (reddening), edema (swelling), blistering. ● DTH antigens (chemicals) are often non-immunogenic, but can react with skin proteins to form novel, immunoreactive antigens (contact dermatitis). ○ Think of an example? ● Local immune response to antigens encountered before also causes DTH symptoms ○ Tuberculin test. ● Treatment is often symptomatic (antihistamines, or steroid anti-inflammatory drugs). 5 Autoimmunity Condition when immune system attack self-antigens. We aren’t quite sure what causes autoimmune disorders. ● ● Out of all the theories, we have the most evidence for genetic factors. Women are often significantly more likely than men to develop an autoimmune disorder. Cell-mediated autoimmune disorders: Type 1 diabetes Some diseases are also caused by autoantibodies. ● Hyperthyroidism: B-cells make antibodies against thyroglobulin that assists in synthesis of thyroid hormones. 6 Autoimmunity Treatments: ● Easier to treat organ/site-specific disorders. ○ ○ Type 1 diabetes: supply insulin Hyperthyroidism: supply thyroxine ● Multi-organ/site disorders are challenging to treat. ○ ○ General immunosuppression is often required. ■ Weakened immune response opens patient up to infections. Monoclonal antibodies are emerging as attractive options. ■ Antibodies to neutralize inflammatory cytokines. ● Example: anti-TNF-α antibodies to neutralize TNF-α involved in rheumatoid arthritis. 7 Superantigens Superantigens bring together APCs and T-cells, but bypass the antigen-TCR complementarity. They do this by targeting conserved regions outside the antigen-binding sites. This activates a large fraction of T cells in the body: up to 25%. Causes superantigen shock. Examples: ● ● Staphylococcus aureus: enterotoxins Streptococcus pyogenes: erythrogenic toxin (Scarlet fever) 8 Immunodeficiency ● Genetic ○ ○ Example: severe combined immune deficiency (SCID). Individuals cannot form B and T cells. Treatment: bone marrow transplantation, gene therapy (commonly viral vectors; new gene delivery systems are developed for safety), continuous antibiotic therapy. ● Infections ○ ○ Example: AIDS. HIV infects and kills macrophages and T-helper cells. Treatment: antiretroviral therapy. 9 Vaccines: Our most effective weapon for disease prevention ● Inoculate person with an inactivated pathogen or pathogenic epitope. ○ This causes the production of memory cells which can mount a swift and strong response if actually infected. ● Types: ○ Inactivated: Heat/chemical treated pathogens (e.g. Vibrio cholerae, Influenza) ○ Attenuated: avirulent strains of a pathogen (e.g. Tuberculosis, measles, Rubella) ○ Subunit: component of pathogens like toxoids, isolated virulence antigens (e.g. Tetanus toxoid, meningitis caused by Neisseria meningitidis) ○ Conjugate: genetically engineered antigens (often polysaccharides) coupled with large harmless proteins that elicits an effective immune response (pneumococcal vaccines, meningitis caused by Haemophilus influenzae) 10 Conjugate vaccines 11 Vaccine types (continued) Nucleic acid vaccines: ● DNA vaccines: antigens delivered to cells directly in plasmids. Host cells transcribe and translate the antigen to produce the antigen (e.g. Hepatitis A, B) ● mRNA vaccines: antigens delivered as pre-processed mRNA for translation in the host cells (e.g. Pfizer’s COVID-19 vaccine). ● Advantages: virtually zero risk of infection from the vaccine itself. mRNA vaccines also have short half life. ● Disadvantages: vaccine delivery and host cell update; mRNA vaccines can be unstable 12 Vaccine types (continued) Plant-based vaccines: Antigen delivered into plants using Agrobacterium tumefaciens. These antigens can be extracted from plant cells in the form of virus-like particles (VLP): antigens embedded in phospholipid vesicles. Elicits a strong immune response, but lacks pathogen DNA, hence cannot cause disease. Some vaccines in development for rotavirus (diarrhea in children), hepatitis B, West Nile virus (meningitis in immunocompromised hosts). 13 Immunotherapy: Harnessing the power of the immune system Anticancer vaccines: ● Prophylactic: preventive; targets oncogenic pathogens like HPV (cervical cancers) ● Therapeutic: Immune cells can be sensitized to tumor antigens to mount a response against cancer cells. 14 Anticancer therapies:Checkpoint inhibitors Cancer cells overexpress immune-suppressing checkpoint proteins (e.g. programmed cell death protein 1 (PD-1)). Checkpoint inhibitors block the activity of these proteins to prevent neutralization of cytotoxic T cells. Example: pembrolizumab; binds to PD-1 receptors of T-cells Side effects? 15 Anticancer therapies: Adoptive T-cell transfer Tumor infiltrating T cells (TILs): ● Extract T-cells that have natural anticancer ability from within tumors. ● Propagate in the lab. ● Infuse back into patient. ● In use to treat melanoma. Chimeric antigen receptor (CAR) T cells: T cells with engineered receptors that can recognize tumor antigens even without their presentation on MHC complexes. ● T cells extracted from patient. ● Engineered using viral vectors to give cells enhanced receptors. ● Infuse back into patients. ● In use to treat melanoma. 16 Anticancer therapies: Adoptive T-cell transfer Challenges: Overcoming immunosuppressive tumor microenvironments. Checkpoint inhibitors often used in combination to improve this. Side effects: ● Neurologic toxicity ● Inflammation ● Variation in treatment outcome from person to person. 17 Anticancer therapies: The role of the gut microbiome Beneficial gut bacteria like Bifidobacterium are thought to induce release of immune-stimulating cytokines. Shown to enhance tumor clearance in mice. Patients that seem to respond better to anticancer treatments show higher amounts of Bifidobacterium in their feces. Clinical trials of fecal transplants into therapy non-responders are underway. 18 Antibacterial drugs Target: ● Cell wall synthesis: ○ Β-lactams: inhibits transpeptidation reaction (catalyzed by penicillin binding proteins) during peptidoglycan cross-linking © Katharina Brandl 19 Antibacterial drugs Target: ● Cell wall synthesis: ○ ○ Β-lactams: inhibits transpeptidation reaction (catalyzed by penicillin binding proteins) during peptidoglycan cross-linking Accounts for ~⅔ of all the antibiotics used and produced worldwide. ● Why does it not harm us? 20 Antibacterial drugs Target: ● Cell wall synthesis: ○ Isoniazid: analog of nicotinamide, a vitamin required for mycolic acid essential for mycobacterium cell wall synthesis. Used to treat tuberculosis. ○ Vancomycin: akin to β-lactams, but binds to the two D-ala residues on the end of the peptide chains, preventing cross-linking of peptidoglycan. Only effective in Gram positive bacteria. Wikipedia 21 Antibacterial drugs Target: ● Protein synthesis: ○ Inhibits 70S prokaryotic ribosomes (50S+30S). ■ Aminoglycosides: Inhibits the 30S subunit. Broad spectrum. Side effects like nephrotoxicity limit their use. Example: gentamicin. ■ Tetracyclines: Inhibits the 30S subunit. Broad spectrum. Both aminoglycosides and tetracyclines are produced by several species of streptomyces. Example: tigecycline. ■ ○ Macrolides: Inhibits the 50S subunit. Example: azithromycin. Why are they (relatively) harmless to us? 22 Antibacterial drugs Target: ● Nucleic acid synthesis: ○ Quinolones: Inhibits DNA gyrase, preventing DNA packaging and unpacking in bacteria. Broad spectrum. Fluoroquinolones are the most predominantly used. ○ Rifamycin: Inhibits RNA polymerase. What happens when RNA polymerase is inhibited? ○ Actinomycin: Blocks RNA elongation by binding to DNA. 23 Antibacterial drugs Target: ● Folic acid synthesis inhibitors: ○ Sulfonamides (sulfa drugs): growth factor analogs. Sulfanilamide, for example, mimics p-aminobenzoic acid (PABA) required to produce folic acid. Folic acid is essential in nucleic acid synthesis. ■ Commonly used with trimethoprim, which inhibits another step of folic acid synthesis. Microbe notes 24 Antibacterial drugs Target: ● Membrane disruptors: ○ Daptomycin: binds to cytoplasmic membrane of bacteria and forms pores. ○ Polymyxins: disrupts the outer membrane and forms pores in the cytoplasmic membrane of bacteria. ● Lipid biosynthesis: ○ Semantic scholar Platensimycin: inhibits fatty acid synthesis. 25 Antiviral drugs ● Reverse transcriptase inhibitors (RTIs): blocks reverse transcription that converts viral RNA genomes to DNA in retroviruses (e.g. HIV). ○ Nucleoside RTIs (NRTIs): dideoxy analogs of nucleosides. Has toxic side-effects. Example: Zidovudine. ○ Non-nucleoside RTIs (NNRTIs): non-competitive inhibitor of reverse transcriptase. Example: Nevirapine. ○ Protease inhibitors: inhibits viral protease required for viral protein processing. Example: Amprenavir. ○ Fusion inhibitors: binds to viral membrane proteins required for docking and host-cell entry. Example: Enfuvirtide. ○ Neuraminidase inhibitors: blocks release influenza particles from host cell surface. Example: Oseltamivir ○ Interferons: IFNs, produced by host cells against viruses, may have therapeutic uses. 26 Antifungal drugs 27 Anti-protozoan drugs ● Quinine and derivatives: blocks hemoglobin metabolism in species of Plasmodium which cause ______? ● Artemisinin: antimalarial drug derived from Artemisia plants. Unclear mechanism of action, but possibly produces free-radicals upon haem metabolism. ● Metronidazole: blocks nucleic acid synthesis in anaerobic organisms. Used to treat infections caused by Giardia intestinalis, Trichomonas vaginalis, Entamoeba histolytica. ● Mebendazole: inhibits synthesis of microtubules. Popularly used to treat helminth infections. 28 Antibiotic resistance ● More than a million people die every year due to antibiotic-resistant pathogens. ● Death toll estimated to rise to 10 million by the year 2050. ● Without antibiotics, access to even the most basic medical intervention becomes impossible. 29 The drivers of antibiotic resistance Development of resistance is inevitable, but it is massively accelerated by: ● Widespread (mis)use of antibiotics. ○ ○ ○ Unnecessary prescriptions Self-prescriptions, often in LMICs. Patients not completing treatment regimens. ● Use in animals in agriculture. 30 Antibiotic resistance mechanisms 31 The fight against antibiotic resistance ● Proper use of antibiotics ● Limiting use in agriculture ● Incentives to discover and commercialize new antibiotics ○ Antibiotics that inhibit novel targets: platensimycin inhibits lipid biosynthesis, a target largely not targeted in bacteria. ○ Antibiotics that inhibit hard-to-evolve targets: teixobactin inhibits a small lipid molecule involved in bacterial cell wall synthesis, and is difficult to evolve resistance against. ● Enzyme inhibitors: β-lactamase inhibitors e.g. clavulanic acid ● Drug combinations 32 Thank you! Please feel free to leave your feedback in the link posted on Moodle c: 33 34 35