Infections Evading Immune Systems July 29 2014 Tanaya

Infections: Evading Immune Systems July 29, 2014 Tanaya Bhowmick MD Assistant Professor Dept. of Medicine bhowmita@rutgers. edu Developed as part of the RCSB Collaborative Curriculum Development Program 2014

Historic Perspective • 19 th century – – proof that diseases are caused by infectious agents – founded the discipline of microbiology • 20 th century – – development of antimicrobial agents – vaccines to effectively treat diseases raised hopes for the eventual elimination of many of the diseases • Present day – – infectious diseases cause more than 20% of all deaths – Infections occur in both the resource-rich and the resource-poor world Developed as part of the RCSB Collaborative Curriculum Development Program 2014

Emerging Infectious Diseases Infectious agents identified within the last twenty years • • • • Hanta virus Human herpes virus 8 Hepatitis E-G Variant Creutzfeldt-Jakob disease (v. CJD) Hendra virus Nipah virus Vibrio cholerae 0139 Cryptosporidium Cyclospora Severe acute respiratory syndrome (SARS) associated coronavirus Epizootic avian influenza H 5 N 1 Human T-cell lymphotropic virus 3 (HTLV-3) HTLV-4 Xenotropic Mu. LV-related virus Developed as part of the RCSB Collaborative Curriculum Development Program 2014

Microorganism : Host Relationships • Mutualistic - provide reciprocal benefits for the two organisms involved. Example • Bacteria and protozoa living in the stomachs of domestic ruminants play an essential role in the digestion and utilization of cellulose, while receiving both an environment and the nutrition essential for their survival • Commensal - occur when one species of organism lives harmlessly in or on the body of a larger species. Example • Humans support an extensive commensal microbial flora on the skin, in the mouth and in the alimentary tract – Commensal microbes can benefit the host preventing colonization by more pathogenic species (e. g. the intestinal flora) • Parasitic - where the relationship benefits only the parasite – all pathogens are parasites – many 'parasites' establish benign associations with their natural hosts but become pathogenic if there are changes in the host's health or if they infect an unnatural host. Example • the rabies virus, coexists harmlessly with many wild mammals but can cause fatal disease in humans Developed as part of the RCSB Collaborative Curriculum Development Program 2014

Categories of Infectious Agents • Bacteriophages, Plasmids, Transposons • Bacteria – Extracellular – Intracellular • Chlamydiae, Rickettsiae, Mycoplasmas • Fungi • Parasites – Helminths – Ectoparasites • Prions • Protozoa • Viruses Developed as part of the RCSB Collaborative Curriculum Development Program 2014

Immunity Developed as part of the RCSB Collaborative Curriculum Development Program 2014

Host Barriers to Infection • Innate Immune response – Exists before infection occurs – Physical barriers to infection, – Cells - phagocytic cells, NK cells, – plasma proteins (complement proteins, cytokines, acute phase reactants) • Adaptive Immune response – Stimulated by exposure to microbes and increase in magnitude, speed & effectiveness with successive exposures to microbes – Mediated by T and B lymphocytes Developed as part of the RCSB Collaborative Curriculum Development Program 2014

Evasion of Host Barriers • Skin – penetrate through breaks in the skin e. g. cuts, burns, foot sores, animal/human bites – penetrate unbroken skin (some specific parasites) • Gastro-intestinal tract – Cut/break in mucosa • Respiratory tract – Non-functional mucosa and ciliary function e. g. in smokers, individuals with Cystic Fibrosis – Toxins that paralyze mucosal cilia (e. g. causing the flu, pertussis) • Urogenital tract – Entry through urethra leading to kidney infections Developed as part of the RCSB Collaborative Curriculum Development Program 2014

Immune Evasion By Microbes • Hiding from immune cells – Change/shed antigens – remain inaccessible to the host immune system • Resist innate immune defenses – Carbohydrate capsule prevents phagocytosis – Replication within phagocytes – Resistance to antimicrobial peptides • Activate/interfere with signaling pathways • Inhibit antigen presentation Developed as part of the RCSB Collaborative Curriculum Development Program 2014

Immune Evasion by Microbes Developed as part of the RCSB Collaborative Curriculum Development Program 2014

Infections Developed as part of the RCSB Collaborative Curriculum Development Program 2014

How Do Microorganisms Cause Disease? • Contact or enter host cells and directly cause cell death. • Release toxins that kill cells at a distance • Release enzymes that degrade tissue components • Damage blood vessels and cause cell injury or death due to lack of blood supply. • Induce host cellular responses that, although directed against the invader, cause additional tissue damage, usually by immune-mediated mechanisms Developed as part of the RCSB Collaborative Curriculum Development Program 2014

Bacterial Infections Pathogen Innate immunity Adaptive immunity Evasion of immunity Example Extracellular bacteria -Phagocytosis -Activation of complement pathway. -Cytokines (TNF, IL-1 and IL-6) -Antibodies block infection, neutralize toxins, promote microbial elimination - Bacterial proteins activate T helper cells -Resistance to complement activation -Antigenic variation Staphylococcus aureus Intracellular bacteria - Injury to host due to immune responses - Secondary infections - Cell mediated immunity by Cytotoxic T cells - Persistent bacteria leads to granuloma Mycobacterium Phagocytosis/i tuberculosis ntracellular killing resistant -Adapted to survive within host cells Developed as part of the RCSB Collaborative Curriculum Development Program 2014

Viral Infections Pathogen Innate immunity Adaptive immunity Evasion of immunity Virus - Type 1 IFNs - Antibodies block - Latent - NK cells viral binding to and infections entry into cells, Promote viral elimination, activate the complement system and block the spread of viruses from infected cells - Cytotoxic T cells Example --HIV -Rubeola -Herpes Simplex Virus 1 and 2 Gingivostomatitis (Herpes) Developed as part of the RCSB Collaborative Curriculum Development Program 2014

Parasitic Infections Pathogen Innate immunity Adaptive immunity Evasion of immunity Example Parasite Animal (vertebrate) stages of most parasites are resistant to innate immunity. Distinct cell mediated immune responses for different parasites - Hiding away from immune system in special compartments - Masking Ag -Change coat/shed Ag -Suppress immune response - Plasmodium falciparum -Schistosoma haematobium Developed as part of the RCSB Collaborative Curriculum Development Program 2014 Schistosomiasis

Summary • Infectious diseases understood as recently as 19 th century • Many new pathogens recently identified • In Infectious diseases - pathogens have parasitic relationship with human hosts • Pathogens have figured out a number of different ways to bypass the immune processes – leading to disease • Bacterial, viral and parasitic infections are handled by different components of the immune system Developed as part of the RCSB Collaborative Curriculum Development Program 2014