22/01/2024-Lecture 01

Infectious Disease

Viruses

Viruses are acellular, They do not fit into any of the 3 domains of life.

It is not clearly understood how they are related to the domains or their members.

• Each viral unit as a particle.

• Each viral particle consists of a nucleic acid genome wrapped in a protein coat.

• The protein coat is referred to as the capsid.

• In some viruses this capsid is surrounded by a lipid envelope.

• Compared to the structure and organisation of cellular life, the structure and orgganisation of viruses is clearly minimalistic.

• Smaller than eukaryotic cells,

Viral structure

• Viral capsid- madebup of repeating, identical subunits which self assemble into structures.

• Since viruses require host for their replication, they are under constant pressure to have compact genomes.

• They have evolved to produce proteins that can self-assemble into structures.

• Capsid protein can self assemble on their own or with the help of other proteins into structures.

• Capsid protein form different viruses can self-assemble in different ways thereby determining the overall shape the virus.

• Based on the capsid shape viruses can be broadly classififed into 3 types; Helical, Icosahedral and Complex.

Bacteria

Fungi

• Eukaryotes

Types of Phylum of Fungi

Microsporidia

• LAck Mitochondria

• Unicellular

• Replicate via host cell.

• Produce spores for reproduction

Ascomycota

• Morphologically diverse, yeast to moulds.

• Ascus-sac with 8 spores.

Basidiomycota

• Club Shaped end cells- basidia,

• Usually 4 spores.

Zygomycota

• Sporangium- Ball of wool like appearance.

• May be aseptate

• Chitosan cell wall.

• Fungi are a kingdom in Eukaryota

  • In between Plantae and animalia/

  • There is a presence of membrane bound organelles

  • They are similar to plants have they have a cell wall.

• Evolutionary Level

  • Fungal cells are similar to human cells compared to bacterial cells.

  • This has implications in therapeutic interventions.

• Unicellular

  • Yeasts

• Multicellular

  • Moulds

• Dimorphic Fungi

  • Existance in both yeast and mould forms.

  • E.g Candida ALbicans, Is a yeast outside the body and a mould inside the human body.

Terminology

• Mycology

  • Study of Fungi

• Mukes

  • Fungi

• Mycoses

  • Fungal Diseases

• Dermato Mycoses

  • Fungal Diseases of the skin

Moulds

• Long Branching filamentous structure (Hyphae)

• Sometimes filamentous structures are separated into cell-like units by septa.

• Hyphae; Vegetative (mycelium) & Aerial.

• Multicellular

• Aerial produces spores

• Mycelium- root like structures.

Yeasts

• Unicellular

• Non filamentous

• Spherical or Oval

• Divide by Budding and Fission.

Dimorphic Fungi

• Fungo can be broadly classifies into yeasts and moulds, dependent upon the growth phenotype.

• Dimorphic- Some fungi have both the growth forms, a yeast and mould for,.

• Many dimorphic fungi are pathogenic.

• In most cases, alteration between the two forms is dependent on temperature.

Fungi Characteristics

• Fungi are eukaryotic, cellular processes are similar to other eukaryotic organisms.

• Similar to plant cells. Fungal cells have a cell wall, but the cell wall is made up of chitin,.

• They reproduce via Budding, fission or spores.

• Capable of growing at different pH;s.

• Most fungi require less nitrogen than bacteria.

• They are more resistant to osmotic pressure than bacteria.

• Fungi can metabolise complex carbohydrates.

• They are chemoheterotrophs.

  • Derives its energy from chemicals.

• Most filamentous fungi require oxygen

• Most yeasts are anaerobic.

Fungal Reproduction

• Can be sexual and Asexual

• In asexual reproduction;

  • The mycelium produces genetically identical unicellular haploid spores.

• In sexual reproduction;

  • Teo different mycelia mate and produce a diploid zygote.

  • The diploid zygote then undergoes meiosis producing haploid spores.

  • Haploid spores germinate into mycelium.

Ascomycota Reproduction

Microsporidia Reproduction

Basidiomycota

Zygomycota

Yeast Reproduction

Microsporidiosis.

CAndidiasis.

ASpergillosis.

Histoplasmosis.

Coccidiodomycosis.

Ergotism.

Parasitology

Parasite - An organism which lives in or on another organism and benefits by deriving nutrients at the other's expense.

Parasitoid- An insect whose larvae live as parasites which eventually kill their hosts.

Obligate Parasaite - Only purpose is to exist in the parasitic relationship.

Many organisms have complex life cycles involving one or more host or hoshts.

Human parasitic infections are a huge problem in tropical regions- but not exclusively.

Definitive Hosts- Final host in which the parasite reaches maturity and undergoes sexual reproduction,

Intermediate Hosts- Host in which the parasite undergoes developmental stages.

Advantages

Disadvantages

Ectoparasites.

• Ticks and Mites

• Visit the surface of the host to feed.

• Some may be the vectors for endoparasitic organisms (Malaria and mosquitous)

• They are macroscopic.

• Classed as macropatasites.

Pediculosis

• Lice

Endo- Parasites

Protozoa

Malaria

Other infectious agents

Microbiome

‘Germ Theory’ - Infectious disease is spread by microscopic, living, causative agents.

Environmental sources of microorganisms

• Soil

• Cooking Meat (or not cooking lol)

• Contamination of Water

• Cough Droplets.

• We are all inhabited by commensal microorganisms and a balance exists between the microorganisms and the epithelium.

• This allows for microbial survival and the prevention of induction of inflammation.

• Benefits of Commensals

  • Aids in maturation of immune system

  • Assist in digestions

  • Role in toxic degradation.

• When there is an imbalance, the microorganisms can cause tissue damage.

The human microbiome

• The microbiome works in harmony with various organs in the body and aids in their function.

• From newborn, the newborns mouth is sterile and is then inoculated from the first feed onwards from mothers food.

• This transmits the microorganisms to colonisation sites.

• Acquisition of Oral Microbial flora

  • The moutb is initalluy hihgly selective for microorganisms.

  • On Epithelial Surfaces

    • Only a few oral species colonise,

    • They are Gram Positive and aerobic.

    • Mainly streptococci.

    • Thye are the pioneer species.

    • Within 2-3 months, gram negative anaerobic bacteria begin to appear.

  • It is not accidental.

  • It is a natural acquisition and selection process.

• Microorganism Host Relationship

  • Symbiosis refers to the relationship between different organisms.

  • Various types of symbiotic relationships exists such as commensalism, mutalism and parasitism.

  • Commensalism.

    • Microorganism benefits, host is neither harmed nor helped.

  • Mutualism or True Symbiosis

    • Both microorganism and host benefits.

    • The host is not harmed and derives a clear benefit.

  • Parasitism

    • Microroganism benefits but the host is harmed.

COnsequences of a parasitic relationship

• Infection!!!!!!!!!!!!!!!!!!!!!!!

• Exogenous Infections

  • Aquatic

  • Zoonoitc e.g Salmonella

  • Saprophytic e.g Tetanus

• Endogeneous

  • Infective endocarditis

Microbial symbiosis with human host

• Normal microbial flora consists of microorganisms that engage in commensal in mutualistic relationship with us. If it was a parasitic relationship, they would be caustyaive agents of disease.

• We are therefore not activelyu harmed by a microbial flora and derive some degree of benefit from many microbial components.

• TMany of these organisms can engage in a aprarsitic relationship if given the opportunity.

THe human microbiome

• The human microbiome is not a composed homogenouslt in all areas of the host.

• Different physiological sotr are primarily colonised by different microbial species.

• This is primarily due to different site being chatacterised by different environments that microgransims can specialse to colonise.

• Colonisation of the intestine can require different specialisation to colonisation of the skin.

Nosocomial Infection- Infection picked up in a hospital.

The Virome

• This is the viral component to the microbiome

• A significant amount of our genome is of viral origin,

• REtroviruses utilse reverse transcription to produce DNA from RNA.

The Mycobiome

• Fungal composition of the microbiome

• Composition is fairly well characterisedf but the impact on human health is not as clear,

• There is not as much research available as to the mycobiome. #

The microbiome and Human Health

• Synthesis of vitamins

• Promotion of intestinal angiogenesis .

• SCFA production of fermentation of fibre.

• Modulation of CNS,

• Protection afaint=st pathogens,

• Immune system development,

• Promotion of fat storage.

• Enhances metabolis,

• Prevention against autoimmunity..

Innate Immunity

Ef bb fv

Specific & Non-SPecific Immune Systems

• Innate- Non-specific, rapid, aspects are inducible

  • Broad response effective against a range of threats.

• Adaptive- Specific, targeted, inducible and capable of adapting to threats, (specificity and memory.

The Innate Immune System

• COnsists of

  • Physcial Barriers

  • Antimicrobial peptides and enzymes

  • The complement system

  • Non-SPecific Cellls

  • Inflammation

• Exterior Defences

  • They are an effective barrier, very few infectious agents can penetrate intact skin.

    • Mechanical Barriers- Skin, cillia, hair, earwax, sweat.

  • Pathogens gain access through the mucosal epithelia such as gastrointestinal,urogenital, nasipharynx and lung.

    • Physiological barriers- coughing, sneezing, urination, diarrhoea.

  • SOme pathogens infect the body by entering the blood directly.

    • Immune response- Eliminate infectious agents and minimise the damage they cause.

• Physica Barriers

  • Pathogens can enter the body at different points, each of these points have their own physical barriers, these barriers must be breached in order to initiate an infection.

  • Defence depends on, the breaching of these physical barriers.

  • The innate defence are dependent on where the pathogen resides.

• Epithelial Barriers

  • Tight junctions are the basis of the epithelial barrier.

  • Epithelium provides a location for other immune factors.

    • Enzymes such as lysozyme

    • Cryptdins and a-defensins

    • B-defensins,

    • Acidic stomach pH,

    • Surfactants.

  • Mucus and Villi

  • Normal Gut flora.

• First Line of Defence

  • We are born with non-specific defences that do not require prior exposure to a harmful substance or threatnenitn cell, thus called innate immunity,

  • Such as,

    • Granulocytes

    • Mast Cells,

    • Monocytes.

    • Dendritic Cells, Macrophages.

    • NAtural Killer Cells..

• Physical Barriers- EPithelia

  • Epithelia comprise both the skin and the linings of the bodys passages.

    • Including the Respiratory Tract, Gastrointestinal Tract, Urogenitaltracts.

  • Epithelial Cells are held together by tight junctions, multiprotein junction complexes form a seal to prevent leakage of fluids and entry of pathogens,

  • A pathogen must bind to, or cross an epithelia in order to cause an infection.

• Immune System cells derive from haematopoietic stem cells.

• Physical Barriers- EPidermis

  • Epidermis is the skin, consists of multiple layers of cells.

  • The stratum granulosim and spinosum contain lamellar bodies.

  • These organelles contain lipids which form a watertight lipid layer.

• REspiratory Tract

  • Bronchial Cilliated EPithlial Cells.

• Gut

  • Mucus secreting goblet cells.

  • Antimicrobial proteins e.g PAtoeth Cells.

  • COmmensal bacteria out compete pathogens.

• ANtimicrobial peptides.

• Protection by immune system

  • REcognition of pathogen & REsponse

  • Any pathogen needs recognisinf

  • Mount a reaction to eliminate it.

  • Specific recognition enable a specific response.

  • Non-specidic recognition ebables a non specific response

• Immune recognition- distinguishign foreign invaders from self-components. Triggers an effector response that eliminates or neutralises the invader.

• Immunological Memory- Certain exposures induce a rapid and heightened immune reaction upon a later attach called a memory response.

• Site of the infectoo and type of pathogen determine which immune response is effective.

• Viruses, bacteria and some protozoa replicate inside host cells, therefore these infectred cells have to be destroyed.

• Many bacteria a nd parasites live in tissues therefore different immune response is neede.d

• Phagocytosis

  • Plasma membrane of phagocytic cells, expands around the particulate material which may include whole pathogenic organis,s

  • Phagosomes in macrophages have reactive oxygen species, neutrophils contain lactoferrin.

  • Granules and lysosoymes fuse with phagosome producing phagolysosume where digestive enzymes are secreted into.

• Receptor Mediated Endocytosis

  • 1)Molecule binds to protein receptor

  • 2) Receptor-molecule moves to clatharin-coated pit.

  • 3) Cell membrane folds inwards.

  • 4) Formation of a coated vesicle/

  • 5) Vesicl e fuses with an endosome

  • 6) REceptors and molecules separate.

• Soluble molecules in innate immune response.

  • Lysosymes- Hydrolytic enzyme able to cleave bacterial cell wall.

  • Inteferons - A group of proteins produces by virus-infected cells.

  • Cytokines- Chemokines, interleukins,

  • Collectins - Proteins that directly disrupt the vace=terial lipid membranes or by aggravating the bacteria to enhanac e susceptibilyty to phagocytosis.

  • COmpliment- A group of serum proteins in an inactive state. When activated, able to damage the membranes of pathogenic organisms. Activation is a cascade reaction with each component sequentially acting on others.

• AMP- AntiMicrobial PEptides

  • Hsot defence peptides- usually 10 to 50 residues long.

  • A key com[onent of the innate immune system, they act against resistanc epathogenic organisms.

  • Defensisn- by neutrophils, macrophages and epithelial cells.

  • Cathelicidin, by neutrophils and epithelilals cells.

  • Lactoferrin - in milk and secretions.

• AMP Mechanisms

  • Teo modes of action - Direct Killing & Immuene modulation.

  • Direct Killing

PAMPS - PAthogen ASsociated Molecular Pattens

• A successful PAMP induces a widespread non specific response.

• Must be

  • Easily distinguishable

  • Essential for pathogen survival.

  • PResent on a wide range of pathogens.

• There is a constant selective pressure on the immune system to respond to these PAMPS.

• Microbial PAMPS- Lipopolysscccharides, Porins, peptidoglycans, glycodlipids…….

PPRS- Pattern REcognition receptors.

• p

Thr complement Pathway

Pattern REcognition

Adaptive Immunity

Adaptive Immunity

• Provided by lymphocytes

• Adapts to pathogens

• Long Lasting (memory cells).

Neutrophils & Macrophages

• Key cells of innate immunity

B & T cells

• Key cells of adaptive immunity

• Antibodies, amde by B cells, are important molecules and mediators of the adaptive immunity.

• T cells need the help of MHC to see antigens.

Lymph and Kymph nodes

• Lymoh percolates through the tissues, collecting cells and antigens,

• Cell encounters occur in specialised lymphoid tissue

• Lymphocyte training,

Antigenic Specificity

• Can distinguish subtle differences among antigens.

• ANtibodies can identify a single amino acid difference between two pathogenic proteins,

Diversity

• In the recognition of molecules; can recognisea single type of organism and differentiate among this with minor genetic variations.

Immunologic Memory

• A second encounter with the dame antigen induces a heigthenes state of immune reactivity.

• Confers immunity.

Self-Non Self recognition

• Ability to distinguis self from non self and respond only to nonself is essential

Primary Immune response

• The first encounter with a pathogen.

• Longer lag time.

• Less specific response.

Secondary Immune REsponse

• Faster response.

• Second and subsequent infections eith the same pahtogen,

• More specific response.

• Principle of vaccination.

COmponents of adaptive immunity

• Cellular- T cells

• Humoral- B cells

• Success of acquires immune response depends on the functions of both the cellular and humoeal responses as well as interactions with them.

Immune System Cells

• All immune system cells are derived from haematiopoitic stem cells.

• Heamtopoeiss is the formation of blood cells.

• White blood cells, leukpcutyes, immune system cells.

• Haematopoeisis shifts during development and occurs throughout life in bone marrow.

Where do lymphocytes come from?

• Both B cells and T cells start off in the bone marrow.

• They develop from Haematopoietic Stem Cells by a process ca;;ed Haematopoiesis.

• HSCs become common lymphocyte progenitors which then differentiate into the different Cells.

• B cells stay in the bone marrow whilst T cells go to the thymus to mature.

• Generation of CLonal Diversity- Production of T and B cells with all possible receptors.

• Clonal Selection - Selection, proliferation and differentiation of individual T and B cell receptors for a specific antigen.

T and B cells

• T cells can wipe out infected or cancerous cells.

  • Also direct the immune response by helping B lymphocytes to eliminate invading pathogens.

• B cells have the ability to transform into plasmacytes and are responsible for producing antibodies.

• Lymphocytes present receptors for antigen recognition with different specificity on their surfaces.

Cell-Mediated Immunity

• REsistance to pathogens or cancerous cells from the activation of T cells.

• ACtivated T cells form subsets of effector cells along with memory cells.

  • Effector cells actively engage in immune responses.

  • Memory Cells remember the specific antigen and responding more rapidly and effectively against future infections.

• T cells are particulary important in protection against viruses and pathogens that are resistant to killing by normal neutrophiles and macrophages.

Types of T cells

• Cytotoxic T cells (Tc)

  • Attack and kill targets directly such as cells infected by viruses or cancerous cells.

• Helper T cells (Th)

  • Stimulates the activity of other leukocytes through cell to cell contact or through the secretion of cytokines (assembly of macrophages for pahgocytosis, trigger B cell activation).

• REgulatory t cells (Tr)

  • Shut down an immune response after the antigens have been destroyed and prevent inapporpriate immune reactions.

• Memory T cells (™)

  • Respons quickly to a second challenge of the same antigen.

B Cells

• Stromal cells of the bone marrow.

• Humoral Immune Response

  ANtibody Mediatied Immunity

  • Mediated by a population of antibodies, that can produce more antibodies rapidlyty to a second challenge with the same antige, 

  • Antibodies circulate in the blood and bind to antigens on infectious agents, resulting in direct activation of the microorganis, or activation of a variety of inflammatory mediators to destroy pathogens. 

  • ANtibodies are primarily responsible for protection against many bacteria and viruses. 

  
  

  Antibodies

  • Y shaped proteins that are specific to each pathogen 

  • Able to lock onto the surface of an invading cell and mark it for destruction by other immune cells. 

  • Immunoglobulin is a serum glycoprotein produced by plasma cells. 

  • Antibody is one particular set of immunoglobulin which have a specificity to a particular antigen. 

  • Consists of four polypeptides; Two heavy chains and two light chains. 

  • Dual functions; Antigen binding and biological activity mediation. 

  
  

  

  Types of Immunoglobulins

  • IgA

    • Secreted into mucus, saliva, tears and colostrum

    • Tags pathogens for destruction

  • IgD

    • B cell receptor, stimulates release of igM. 

  • IgE

    • Binds to mast cells and basophils. 

    • Allergy and antiparasitic activity. 

  • IgG

    • Bidns to phagocytes. 

    • Main blood antibody for secondary responses. 

    • Crosses placenta. 

  • IgM

    • Fixes complement. 

    • Main antibody of primary responses. 

    • B-cell receptor

    • Immune system memory. 

  
  
  

  Antigen-Antibody Binding

  • When antigens bind to antibodies it changes the shape of the antigen molecule slightly so the hidden regions are exposed. 

  • ANtibodies may protect the host by covering sites on the microorganism that are needed for attachment thereby preventing infection. 

  • Most toxins of bacteria are proteins that bind to cell surface molecules and damage cells. 

  • Protective antibodies can bind to the toxins and prevent their interaction with host cells. 

  
  
  
  

  Active Immunity Vs Passive Immunity

  
  

  Natural Immunity

  Natural immunity is the deliberate exposure to a causative agent. 

  
  

  Active Natural Immunity

  • A child develops measles and acquires an immunity to subsequent infection. 

  
  

  Passive Natural Immunity

  • A foetus receives protection from the mother through the placenta or an infant from the mother's milk. 

  
  

  Artificial Immunity

  Articial immunity is another deliberate exposure to a causative agent. 

  
  

  Active Artificial immunity

  • Intentional exposure e.g Vaccination

  
  

  Passive Artificial Immunity

  • Injection of protective materials taht was developed by another individuals immune system 

  
  
  

  Immunisation

  • The principle of vaccination is based on specificit abd memory of adaptive immunity. 

  • MEmory cells allow the immune system to mount a much stronger response on a second encounter with the antigen where the secondary response is faster and more effective than the primary response. 

  • After a pthofen or is toxinf in a way that hey become innocuous without losing antigenicity. 

  • Antibodies and T cells recognise particular parts of antigens, the epitopes and not the whole organism or toxin. 

  • T-lymphocytes and ANtibodies are produces. 

  
  

  Vaccines

  • A weakened or dead form of a pathogen or subunits from it that aew known to stimulate the immune system to generate an immune response. 

  • Vaccines are typically administered using an injection, some through nasal spray. 

Pathogenesis

Host-Parasite Relationship

• Microorganisms engage in relationships with host species.

• This relationship is referred to as symbiotic.

Mutualism

• A mutually beneficial relationship.

Commensalism

• A relationship in which the host is neither harmed nor benefited whilst the coloniser benefits.

• Many feeding relationships are commensal.

Parasitism

• Oarasitism is a relationship in which the host is harmed and the parasite benefits.

• This is the relationship microorganisms engage in when causing human disease.

• The same microorganism can potentially engae in a parasitic of commensal/mutualistic relationship with the host dependant on the circumstances.

• Whilst parasitic relationships benefit the parasite causing excessive harm to the host does not necessarily benefit the parasite.

• It invites the possibility of coextinction.

• If the parasite causes extinction of the host, it is also at risk of extinction,

• Most parasites have not evolved to cause severe or debilitating disease but have evolved to conventional parasitism.

Direct & Indirect Pathogenesis.

• Microorganisms ay directly cause disease or the immune sustem may cause inadvertant damage in attempts to target infecting microorganisms.

• Direct Pathogenesis

  • In direct pathogenesis the microorganism directly induces harm to the host.

  • E.g Polio causies the lysis of motor neurones and therefore paralysis.

  • One form of direct pathogenesis is the lysis of host cells.

    • HIV mediation lysis of immune cells, which leads to immunodeficiency and ultimately AIDS.

    • Often associated with viruses as they are intracellulaar pathogens,

  • ANother form of direct pathogenesis is the release of exotixins that cause host damage.

    • Exotoxins are proteins released by bacterium

    • E.g Clostridium botulinum, releases a neurotoxin that acts at the nerve muscle junction and inhibits the release of acetylcholine, prevents the signalling events required for muscle stimulation.

• Indirect Pathogenesis

  • The microorganism indirectly induces harm to the host.

  • HArm occurs as a consequence of immune activation.

  • AS the immune activation is a response to the presence of the microorganism, the microorganism can be considered responsible for the harm just indirectly.

    • E.g symptoms of the common cols are caused by localised inflammation as a response to the virus.

  • LPS stimulates a potent, widespread immune response, which immediately causes fever and inflammation,

  • Pathogenesis dissemination can cause septic shock, not primarily antibody based.

  • Hypersensitivity

    • Essentially hyperactivation of the immune system

    • Type 1- Immediate hypersensitivity, allergen triggers degranuation of mast cells to release histamine,

    • Type 2- Mediated by antibodies tagetins the infectious organism.

    • Type 3- Caused by high levels of immune complezxes, accumulating in tissues and blood vessels.

    • Type 4-m Cell mediated immunity invariably causes tissue damage.

• Extreme Parasitism and coextinction

  • In general it os not beneficial for a parasite to cause dearh in the host.

  • In a symbiosis, the microorganism is dependant on a the host organism to some degree.

  • These relationships are often very specialised which creates th eissue of host availability, there is a threat of coextinction.

  • Parasitic microorganisms therefore typically cause limited disease.

  • The exceptions tend to be emerginf parasites where no abalance has evolced, other example have simply evolved to be extreme parasites.

• Parasitic Castraters

  • Cause severe damage to the host in the form of castration but derive hughe benefits.

  • E.g Green Crabm penetrates the host results in gonad atrophy.

• Parasitoids

  • Cause severe damage (death) but derive huge benefits.

Diagnosis

Eifexq