Lectures 2-9 Notes PDF

lOMoARcPSD|28574464 LECTURE 2 – INTRODUCTION TO MICROBIOLOGY MICROORGANISM  Simplest terms  An organism that is too small to be seen with the naked eye.  Cellular microorganisms  Fungi, protists...

lOMoARcPSD|28574464 LECTURE 2 – INTRODUCTION TO MICROBIOLOGY MICROORGANISM  Simplest terms  An organism that is too small to be seen with the naked eye.  Cellular microorganisms  Fungi, protists, bacteria, archaea o Prokaryote  Have membrane bound organelles (Fungi, Protists) o Eukaryote  Generally lack membrane-bound organelles (Bacteria) o Have features common to prokaryote and eukaryotes (archaea)  currently no known pathogenic species  Acellular Microorganisms  Viruses, Viroids, Satellites, Prions BACTERIA (PROKARYOTE)  Single-celled organisms  Generally, 0.5 um) o Triggered by binding to pattern recognition receptors (PRRs) or phagocytosis receptors o Membrane closes around the particle o Internalised into phagosome o Phagosome fuses with a lysosome  phagolysosome o Reactive oxygen species (ROS), nitric oxide (NO) and lysosome enzymes kill the microbe ACUTE INFLAMMATION  The process of recruiting immune cells and plasma protein to sites of infection and injury  Typically result in heat, redness and swelling  Essential step in activating the adaptive immune response THE INNATE IMMUNE RESPONSE  Global recognition system (patter recognition receptors)  Rapid  Repetitive  Interactive  Does not react to self  Needed for initiation of adaptive immune response ADAPTIVE IMMUNE RESPONSE Downloaded by Caleb Zhou ([email protected])  lOMoARcPSD|28574464 NAÏVE LYMPOCYTES REQUIRE ACTIVATION  Naïve lymphocytes require activation  Naive T cells cannot perform effector function  Need antigens recognition and other signals – co-stimulation – to proliferate and become effector cells COMPNENTS OF THE ADAPTIVE IMMUNE SYSTEM  Humoral immunity o B Lymphocytes  Produce anti-bodies immunoglobulins: IgA, IgG, IgM, IgE, IgD o Block infections and eliminate extracellular microbes  Cell mediated immunity o T lymphocytes  Cytotoxic (CD8+)  deal with intracellular microbes (viruses)  Kill infected cells and eliminate reservoirs of infection  Helper T cells (CD4+)  Help phagocytosed microbes in macrophages – Secrete cytokines to aid elimination of phagocytosed microbes  Th1  Th2  Th17  Serology: study or antibodies in the blood  Serotype: a subset of a species that can be recognised by the same antibody ANTIGEN, EPITODE AND PEPTIDES  Antigen  derived from “antibody generator” but now we refer to antigens as anything that a B cell or T cell receptor binds to: o Proteins o Lipids o Polysaccharides  Epitope  the specific region of the antigen that the lymphocyte receptor recognises  Cognate T and B cells recognise the same antigen  T cell receptor can only recognise proteins B CELLS VS T CELLS  B cells ‘see’ free antigens  T cells looks for a complex on the cell surface o Major histocompatibility complex (MHC) + foreign peptide  T cells work with other host cells – by directly killing infected (or damaged) cells (CD8+) or providing ‘help’ (CD4+) CLONAL SELECTION AND IMMUNOLOGICAL MEMORY Downloaded by Caleb Zhou ([email protected])  lOMoARcPSD|28574464  We maintain a vast supply of T and B cells each with unique antigen recognition receptors  When we encounter a pathogen only those T or B cells that recognise the pathogen are triggered to respond – multiple in number  clonal expansion  Some convert to memory cells – poised to attack again if we re- encounter the pathogen THE ADAPTIVE IMMUNE SYSTEM  Takes days to mount a response o Requires activation  Highly specific recognition o Recognises distinct parts of a molecule (antigens, epitopes)  HUGE diversity  Clonal expansion  Memory  Does not react to self THE IMMUNE SYSTEM VS THE PATHOGEN  Its complex, integrated and coordinated response  The response to tailored to each different pathogen  The pathogen fights back LECTURE 5 – INTRODUCTION TO IMMUNOLOGY  Identify features and cells of the innate immune response  Identify feature and cells of the adaptive immune response  Compare and contrast the main features of the innate and adaptive immune systems  Outline how immune cells are recruited into sites of infection and lymph nodes  Discuss the role of lymph nodes in the immune response Downloaded by Caleb Zhou ([email protected])  lOMoARcPSD|28574464 THE INNATE IMMUNE RESPONSE  Rapid  Repetitive  exactly the same response each time.  Global recognition system (pattern recognition receptors)  Does not react to self *  Normal healthy self  Needed for initiation of adaptive immune response  Interactive HOW DO IMMUNE CELLS TRAFFIC TO THE SITE OF INFECTION RECRUITMENT OF CELLS  Leukocytes need to leave the blood to migrate to sites of infection  Step wise process: o Infection is sensed and resident cells respond by producing cytokines and chemokines o Cytokines increase adhesion molecules selectins (E- and P-selectin), on endothelial cells o Leukocytes express selectin ligand o Leads to initial interaction between leukocytes and endothelial cells  Chemokines displayed on endothelial cells by proteoglycans  Leukocytes express chemokines receptors which bind to high affinity state  Induce integrins (LFA-1 and VFA-4) to change from a low to a high affinity state  Integrin ligands (ICAM-1 and VCAM-1) are also upregulated on the endothelial cells  Strengthens the interaction between the leukocyte and endothelial cell, leading to arrest  Cells squeeze through junctions between endothelial cells  Migrate towards chemokine gradients and complement fragments in the tissue. THE ADAPTIVE IMMUNE SYSTEM  Takes days to mount a response Downloaded by Caleb Zhou ([email protected])  lOMoARcPSD|28574464 o Requires activation  Highly specific recognition o Recognises distinct parts of a molecules (antigens, epitopes)  HUGE diversity  Clonal expansion  Memory  Does not react to self  needs education THE ADAPTIVE IMMUNE RESPONSE REQUIRE ACTIVATION  Naïve T and B cells responses to foreign antigens are initiated and develop in secondary lymphoid tissue LYMPHOID TISSUE  Primary o Provide growth signals and educate lymphocytes  Bone marrow (B cells mature)  Thymus (T cells mature)  Secondary o Lymph nodes o Spleen o Mucosal and cutaneous associated lymphoid tissue THE LYMPHATIC SYSTEM  Lymphatics: specialised vessels, drain fluids from tissue into lymph nodes  Essential for tissue fluid homeostasis and the immune response.  Antigen presenting cells such as Dendritic Cells capture antigens and travel via lymphatics to lymph nodes  Free antigens can drain to lymph nodes in fluid o Picked up by macrophages and DCs in the lymph node LYMPH NODES  Specific B and T cell zones  Lymph fluid and migrating DCs enter via afferent lymphatic vessels  Naïve lymphocytes enter via high endothelial venules and migrate to their zones NAÏVE LYMPOCTYES  Naïve lymphocytes cells circulate through secondary lymphoid tissue NAÏVE T CELL TRAFFICKING  Naïve T cells enter lymph node via high endothelial venules (HEV) – T cell zone o HEV express selectin ligands, ICAM-1 and chemokines o Naïve T cells express L-selectin LFA-1 and CCR7  binds to CCR19 and CCR21  T cells leave via efferent lymphatic vessels Downloaded by Caleb Zhou ([email protected])  lOMoARcPSD|28574464 ANTOGEN, EPITOPE AND PEPTIDES  Antigen  derived from “antibody generator” but now we refer to antigens as anything that a B cell or T cell receptor binds to: o Proteins o Lipids o Polysaccharides  Epitope  the specific region of the antigen that the lymphocyte receptor recognises  Cognate T and B cells recognise the same antigen  T cell receptor can only recognise proteins B CELLS VS T CELLS  B cells ‘see’ free antigens  T cells looks for a complex on the cell surface o Major histocompatibility complex (MHC) + foreign peptide  T cells work with other host cells – by directly killing infected (or damaged) cells (CD8+) or providing ‘help’ (CD4+) MHC-1 AND CD* T CELLS  CD8 T cells recognises peptides on MHC-I o MHC-I derived peptides come from inside the cell  Activated CD8 T cells are cytotoxic T cells o Destroy infected cells o MHC-I is expressed on all nucleated cells MHC-II AND CD4 T CELLS  CD4 cells recognised peptides on MHC-II o MHC-II derived peptides come from outside the cell, following phagocytosis  CD$ T cells provide help to other cells e.g., macrophages and B cells  MHC-II is expressed on DCs, macrophages and B cells APC PROVIDE SIGNALS TO T CELLS TO ACTIVATE THEM  Naïve T cells can’t perform effector functions  Activated by mature APCs in secondary lymphoid tissue o MHC recognition o Co-stimulatory signals  Drives proliferation and gain of effector function  Antigen specificity unchanged CLONAL SLECTION AND IMMUNOLOGICAL MEMORY  We maintain a vast supply of T and B cells each with unique antigen recognition receptors  When we encounter a pathogen only those T or B cells that recognise the pathogen are triggered to respond – multiply in number  clonal expansion  Some convert to memory cells – poised to attack if we re-encounter the pathogen Downloaded by Caleb Zhou ([email protected])  lOMoARcPSD|28574464 LECTURE 6 – MICROBIAL DISEASE  distinguish the various causative agents of disease  explain the links in the infectious disease chain and appreciate how they interrelate to increase incidence of disease  explain how breaking any link will control an epidemic outbreak  compare differences in occurrence of disease: terms in the science of epidemiology  understand how epidemiologists recognise epidemics  explain how spread of disease can be controlled EVOLUTION OF MICROBIAL DISEASE CONCEPTS  Ancient peoples recognised the relationship between the disease Malaria and living near swamps, “mal” – “aria” (Latin) literally means bad air.  Understood the concept of quarantine to control spread of disease  “Miasma Theory” (Hippocrates, 4th Century BC) suggested contagious disease caused by a Miasma  a noxious form of “bad air” from rotting organic matter  Germ theory of disease  1800s: o Fungus (Phytophthora infestans) cause of Irish Potato blight, fungal infection of cereal crops, etc. o Louis Pasteur  work around fermentation and pasteurisation recognised microbial relationship o Joseph Lister: antiseptic surgery MICROBIAL DISEASE CONCEPTS  Causal relationship between microbe and a specific disease o 1890  Robert Koch – “Koch’s postulates” o 1988  Stanley Falkow developed “Molecular Koch’s Postulates” INFECTIOUS DISEASE CHAIN PRINCIPLE EXPOSURE TO INFECTIOUS DISEASES: RESERVOIRS AND EXPOSURE  Inanimate objects  water , food, cups, towel  Animals (zoonoses)  Cow with TB via milk, rabies via bite  Contagious humans  Symptomatic with active disease o Temperature, cough, sore throat, vomiting, diarrhoea, etc.  Human Carrier (asymptomatic) Downloaded by Caleb Zhou ([email protected])  lOMoARcPSD|28574464 o Acute: incubation stage o Chronic recovered from disease, possibly shed > infective for years TRANSMISSION Direct  Contact: usu. skin to skin: shaking hands (staphylococci), kissing (streptococcal sore throat); STI's (chlamydia, gonorrhoea, syphilis, HIV-AIDS, trichomoniasis, HSV)  Air-borne: aerosols: coughing, talking, sneezing ('flu, chicken pox, mumps, measles etc)  Vectors: insect: mosquito (malaria), tsetse fly (trypanosomiasis sleeping sickness), flea (plague)  Mother to baby in utero: microcephaly (Zika virus), AIDS (HIV)  Trauma: tattoo, burn, bite, injury (polymicrobial / staphylococci) Indirect  Vehicles: contaminated food/water: cholera, food poisoning (Salmonella, Listeria etc)  Fomites: dust/linen: hospitals = nosocomial infection (staphylococci) CONTROL TRANSMISSION  People: o Physical barriers -> wear masks, condoms o Physical distancing  COVID-19 1.5 meters o Isolation/Quarantine  Isolation of cases/carriers/contacts (cholera, plague, rabies, smallpox, yellow fever, SARS, HPAIH, Viral haemorrhagic fevers, Ebola, COVID-19 in some countries)  Animals o Control disease in animals: zoonoses o (Rodent fleas = plague; dogs/canines (unvaccinated) = rabies; cattle = brucellosis, mad cow disease)  Water o Treat sewage to reduce water contamination (Vibrio cholerae = cholera; round worm = ascariasis; Giardia lamblia = giardiasis) o Provide safe drinking water: chlorination, filtration; eliminate water-borne pathogens  Food  safe good practices: manufacturing, manage food poisoning risks o Pasteurise milk; food handling; food storage  Eliminate Vectors  mosquito: malaria  Use therapeutics  antibiotics: penicillin: Syphilis: Yaws  Infection control  practices in hospitals THE INFECTIOUS DISEASE CHAIN  Change behaviour; wear masks; wash hands  Quarantine  Destroy animal carries/control animal vectors  Eliminate contaminated food or water  Destroy insect vectors  Use therapeutics  Infection control Downloaded by Caleb Zhou ([email protected])  lOMoARcPSD|28574464 EPIDEMIOLOGY  Epidemiology  how do diseases move through a population  An Epidemiology investigation needs to find out: o What caused the disease o Where is came from o How it got into the population o Why it became a problem  Goals of an epidemiological study include: o Control transmission/speed of spread o Eliminate pathogen from population HERD IMMUNITY HERD IMMUNITY THRESHOLDS Downloaded by Caleb Zhou ([email protected])  lOMoARcPSD|28574464 CLASSIFCATIONS OF DISEASES  Endemic  disease is constantly present in a population usu. At low frequency  Epidemic  disease suddenly increases in a population  Pandemic  disease increases within a large widespread population usu. Worldwide EPIDEMICS  Epidemics are shown at three main peaks that lie outside the predicted cases  Disease suddenly increases within a population EPIDMEIC TYPES: COMMON-SOURCE VS PROPAGATED Downloaded by Caleb Zhou ([email protected])  lOMoARcPSD|28574464 LECTURE 7 – THE HOST-PATHOGEN RELATIONSHIP Downloaded by Caleb Zhou ([email protected])  lOMoARcPSD|28574464  critically comment on what causes the shift to parasitic relationships in the symbiosis spectrum  distinguish commensals from pathogens  build on Lecture 6 outcomes to explain the links in the infectious disease chain and appreciate how they interrelate to increase incidence and spread of disease  explain how breaking any link will control an epidemic outbreak  understand how microbial strategies and/or products allow them to: colonise, invade, evade the immune response and damage the host  understand the role of the host immune system in responding to infection THE NORMAL HUMAN MICROBIOTA A COMMENSAL YET SOMETIMES A PATHOGEN – ENDOGENOUS  Example: Staphylococcus Aureus  Commensal: normal microbiota, carried in noses of 20-40% of a population  Pathogen: causes impetigo, boils, bone and blood infection … in susceptible people “ALWAYS A PATHOGEN – EXPGENOUS (AND ENDOGENOUS)  Example: smallpox  Worldwide vaccination program  Symptoms obvious  Quarantine effective  No other host THE SYMBIOSIS SPECTRUM Downloaded by Caleb Zhou ([email protected])  lOMoARcPSD|28574464 PARASITIC RELATIONSHIP  A constant battle between Host and Microbe  Parasitic relationship  Example: Trypanosomiasis (African sleeping sickness) HOST/MICROBE (PARASITE/PATHOGEN) INTERACTION FACTORS GOVERNING SYMBIOSES  Virulence of microorganisms  i.e., increase virulence = shift to parasitism  Host susceptibility  i.e., decreased immunocompetence = shift to parasitism  Load of microorganisms  i.e., increased load (e.g., poor hygiene habits, chemotherapeutic agents) = shift to parasitism. MICROBIAL VIRULENCE  Microbial Virulence: Degree or intensity or pathogenicity of a microbe o pathogenicity  the ability to cause disease  Increase virulence= increased likelihood to cause harm  therefore moving parasitism  Indicated by fatality rates, and the ability to invade host tissue and cause disease symptoms Downloaded by Caleb Zhou ([email protected])  lOMoARcPSD|28574464 WHAT ARE VIRULENCE FACTORS?  Microbial strategy/traits that contribute to virulence = virulence Fm  There is a clear connection. Between virulence and infection  Virulence is influence by microbial traits (i.e., genes) that mainly fall in four categories: 1. Those that affect the ability of the pathogen to replicate 2. Those that affect host defence mechanisms (i.e., immune-evasion mechanisms) 3. Those that affect tropism, spread throughout the host and transmissibility 4. Those that encode products that directly damage host cells  Can include “housekeeping” functions, i.e., deriving nutrients/energy for survival in host What do Virulence Facts do?  Aid Colonisation  Allow penetration of host tissue  Prevent/reduce host response: evade immune system o Evade phagocytosis and immune clearance o Encapsulation  Cause direct damage to host o Toxic metabolism and products: acid and gas o Proteins: cytosines, degradative enzymes o Exotoxins: A-B, membrane disrupting, superantigens o Endotoxins: Gram -ve: LPS; Gram +ve: peptidoglycans, LTA, TA  Induce inflammation o Pathogenicity islands  PLUS, antibiotic resistance HOST SUSCEPTIBILITY  IMPACTED BY:  Host factors  age, socio-economic status, occupation, sex, also inherited factors  Non-specific host defence and barriers to infection  physical, chemical and biological  Immune status  immunocompromised INFECTIOUS DOSE (LOAD)  Successful infection results from: o Initial inoculum/virulence or microbe/host susceptibility  Infectious Dose = ID50 o = no. microbes required to cause disease in 50% inoculated hosts  For example: o Dental Caries: polymicrobial LIMITATIONS OF HOST-PATHOGEN RELATIONSHIP  Cohort selection  what happens in a Caucasian male (or a mouse model) is not always relevant to other races and sexes  Ethical considerations  The integrated aspects of health and our world  multifactorial o The One Health Concept o Understanding holobionts (holobiont = the network formed by a host and the many other species living in or around it, which together form a discrete ecological niche) Downloaded by Caleb Zhou ([email protected])  lOMoARcPSD|28574464 LECTURE 8 – THE GENITOURINARY SYSTEM  MICROBES AND DISEASE THE GENITOURINARY SYSTEM – OVERVIEW  There is significant difference in the structure and function between sexes MICROBIOME OF THE GENITOURINARY TRACT  The bladder and urethra are continuously flushed by urine  Very low number of normal microbiotas in males  In healthy individuals, microbiota consist of resident microbes found on the skin, e.g., Staphylococcus  Complex and dynamic normal microbiota  Lower reproductive tract dominated by Lactobacillus species  Major role in non-specific defence against infections o Low pH (lactic acid) o Bacteriocins o Competition for nutrients and binding sites Downloaded by Caleb Zhou ([email protected])  lOMoARcPSD|28574464 THE GENITOURINARY SYSTEM – SEXUALLY TRANSMITTED INFECTIONS (STI) CAUSATIVE MICROORGANISMS  Over 30 different bacteria, viruses and parasites are known to be transmitted between humans via sexual contact o Neisseria Gonorrhoeae o Treponema Pallidum o Chlamydia trachomatis o Trichomonas vaginalis NEISSERIA GONORRHOEAE  Diseases  Gonorrhoea, pelvic inflammatory disease, urethritis  One of the most common STI, ~82 million cases globally (2020)  Gram negative diplococci bacteria, can infect the urethra, cervix, throat, anus and eyes  Obligate human pathogen  Transmitted via sexual contact with penis, vagina, mouth or anus  Can also be transmitted from mother to child during vagina childbirth  Many people with Gonorrhoea are asymptomatic (female and male)  When symptoms appear, they can include: o Males, penile discharge, irritation or pain when urinating, anal discharge or discomfort, conjunctivitis and eye inflammation o Female: unusual vagina discharge, irregular vaginal bleeding, pain when urinating, pelvic pain, especially during sex, anal discharge or discomfort, conjunctivitis and eye inflammation.  Suite of virus mechanisms o Type IV pill – adhesion, immune evasion (antigenic/phase variation) natural transformation o PorB – outer membrane protein, immune system evasion (suppression) o IgA protease – immune evasion (direct damage to immunoglobulin), tissue invasion  Infection with Neisseria Gonorrhoeae increases susceptibility to HIV infection  Can be cured with antibiotics  ceftriaxone, azithromycin  Penicillin, Tetracycline, Cefixime, Ceftriaxone – inhibits bacterial cell membrane synthesis  Ciprofloxacin – inhibits DNA replication  Azithromycin - inhibits protein synthesis, binds 50S ribosomal subunit) CHLAMYDIA TRACHOMATIS  One of the most common STI, 129 million cases globally (2020)  Gram-negative obligate intracellular bacterial parasite, only found in humans  Intracellular lifestyle means they avoid detection by immune system  Sexually transmitted, can also be transmitted from mother to child during vaginal childbirth  Silent epidemic as up to 70% of infections in women are asymptomatic  Suite of virulence mechanisms: o Type III secretion system - effector protein delivery o TARP - host cell remodelling for pathogen survival o Pgp3 - immune evasion (suppression)  Can be cured with antibiotics  e.g., azithromycin, doxycycline, erythromycin (all inhibit protein synthesis, binds 50S or 30S ribosomal subunit)  Antibiotic resistance is uncommon but increasing in prevalence TREPONEMA PALLIDUM  One of the most common STI, 7.1 million cases globally (2020)  Gram-negative bacteria, distinct spiral cell shape, motile Downloaded by Caleb Zhou ([email protected])  lOMoARcPSD|28574464  Sexually transmitted, can also be transmitted from mother to child during pregnancy and vaginal childbirth (congenital syphilis)  4 stages of disease - primary, secondary, latent, tertiary  Suite of virulence mechanisms: o Shape of the bacteria - entry & movement o TprK - surface protein, attachment, immune evasion (antigenic variation) o Outer membrane sheath - immune evasion (masking)  Can be cured with antibiotics e.g., benzathine benzylpenicillin o (Inhibits bacterial cell membrane synthesis)  Recent global shortage of this antibiotic is contributing to rises in incidence.  Antimicrobial resistance is not common but is increasing. TRICHOMONAS VAGINALIS  One of the most common STIs, 156 million cases globally (2020)  Single-celled protozoan, parasite exerts mechanical stress on host cells and then ingests cell fragments after cell death, only found in humans  Sexually transmitted, also spread via genital touching  Can cause pregnancy complications e.g., pre- term delivery and low birth weight.  Some virulence mechanisms: o AP65, AP51 and AP33 - adherence, immune evasion (mimicry) o CP65 - cysteine protease, tissue damage, o Dysbiosis - phagocytosis of protective normal microbiota  Infection is resolved after one dose of metronidazole o (Inhibits protein synthesis by interacting with DNA, causes a loss of helical DNA structure and strand breakage)  Antimicrobial resistance is not common but is increasing in prevalence MAJOR VIRAL PATHOGENS OF THE GENITOURINARY SYSTEM  Human immunodeficiency virus o Disease = acquired immunodeficiency (AIDS)  Human Papillomavirus (200+ strains, 40 responsible for STI) o Disease = genital warts or cervical cancer (also vaginal, anal, vulvar and penile cancers) o Vaccine available to protect against strains 6, 11, 16 and 18  Herpes Simplex -1 and -2 o Genital Herpes HERPES SIMPLEX VIRUS  Herpesviridae family  Alphaherpesvirus subfamily o Herpes Simplex virus type 1 (HSV-1) o Herpes Simplex Virus type 2 (HSV-2) o Varicella Zoster Virus (VZV) HSV-1 AND HSV-2  Double stranded DNA viruses  Viral genome replication occurs in the host cell nucleus  HSV-1 and 2 share a high degree of genome sequence homology  HSV-1 more commonly associated with cold sores  HSV-2 more commonly associated with genital infections  However, both can cause frequent and painful genital lesions  Can be distinguished serologically (by antibodies) Downloaded by Caleb Zhou ([email protected])  lOMoARcPSD|28574464  ~22% of Australians seropositive to HSV-2  As serology tests for antibodies, can't distinguish between an infection which causes cold sores or genital lesions HSV PATHOGENESIS  Primary infection: o Break the skin, virus accesses the mucosa, infection established in epithelial cells o Virus replication in oral or genital mucosa o Newly made virus particles released from infected cells access sensory nerve endings  Latent Infection: o Viral genome is sequestered in a non-replicating state in primary sensory neurons o No virus proteins or particles being made o Hidden from the immune system  Recurrent infection: o Viral genomes reactivate from the latent state o Enter replication cycle again o New infectious virus particles made o Trigger/s for reactivation unclear, immune suppression plays a role  Herpes for Life! The virus is never cleared from sensory neurons  HSV establishes latency in the ganglia that innervates the site of primary infection  It will then reactivate from that same ganglion, meaning that if you get cold sores the virus cannot suddenly travel and cause genital lesions GENITAL HERPES: TRANSMISSION AND SYMPTOMS  Transmitted during sexual intercourse, oral genital  More common in females  suggests female genital tract more permissive to infection  Only 10-25% of infected people are aware of the infection  Blisters visible 4-7 days after transmission  Associated with pain, itching and Burning sensations  Asymptomatic shedding of the virus can occur, this is a large driver of transmission PREVENTION AND CONTROL OF PATHOGENS OF THE GENITOURINARY SYSTEM – STI  Best to prevent initial infection o Comprehensive education about STIs o Counselling and support particularly for at risk popula1ons o Promotion of barrier protection - use of condoms o Development of vaccines - currently no vaccine for any bacterial or protozoan STIs  Easy to control these pathogens after infection, however, STIGMA o MUST have de-stigmatisation of STIs o education about symptoms and importance of early diagnosis & control of spread to sexual partners o Access to health care and timely and effective treatment Downloaded by Caleb Zhou ([email protected])  lOMoARcPSD|28574464 LECTURE 9 – THE IMMUNE RESPONSE TO HSV IMMUNE RESPONSE IN GENITOURINARY GLAND IMMUNE RESPONSE IN THE FEMALE REPRODUCTIVE TRACT  Hormone fluctuations occur  Tissue remodelling, cyclic shedding and regeneration  Balance between tolerance to infection and immunity to infection  During pregnancy the mother must tolerate foreign antigens TYPICAL IMMUNE RESPONSE TO VIRAL INFECTIONS  Interferons (IFN) and proinflammatory cytokines produced o By local immune cells e.g., tissue residents’ dendritic cells, as well as keratinocytes and epithelial cells  Natural killer cells  CD8+ T cells  B cells and CD4+ T cells IMMUNOPATHOLOGY OF HERPES LESIONS  HSV replication in mucosa/skin causes cell death, leads to blisters containing cellular debris, immune cells and virus particles  Generally, the primary infection is the most severe o Lack of adaptive immune response  Secondary lesions heal faster o Memory T cells quick to act to control STARTING THE IMMUNE RESPONSE  Before the immune response can begin, we first need a way to detach the pathogen  Distinguish: self from non-self, danger from harmless  Need receptors at all possible sites where pathogens could be Downloaded by Caleb Zhou ([email protected])  lOMoARcPSD|28574464 HOW DOES THE HOST CELL INITIALLY RECOGNISE A PATHOGEN? Pattern Recognition receptors Recognise Pathogen Associated Molecular patterns (PAMPs) PATTERN RECOGNITION RECEPTORS (PRRS)  Expressed by virtually all cells o But not all cells express all the receptors, each different cell type express a certain subset  High levels on resident and innate immune cells such as macrophages  PRRs found on the cell surface, in endosomes and in the cytoplasm and nucleus  Five major families: o Toll-like receptors (TLRs) o C-type lectin receptors (CLRs) o Nod-like receptors (NLRs) o RIG-like receptors (RLRs) o Cytosolic DNA sensors (CDSs) PATHOGEN ASSOCIATED MOLECULAR PATTERNS (PAMPS)  PAMPs (pathogen associated molecular patterns) o Structures common to many different pathogens which are not present in healthy cells  Components of bacteria, fungi or viruses which are generally essential e.g., nucleic acids, cell wall lipids, carbohydrates and proteins  DAMPs (damage associated molecular patterns) o Released from damaged/dying cells  In the wrong place at the wrong time PAMPS VS ANTIGEN  Common structure shared by different microbes e.g., LPS  Recognised by innate receptors – germline encoded  Features unique to each individual pathogen  Recognised by specific adaptive immune cell receptors – arise through gene recombination - unique PRRS TRIGGER INFLAMMATION AND ANTIVIRAL DEFENCE 1. Engagement of PRR 2. Signalling cascade 3. Drives:  Production of proinflammatory cytokines (e.g., TNF, interleukins IL-6, IL-1B)  Production of type I interferons  Programmed cell death (apoptosis)  Stimulation of adaptive immunity 4. This Kick starts the immune system Interferons (IFN) Downloaded by Caleb Zhou ([email protected])  lOMoARcPSD|28574464 WHAT DO THE RECEPTORS SENSE DURING A VIRAL INFECTION  Viruses replicate using host cells  limited targets for PPRs  Viral PAMPs: o Viral RNA (e.g., double-stranded RNA) o Viral DNA o Viral Glycoproteins  Major response to PRR recognition of viral PAMPs: Type 1 interferon production  Secondary response: cytokines – e.g., TNF, IL-12, IL-1B HSV PAMPS  Different PRRs trigger different responses  Pathogens trigger multiple PRRs  HSV-1 PAMPs: o Viral glycoproteins o DNA genome o Viral RNA TYPICAL IMMUNE RESPONSE TO A VIRAL INFECTION  Type I interferon (IFN) and proinflammatory cytokines produced o By local immune cells e.g., tissue resident dendritic cells as well as keratinocytes and epithelial cells  Establish an ‘anti-viral state’ and recruit immune cells INTERFERONS (IFN)  3 types of IFNs: o Type I interferon; alpha and beta o Type II interferon: y o Type III: gamma  Main sources of IFNs: o IFN-alpha: dendritic cells and macrophages o IFN-beta: Fibroblasts o IFN-y: Natural Killer cells, T cells  Type I IFN (Alpha and beta) can be secreted from virally infected cells and induce an ‘anti-viral’ state in surrounding uninfected cells o Induce interferon stimulated genes  Anti-viral enzymes  Shut-down host cells metabolism  IFNs increase MHC-1 expression  increased changes of CD8+ T cells detecting infected cells HSV LESIONS AND INTERFERON PRODUCTION  Infected keratinocytes, epithelial cells, tissue resident immune cells, dendritic cells and macrophages can all produce type 1 interferon in response to HSV infection  (Lymphocytes can produce type II interferon/IFN-g ) HSV INVASION AND TYPE 1 IFN RESPONSES  HSV encodes numerous gene products that inhibit the induction of Type 1 IFN and IFN signalling Downloaded by Caleb Zhou ([email protected])  lOMoARcPSD|28574464 NATURAL KILLER CELLS  Innate lymphocyte  Circulate in the blood  Recruited to sites of infection by chemokines  Found in HSV lesions  People who lack NK cells are extremely susceptible to severe HSV infections  Express a mosaic of activating and inhibitory receptors  Can recognise and lyse virally infected cell  Decision to Kill: o Summation of positive and negative signals  Use same cytotoxic mechanisms as CD8+ T cells to induce cell death  Release cytokines- IFN-gamma, helps adaptive immune response, and macrophages NK CELL ACTIVATION  Cell stress (e.g., infection) drives expression of activator ligands  Some viruses cause a down-regulation of MHC-I o Missing self-hypothesis  If activation signal is engaged, and the inhibitory receptor Is not, this leads to NK cell activation ADAPTIVE IMMUNITY REQUIRES RECOGNITION OF ANTIGENS  T cells are crucial in controlling most viral infections  Need innate response to activate the adaptive response  Activated effector CD8+ T cells then recognise and directly kill virally infected cells and CD4+ T cells produce cytokines and provide help to B cells to generate antibody responses  Antibody responses are important, particularly for preventing reinfection with viruses Downloaded by Caleb Zhou ([email protected])  lOMoARcPSD|28574464 IMMUNE RESPONSE TO BACTERIAL STIS  Chlamydia trachomatis o Infects epithelial cells o Can cause mucopurulent cervicitis, pelvic inflammatory disease and non-gonococcal urethritis o Immune response largely responsible for symptoms  Neisseria gonorrhoea: o Very strong immune response leads to symptoms- pus/discharge, and potentially scarring of tissue, can lead to infertility o Neutrophils recruited to phagocytose bacteria, bacteria can survive inside neutrophil, may facilitate transmission  Treponema pallidum: o Chancre contains replicating spirochetes surrounded by immune cells (T cells, plasma cells, macrophages). o Immune response can clear local infection- macrophage phagocytose bacteria, but T. pallidum spreads systemically, antigenic escape  Trichomonas vaginalis: o Triggers inflammation, can be broken down and killed by neutrophils LECTURE 10 – RESPIRATORY SYSTEM PT2  STRUCTURE AND MICROORGANISMS Downloaded by Caleb Zhou ([email protected])