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Microbiology JC089: Defence Against Microbes Flashcards

1
Q

Immune system

A

Double-edged sword

  • Defence against microbes, Defence against cancers
  • Allergic reaction, Autoimmune disease, Malignancy, Aberrant responses to infections
Innate immunity
- Immediate (in place even before infection)
- Non-specific
- Limited diversity
- No memory
- ***Stimulate adaptive immune response
- Consist of
—> Physical + Chemical barriers
—> ***Phagocytic cells (neutrophils, macrophages)
—> ***NK cells
—> Blood proteins e.g. ***complements
—> Cytokines
—> Platelet
Adaptive immunity
- Needs time
—> Stimulated by exposure to antigens
—> ***Activation of lymphocytes
—> Elimination of antigens
- Specific
- Very diverse
- Memory
- Consists of
—> ***B + T Lymphocytes
—> ***Antibodies
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2
Q

***Innate immune system

A
  1. Epithelial barrier
    - skin, GI, genitourinary, respiratory tract
  2. ***Antimicrobial peptides
    - cathelicidins, defensins
  3. Recognition of microbes
    - **Pathogen-associated molecular patterns (PAMPs) (e.g. lipopolysaccharide, nucleic acid) of the microbes recognised by **Pattern recognition receptors (PRR) on host cell surface
    —> **Toll-like receptor (TLR), **Nod-like receptor (NLR), ***RIG-1 like receptor (RLR)
    —> Direct activation of Innate host-defence module by PRR
    —> positive feedback to amplify immune response
    —> eventually trigger adaptive immune response
    —> specific clearance of pathogens + establish long term immunological memory against pathogen
  4. Cells involved
    - Neutrophils
    - Macrophages
    - NK cells
  5. Complement system
  6. Communication
    - by Cytokines
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3
Q

Complement system

A
  • Plasma proteins that are activated by microbe
  • Promotes destruction + inflammation
  1. Classical pathway (Ag-Ab complex bound by C1)
  2. Alternative pathway (Ag bound by C3b)
  3. Lectin pathway (Mannose bound by MBL)
    —> Activation of C3
    —> C3a (Inflammation), C3b (Opsonisation)
    —> C5a (Inflammation)
    —> C5b-C9 (MAC)
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4
Q

Adaptive immune response

A

Humoral:
- B cell —> Plasma cell —> Ab

Cellular:
- T cell
—> T helper cell (CD4+) —> Th1 (Cell-mediated immunity), Th2 (Humoral immunity), Th17
—> T cytotoxic cell (CD8+)

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5
Q

Antibody

A
  • 2 Heavy chains
  • 2 Light chains
  • Fc fragment: Low portion, only heavy chains —> bind to Fc receptor
  • Fab fragment: Upper portion, heavy + light chains —> bind to Ag

Functions

  1. Ab bind to pathogen / toxin
    - **Neutralisation of toxin / viruses
    - **    Direct antimicrobial activity
    - **Complement activation
    - **    Opsonisation (Ab-bound pathogen phagocytosed by neutrophils / macrophages)
    - ***ADCC (trigger effector cells to kill targets via cell-mediated immunity e.g. Cytotoxic T cell response: CTL kill virus-infected cells / tumour cells)
  2. Ab bind to host cells / tissues
    - Immunomodulation

Types of Ab:

  1. IgM
    - early phase of infection, appear before IgG
  2. IgG
    - appear later
    - large amount in serum
    - ***remain positive for long period of time
  3. IgE
    - bound to mast cell —> Type 1 hypersensitivity reaction
  4. IgA
    - secreted
    - mucosal surfaces
  5. IgD
    - cell bound on B cell —> cell signaling
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6
Q

T cells

A
  1. Cytotoxic T cells (CD8+)
    - eliminate intracellular microbes by killing infected cells
  2. Helper T cells (CD4+) (Master regulator)
    - Th1:
    —> Phagocyte-mediated
    —> **Intracellular microbes (bacteria / protozoa)
    —> produce **    IFNγ (e.g. in MTB)
  • Th2:
    —> Promote **IgE and Eosinophil / Basophil / Mast cell-mediated immune reactions
    —> produce **    IL-4 (e.g. Helminth infection)
    —> also cause ***Atopy (e.g. Asthma)
  • Th17: Protect against **Extracellular bacterial + **Fungal infections
  • Th1, 2, 17: Promote production of Ab from B cells
    3. Regulatory T cells
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7
Q

Important clinical syndromes associated with immune defects: Impaired ***innate immunity

A
  1. Complement defects
  2. Neutrophils defects
    - **Chronic granulomatous disease (CGD)
    - **    Leukocyte adhesion deficiency syndromes (LAD)
  3. AutoAb against IFNγ
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8
Q
  1. Complement defects
A

Defects in:

  1. Classical pathway
    - Encapsulated bacteria (e.g. S. pneumoniae, Hib, ***N. meningitidis)
  2. Mannose binding lectin pathway
    - Sinopulmonary infection
    - ***N. meningitidis
  3. Alternative pathway
    - Less common
    - ***N. meningitidis
  4. Terminal components (C5-9)
    - ***N. meningitidis

Implications: Must consider **meningococcal vaccination in treatment of **SLE which wipes out complement system

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9
Q
  1. Neutrophils defect
A
  1. Quantitative defect: **Neutropenia
    - **    Chemotherapy, Antibiotics
    - ***Haematological malignancy
  2. Qualitative defect: ***Chronic granulomatous disease

Problems:
1. Bacterial infection
- Gram +ve: Staphylococcus, Streptococcus, Enterococcus
- Gram -ve: E. coli, PA (>50% mortality)
—> Sepsis
- ***Neutropenic fever / Neutropenic sepsis: Medical emergency, life-threatening

  1. Fungus
    - Candida
    - Aspergillus, Fusarium, Zygomycetes
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10
Q

Chronic granulomatous disease (CGD)

A
  • Usually X-linked (some autosomal recessive form p47)
  • ***Abnormal respiratory burst oxidase activity —> Phagolysosome lacks superoxides / H2O2 to kill bacteria —> Defects in intracellular killing
- Susceptible to organisms that have ***strong catalase reactions:
—> ***S. aureus
—> Serratia marcescens
—> Burkholderia cepacia
—> Chromobacterium violaceum
—> Nocardia
—> Aspergillus
—> Clinical presentation: Lymphadenitis
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11
Q

Leukocyte adhesion deficiency syndromes (LAD)

A
  • Neutrophils functionally normal
  • But **impaired adhesion of affected inflammatory cells within the vasculature, **inability to migrate into tissues
  • Recurrent infections
    —> Staphylococcus
    —> Pseudomonas aeruginosa (disease: Ecthyma gangrenosum)
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12
Q
  1. AutoAb against IFNγ
A
  • Adult onset
  • ***Acquired condition
  • Asian

IFNγ:

  • involved in Innate + Adaptive immunity
  • Type 2 IFN
  • produced by NK cells, Th1, CTL
  • part of IL12-IFNγ loop —> activate macrophage —> important to kill ***intracellular microbes
Microbes (***Intracellular):
- NTM
- Non-typhoidal salmonella
- Burkholderia pseudomallei
- Penicillium marneffei
- VZV
(- Cryptococcosis, Histoplasmosis)
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13
Q

Type 1 IFN

A
  • Important for ***viral infections

- 10% COVID-19 patients with severe / life-threatening symptoms have AutoAb against Type 1 IFN

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14
Q

Important clinical syndromes associated with immune defects: Impaired ***adaptive immunity

A
  1. Impaired humoral immunity (lack Ab for opsonisation, complement activation)
    - ***Encapsulated bacteria
    —> S. pneumoniae
    —> H. influenzae
    - Diseases associated with Ab deficiencies / defects: Agammaglobulinaemia, IgA deficiency, Nephrotic syndrome
    - Common variable immunodeficiency (CVID)
  2. Impaired cell-mediated immunity
    - ***Intracellular pathogens
    - Acquired immunodeficiency syndrome (AIDS)
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15
Q

Diseases associated with Ab deficiencies / defects

A
  1. Agammaglobulinaemia (prone to **bacterial infections)
    - **    Sinusitis, **Otitis media, **Pneumonia
    —> S. pneumoniae, H. influenzae, Meningococci, Mycoplasma
  • ***Intestinal infection
    —> Salmonella, Shigella, Campylobacter, Giardia, Rotavirus
  1. IgA deficiency
    - Common condition
    - Recurrent ***sinopulmonary infection
    - Anaphylactic reaction if given IVIG (∵ patient may have Ab against IgA)
  2. Nephrotic syndrome
    - Prone to severe ***pneumococcal infection
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16
Q

Common variable immunodeficiency (CVID)

A
  • Onset 15-25 yo
  • Low level Ab
  • Prone to infections:
    —> **Sinopulmonary: recurrent bronchitis, sinusitis, otitis media, pneumonia (Encapsulated bacteria)
    —> **    GI
    —> Systemic bacterial infections
- Other diseases:
—> ***Autoimmune disease (∵ lost check-and-balance mechanisms in immune system)
—> Malabsorption
—> Granulomatous disease
—> ↑ risk of GI malignancy, ***lymphoma
17
Q
  1. Impaired cell-mediated immunity
A

***Intracellular pathogens

  1. Viruses
    - HSV
    - CMV
    - VZV
    - HHV6, 7
    - HIV
  2. Bacteria (Intracellular)
    - Listeria
    - Rhodococcus
    - Salmonella
    - Burkholderia pseudomallei
    - Nocardia
    - Mycobacterium (TB / NTM)
  3. Fungus
    - Pneumocystic jiroveci
    - Cryptococcus
    - Aspergillus species
    - Dimorphic fungi e.g. Penicillium marneffei
  4. Parasite
    - Toxoplasma gondii
    - Strongyloides stercoralis (hyperinfection and disseminated infection)
18
Q

Acquired immunodeficiency syndrome (AIDS)

A
  • Caused by HIV (Human immunodeficiency virus)
  • Main problem: ↓ CD4+ T cells (after many years) —> Cell-mediated immunity most severely affected —> AIDS
  • ∵ Master regulator depleted —> also affect other parts of immune system
  • ***Tip: Always screen for HIV even slight suspicion —> Early detection of HIV is important!!!

Opportunistic infections (***Intracellular) in advanced HIV:

HK:

  • MTB: only Extrapulmonary / if CD4<200: Pulmonary / LN
  • PCP
  • Penicilliosis (disseminated) (caused by Penicillium marneffei)

Others:

  1. Bacteria
    - MAC / M. kansasii
    - MTB
    - NTM
    - Salmonella septicaemia
  2. Virus
    - CMV
    - HSV
    - PML (progressive multifocal leukoencephalopathy)
  3. Fungal
    - candidiasis
    - coccidioidomycosis
    - cryptococcus
    - histoplasmosis
    - PCP
  4. Parasite
    - cryptosporidiosis
    - isosporiasis
    - toxoplasmosis
  5. Cancer
    - cervical cancer
    - lymphoma
  6. HIV-related
    - encephalopathy
    - wasting syndrome
  7. Miscellaneous
    - recurrent pneumonia
19
Q

Important clinical syndromes associated with immune defects: Other systemic disease / conditions that affects immune functions

A
  1. **DM (hinder **neutrophil function)
  2. Breaks in physical barriers (e.g. skin, mucosa)
  3. ***Cirrhosis (liver cannot produce proteins, cannot filter blood)
  4. ***Autoimmune disease e.g. SLE
  5. ***Malignancy
  6. Transplantation
  7. ***Iron overload (pathogens love iron) (in repeated transfusion for Thalassaemia, Myelodysplastic syndrome)
  8. ***Splenectomy
  9. Drugs (e.g. steroids)
  10. Malnutrition
  11. Pregnancy
  12. Extremes of age
20
Q

Post-splenectomy sepsis

A

Cause: Splenectomy / Functional hyposplenism

Major function of spleen in immunity:

  1. ***Production of Ab (esp. Ab against polysaccharide Ag)
  2. ***Clearance of encapsulated bacteria

Organism (mainly bacteria with polysaccharide capsule):

  • ***S. pneumoniae
  • ***Hib
  • ***N. meningitidis
  • Capnocytophaga canimorsus

Rapid progression:
- ***Need urgent antibiotics

Vaccination:

  • S. pneumoniae
  • Influenza
  • Hib
  • N. meningitidis

***Tip: Pay attention to patients with fever without a spleen —> immediate culture + antibiotics

21
Q

Immunisation

A

Anything that ***Artificially induce immunity

Active vs Passive:

  • Active: by Vaccination
  • Passive: by Ig administration

Different types of vaccine:

  • ***Whole organism: Live attenuated (e.g. MMR) / Inactivated (e.g. rabies)
  • Toxoid (e.g. tetanus)
  • ***Soluble capsular material (e.g. Pneumococcal vaccine)
  • Recombinant proteins (e.g. HBV, HPV)
  • Vector vaccines
  • mRNA vaccines
22
Q

How does immunisation work?

A

Exact mechanism is still poorly understood

By triggering:

  1. Humoral immunity (Elicit Ab response)
    - Influenza vaccine
    - Pneumococcal vaccine
  2. Cell-mediated immunity
    - e.g. BCG
  3. Combination of both
23
Q

Treatment of infectious disease by manipulating host immune system

A
  1. Reversing immunodeficient state
    - Glucose control in DM
    - HAART for HIV
    - **G-CSF in patients with neutropenia
    - **    IVIG in patients with CVID
  2. Administration of **immunomodulator —> help patients with refractory infectious diseases
    - Naturally occurring cytokines
    - **    Immunoglobulins
    - **Glucocorticoids
    - Monoclonal Ab
    - Synthetic compound with immunomodulatory activity
    - Anticoagulant proteins e.g. activated protein C
    - **    Interferons
24
Q

Interferons

A

Rationale: ***Antiviral activity

Treatment of:
- HCV (PegIFN, now obsolete)
- HBV (PegIFN, now obsolete)
(- Kaposi sarcoma)
(- Condyloma accuminatum)
- COVID-19 (IFNβ (Type 1 IFN) may be useful in early disease according to local clinical trial)
25
Q

Steroids

A

Rationale: ***Damp down inflammatory response —> Reduce detrimental effect due to inflammation

  • ***Pneumocystis pneumonia (PCP)
  • ***COVID-19 patients supplemental O2
  • TB meningitis
  • ***Bacterial meningitis (Dexamethasone)
  • Chronic disseminated candidiasis
26
Q

Intravenous immunoglobulin (IVIG)

A

Prepared from plasma obtained from many blood donors

MOA:

  • Bind to pathogens / toxins
  • ***Immunomodulation

Treatment of:

  • ***Toxic shock syndrome due to Group A Strept / Staphylococcus (controversial)
  • Parvovirus infection in immunocompromised patients

Prophylaxis (much more effective):

  • Following exposure against VZV, measles, Hep A etc.
  • Patients with ***humoral immunodeficiencies

JC WCS (134 decks)

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