Immune response to pathogens - PDF Free Download

Bari, May 26, 2017 Immune response to pathogens Francesco Dieli Department of Biopathology and Medical Biotechnologies Central Laboratory of Advanced Diagnosis and Biomedical Research University of Palermo francesco.dieli@unipa.it

General scheme of an immune response Pathogens Disease - causing organisms Protozoa, Bacteria, Viruses, Fungi, Worms etc How does the human immune system distinguish pathogens from human tissues?

How does the immune system distinguish pathogens from self tissues? by discriminating between self and non-self proteins (Burnet 1949, Medawar 1953)

How does the immune system distinguish pathogens from human tissues? by discriminating between self and non-self proteins But Most microorganisms do not cause disease in humans What about the non-self proteins of commensals and symbionts? What about the non-self proteins in food? What about the non-self proteins from microrganisms in food? How does the immune system discriminate between useful or harmless sources of non-self protein and pathogens?

How does the immune system distinguish pathogens from self tissues and useful or harmless sources of non-self protein and pathogens? by discriminating between self and non-self proteins (Burnet 1949, Medawar 1953) by detecting danger signals (Matzinger, 1994)

General scheme of an immune response: three lines of defense

General General scheme scheme of an immune of an immune response: response three lines of defense Figure 2-1

First line of defence - Epithelial cells Functions within seconds of contacting a pathogen A mechanical, selectively permeable barrier between the outside and inside May possess motile cilia Outside Rapidly renewable Produce natural antibiotics - cationic antibacterial peptides - defensins and cathelicidins Inside Primary role is to block the entry of microorganisms Produce cytokines - proteins that alter the behaviour of other cells Produce chemokines - proteins that attract other cells

PaAern RecogniBon Receptors of innate immunity

FuncBons of PaAern RecogniBon Receptors SecreBon of cytokines and chemokines SecreBon type I IFN OxidaBve burst inos Killing

A complex issue on CD4 T helper cell subsets Macrophage Neutrophil Eosinophil Mast cell

Signals 1, 2 and 3 Signal 1 antigen & antigen receptor DC Th Signal 2 CD80/86 - CD28 costimulation Signals 1 & 2 activate T cells to proliferation, but what tunes the response to Th1, Th2 or Th17? Signal 3 - pathogen polarised DC

Polarised DC subsets Signal 1 DC Th Signal 2 Signal 3 Th polarising signal Signals from the pathogen polarise the DC to produce qualitatively different signals 3 The properties of the pathogen influence the DC to drive the differentiation of appropriate Th cells.

DC-polarising PAMPs + + T Type 1 PAMPs bind to PRR-X CD80/CD86 Class II CD40 + Th1 polarising factor IL-12 Th17 polarising factor IL-23 Type 3 PAMPs bind to PRR-Y

DCs polarizing Candida Albicans PAMPs Hyphae Yeast

Differentiation of type 2 immune responses

Type 2 immune responses protect against helminths Eosinophils Mast cells

Signals from infected tissues expand and activate ILC1s, ILC2s, and ILC3s Eberl G. et al. Science 2015

ILC1s contribute to type 1 immune responses

ILC2s contribute to type 2 immune responses

ILC3s contribute to type 3 immune responses

Characteris5c infec5ons of primary immunodeficiencies Component T lymphocytes B lymphocytes Pathogen Extracellular and intracellular bacteria, viruses, protozoa, fungi Extracellular bacteria (Staphilococcus auerus, Streptococcus pneumoniae), Enterovirus Gene5c defects of type 1/type 3 immune responses Disease Phenotype Infec5on IL12p40 deficiency Th1, Th17, ILC3 Candida, extracellular and intracellular bacteria IL12Rβ1 deficiency Th1, Th17, ILC3 Candida, extracellular and intracellular bacteria IFN-γR1/R2 deficiency IFN-γ Intracellular bacteria IL-17 deficiency* IL17 Candida, extracellular bacteria IL-17R deficiency IL17 Candida, extracellular bacteria Phagocytes Complement Extracellular bacteria Extracellular bacteria, N. meningi5dis (C5-9) STAT3 deficiency Th17, ILC3 Candida, extracellular bacteria CARD9 deficiency Th17, ILC3 Candida, extracellular bacteria STAT1 GOF Th17, ILC3 Candida, extracellular bacteria STAT1 deficiency IFN-γ, type I IFN Intracellular bacteria, viruses APECED IL17A, IL17F, IL22 Candida

Innate and adaptive immune responses to viruses

The first events following infec5on with M. tuberculosis Ag-specific CD4 T cell priming DC migrate to draining LN CD4 T cells migrate to lung inters55um What then delays immune response to M. tuberculosis?

M. tuberculosis exploits different strategies to pass several host immunological checkpoints Checkpoint one: Avoiding being killed by the macrophage Checkpoint two: DefeaBng innate immunity Checkpoint three: DefeaBng adapbve immunity Novel vaccinabon strategies to target the immune checkpoints where host defense fails or does not fare well in response to M. tuberculosis.

The intracellular lifestyle of M. tuberculosis Kaufmann, Nat. Rev. Immunol. 2001.

M. tuberculosis-mediated modulation of eicosanoid production determines the death modality of the infected macrophages Behar et al., Nat. Rev. Immunol. 2010.

Evasion of innate immunity by M. tuberculosis: is death an exit strategy? Behar et al., Nat. Rev. Immunol. 2010.

An Interferon-Inducible Neutrophil-Driven Blood TranscripBonal Signature in Human Tuberculosis. Nature 2010; 466: 973-77.

Type I Interferon Suppresses Type II Interferon-Triggered Human AnB- Mycobacterial Response. Science 2013; 339: 1448-53.

TargeBng the inflammatory response in tuberculosis. N. Engl. J. Med. 2014; 371:1354-6.

M. tuberculosis infection in Toll/Interleukin-1R (TIR)8 / mice Garlanda et al., 2007; Di Liberto et al., J. Exp. Med. 2008

M. tuberculosis and HIV coinfected targets escape CD8 T cell recogni5on

Summary: the two-tiered design of the immune responses Type 1 and Type 3 immunity Type 2 immunity Modified from Akiko Iwasaki & Ruslan Medzhitov Nat. Immunol. 16, 343-353; 2015.