Immunity against infectious diseases

against viruses

early production of IFNα/ß, TNFα & IL-12 by tissue cells and resident APC

boost cytokine killing activity but an adaptive immune response is needed for clearance

NK-cell mediated killing followed by T-cell mediated killing of infected cells

IFNα/ß/δ

direct antiviral properties & function on immune cells

produced by virus-infected cells & plasmacytoid DC

1 single receptor

interferes with viral replication

IFNγ

function on immune cells

produced by T & NK cells

singlaing by JAK/STAT pathway (as all cytokines)

can mediate several function to inhibit virus

JAK/STAT pathway leads in infected cells to transcription of:

1. Mx proteins: GTPases that interfere with viral replication

2. oligoadenylate synthetase: creates 2’-5’ (instead of 3’-5’) ATP oligomers activating an endoribonuclease active on viral RNA

3. PKR = dsRNA dependent PK that stops protein translation

4. IFIT (interferon-induced proteins with tetratricopeptide repeats) in human IFIT 1/2/3/5 differing in number of repeats and bind viral RNA

5. immune function:

   • increased MHCI expression & antigen presentation in all cells

   • activates DCs, macrophages & NK cells to kill virus-infected cells

   • induce chemokines to recurit lymphocytes

—> resistance to viral replication, induce MHCI expression in most cell types & activation of NK cells

way to escape CD8+ cytotoxic T-cells

cytomegalovirus: persistent virus -> hijacks different genes impairing MHC presenting pathway

inhibits TAP transport

inhibits proteasome

retains MHC upon transport to the cell surface in vesicles in ER or ERGIC

induces transport of vesicles filled with MHC during transport to the surface to the lysosome (degradation)

MHC presentation inhibited by virus -> no persistence due to susceptibility to NK cells but escape CD8+ cytotoxic T-cells

MHCI homologs encoded by viruses

HCMV UL-18 triggers inhibitory NK cell receptors specific for MHCI

->combination allows persistence

against intracellular bacteria

enables macrophages to destroy intracellular bacteria

Th1 cells produce IFNγ and CD40L which induce and activate M1 macrophages

->enhances macrophage killing of engulfed bacteria

Fas ligand produced by Th1 cells induce apoptosis of bacteria-laden macrophages

kills chronically infected cells, releasing bacteria to be destroyed by fresh macrophages

no killing but keeps infection in control

equilibrium between bacteria & the immune response

formation of granuloma: the central core of infected macrophages that fuse to multi-nucleated giant cells surrounded by activated T-cells and control the spread of mycobacteria

any immunosuppression will lead to tuberculosis -> relapse of mycobacteria

mycobacteria resistant to the effects of macrophage activation -> persist in the cells of the granuloma

against parasites

fight big pathogens by secretion of cytokines

Th2 cells produce IL-13 inducing epithelial cell repair & mucus

increased cell turnover & movement help shedding of parasitized epithelial cells

mucus prevents adherence & accelerates the loss of parasite

IL-13 increases smooth muscle contractility -> enhances worm expulsion

IL-5 recruits & activates eosinophils -> produces MPB (major basic protein) which kills parasites

can also mediate ADCC using parasite-specific Ig

against extracellular bacteria

IL17 & IL22 produced by Th17 cells induce the production of antimicrobial peptides by epithelial cells

direct killing or growth inhibition of bacteria attached to the epithelium

IL-22 increases epithelial cell turnover -> regeneration of epithelium

increased epithelial cell division & shedding impairs bacterial colonization

via mucosa

intraepithelial DCs bind HIV using DC-SIGN (DC leptin receptor binding many different compounds)

HIV is internalized into early endosome

DCs that have migrated to lymph nodes transfer HIV to CD4 T cells

activated by binding & present antigen to the immune system

virus particle binds to CD4 (gp120) & coreceptor on T cells (CCR5)

viral envelope fuses with the cell membrane allowing the viral genome to enter the cell (gp41)

reverse transcriptase copies viral RNA genomes into double-stranded cDNA

viral cDNA enters the nucleus & is integrated into host DNA (retrovirus)

individuals at high risk but seronegative due to biallelic mutation in CCR5 (chemokine receptor, mutated form doesn’t bind gp120)

1% of the caucasian population

T-cell activation induces low-level transcription of provirus (NFκB dependent, binds proviral LTR starting the transcription)

RNA transcripts are multiply spliced allowing the translation of early genes tat & rev

tat amplifies transcription of viral RNA, rev increases the transport of singly spliced or unspliced viral RNA to the cytoplasm

late proteins Gag, Pol & Env are translated & assembled into virus particles budding from the cell

death by the production of too many virions

first few weeks typified by an acute influenza-like viral illness (high titers of virus in the blood)

the adaptive immune response follows and controls actual illness & largely restores CD4 T cells but no eradication of the virus -> asymptomatic phase until depletion of CD4 T-cells too high

opportunistic infections more frequent with falling CD4 T-cell count = symptomatic phase

AIDS = acquired immune deficiency syndrome

don’t die by HIV as life without CD4+ Tcells is possible in sterile conditions

common pathogen & also tumors

Kaposi sarcoma (induced by human herpes virus 8), non-Hodgkins lymphoma, primary lymphoma of the brain -> immune surveillance normally prevents these tumors

pathogens requiring effective macrophage activation by CD4 T-cells or effective cytotoxic T-cells

early immune response good -> after a few weeks virus nearly not detectable

Abs against HIV env and HIV p24, HIV specific CTL

but virus still able to escape the response -> control but no cure

high rate of muation leads to immune escape -> HIV RT not a polymerase with an error proof reading activity

many different virions even in a single individual

not achived yet due to high mutation rate

• therapeutic approach

  • CD4+ T cell lymphopenia (vaccination difficult with low CD4+ pool)

  • silent reservoirs (in other CD4+ cells (low in macrophages) but no replication of the virus)

  • high rate of mutations (vaccination needs to induce Abs against many different strains)

• prophylactic approach

  • no universal vaccine because high number of HIV strains

generation of broadly neutralizing Abs recognizing different strains achieved

highly active antiviral therapy targeting proteins important in viral life

entry inhibitors CCR5

RT inhibitors

integrase inhibitors

protease inhibitors (important for budding from infected cells)

-> high cost but efficient reduction of death in infected people