L9- Immunity against infection (virsus and parasites)

What determines the effector mechanism needed (3)

• type of pathogen

• Localisation

• Stage of infection

Whihc mhc presents peptides from extracellular microorganisms

MHC II APCs

Which MHC presents proces peptides from intracellular microorganisms

MHC I

Hat can all nucelated cells be infected by

Viruses

Viruses

Obligate intracelular parasties but can alos be extracelullar at some stages of infection

Innnate defences against viruses (2)

• interferons

• NK cells

How are IFN in particualr IFN alpha dn beta effecive against virus infected host cells (5)

• slow down virus replication by inducing resistnace to viral replication in all cells by inducing Mx proteins, 2’-5’ linked adenosine oligomers and PKR kinase

• Increases MHC I expression and AP in all cells by= more presentation of processed virus = more T cells recruited

• Activate DC and macrophages

• Activate NK cells to kill virus infected cells

• Induce chemokines to recruit lymphocytes

What else can IFN do

Bind to un infected cells and protect them by inducing syntheisi of antiviral molecules

when are interferons present

Sysntehis of IFNalpha dn beta (type I interferon) induced in virus infected cells are present in early response to infection

What is type II interferon and what do they do (1+2)

• TFNgamma secreted by activated T cells and NK cells

• Inhibits TH2 response (antibodes) and promotes TH1 (cell killing)

• Recruits macrophages

Therapeutic uses of interferons and a problem (2+1)

• rIFNalpha can be used to treat hepB and C

• Some cancer treatments

• Can cause very severe side effect

rIFN

Recombinant IFN

Feaures of NK cells (6)

• type of innate lymphoid cell

• Large l granular lymphocytes

• Recongise strucutres on viral infected cells

• Can recognise stressed cells in absence of Igs and MHC

• Kill by extracellular mechanism using perforin and granzymes

• Fast

• Interferons make them angry and better killers

Why do we need NK recpetors

To distinguish between infected and un infected host cells

Type of NK cell receptors (2)

• activating receptors

• Inhibitory receptors

Activating NK receptors

• Recognise carb ligands

• trigger killing

Inhibitory NK receptor

Recognise MHC I moelcuels but dont bind with them (only TCRs bind)

What happens becasue viruses reduce MHC expression

Makes cells more susceptible to NK killing

Process on inhibtory receptor (2)

• MHC I on nomral cells is recognised by inhibitory receprots that inhibit signals from activating receprots

• NK cells doesnt kill normal cell

Examples of activating receptor

• missing or absent MHC I cant stimualtes negative signal

• NK cell is triggered by signals from activating recpeotr

• Activated NK cell releases granule contents including apoptosis in the target cell

Cell mediated specific immunity includes..,(2)

• cytotoxic T cells (CTL, CD8+) that recognise viral peptide + MHC I

• Cytokines with anti viral activity eg IFNgamma

What do cytotoxic T cells recognise

Viral peptide and MHC I

What are the 2 mechanisms that cytotoxic T cell use to indue apoptosis in target

• secretion of cytotoxic granules eg perforin which polymerises in memrbane and granzymes whcih enter cell

• FAS ligand on T cell interacts with FAS receptor on target

How are do cytotoxic t cell (CTLs) trigger apoptosis (4)

• recognise and bind virus infected cell

• Programs target for death inducing dna fragmentation

• CTL migrates to new target

• Target cell dies by apoptosis

Why are CTLs considered silent killers

Dont get a reaction → no inflammation adn no release of virus

Effects of IFNgamma secreted by CTLs(4)

• inhibit viral replciation

• Upregulated MCH I and II expression and antigen presentation

• Increases macrophage phagocyosis of dead cells

• Promtoe NK cell killing activity

Over the course of 10 days when do each component come in to play

• IFNalpa and beta ,TNF alpha nd IL 12 days 1-5, peaking at day 2

• NK cell mediated killing of infected cells days 1-10, people ong days 5-6

• T cell mediated killing of infected cells fas 2-10 peaking on days 6-8

Functions of antibodies (3)

• neutralise free virus preventing entry and spread between cells

  • Prevent spread htrough body and can protect mucosal surfaces against re inejction

  • Opsonise to increase phagocytosis

  • Activate complemetn leading to lysis

Specific immuntiy against viruses (2)

• antibodies

• Cell mediated specific immunity

Antobody and cell mediated immunity in influenza (4)

• infection induces antobody and cytotoxic T cell (CTL) repsons

• Antobody recognises viral haemagglutinin an neuramiidase

• High levels of CTL activity correlates with reduced viral shedding

• Epidemics arise due to new trains not recognised by antibody

Key features of HIV ((3)

• attacks specific immune systems

  • Attacks APC pathwya nad cytokine production is reduced

• Targets CD4+ T cell, macropahges and DC

• Progressive developemtn of AIDS leads to opportunistic infections

Examples of Opportunistic infections a s a reuslt of HIV (3)

• oral candidiasis

• Karposis sarcoma

• Pneumonia

Treatmetns for HIV (4)

• antibodies dont seem to protect

• Infection can be controlled by cytotoxic T cells

  • Patients wiht higher levels of CTL showed slower disease progression

  • Virus mutation that escape CTL recognisiton may lead to progression to AIDS

Feautres of SARS cov 2 (7)

• Firt reported in 2019

• SARS and men’s very simialr outbreaks in last 20 years

• Symptoms 2-14 days post exposure

• 22-32 kilo bases ss +ve rna virus

• Spike glycoprotein binds to ace2 repceotrs on host cells

• Monoclonal antibody to s protien in mice are protected but dont have an animal model

• High mutation rate

Immune repsonse to covid (4)

• dampens antiviral t1 interferon → aids viral replication → those with lower t1 IFN had worse prognosis

• Viral proteins can inhibit RIG1 (a PRR)

• Viral proteins can sitmulate NFkB activation which is proinflammaotry

• Antibodies protective and role of cytotoxic T cells

What was seen in severe cases of covid (6)

• lymphopenia (low WBCs)

• Eosiophenia

• Extensive pneumonia

• Lung damage

• Cytokine storm → acute resp distress syndrome

• Multiple organ failure

Parasites (3)

• a diverse range of organisms, uni or mutli cellualr

• Often multiple complex stages in life cycle

• Different defence mechanisms imporatn

How can antobodies protect against parasites (

• opsonisation

• Complement lysis

• antobody dependent cell mediated cytotoxicity (ADCC)

What do some helminths induce

A strong IgE antobody response → mast cell mediated inflammation, eosinophils ADCC

Cell mediated mmunity against parasite (2)

• Important for Protozoa that can survive in macropahges that stay hidden from Igs eg leishmania

• Cytokine are imortant in inducing the macrophage activation eg IL1

What type of T cell allowe mice infected with leishmania to survive and which didnt

• C57BL/6 survive

• BALB/c had fatal progressive disease

Repsonses of mice strains to leishamina and which cytokines were present

• C57BL/6

  • Th1 repsonse

  • Lots of IFNgamma

  • No IL4

• BALB/c

  • Th2 repsonse

  • Some IFN gamma

  • Lots of IL4

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Why did the C57BL/6 mice survive adn trh BALB/c die

• C57Bl/6 use a Th1 pirmary driven repsonse which actiatesmacorohages so is efficient at killing intrallelcur leishmania

• IL4 produced by BALB/c mice drives th2 response which produces lots of antibodies but this is not that useful with leishamina

Which repsonse do you want with leishmaniasis

TH1

In 2023, what was estimated death toll and case numebr of malaria

• 262 million cases

• 597,000 deaths in 83 coutrnies

Whar % of malaria deaths do children under 5 make up

76%

What does response malaria require

• different effector mechanisms active at different stages

Which stage of malaria are susceptibity to antibodies (2)

• sporozites

• Merozoite

In malaria what ca be used to kill infected RBCs and liver cells

• RBCs→ antibodies

• Liver → cytocic T cells

What is the most recent vaccine against malaria

RTS,S vaccine since 2019 and R21/Matrix M vaccine more recently