Infections: Evading Immune Systems Pathology - Infectious Disease Lecture - 1-27-2012 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 19th century – 20th century – Present day – Pathology - Infectious Disease Lecture - 1-27-2012 Historic Perspective 19th century – proof that diseases are caused by infectious agents founded the discipline of microbiology 20th 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 Understand what is infectious disease – they are caused by pathogens, such as bacteria, virus, fungi, parasites etc. Agents that can remove or destroy the pathogens can treat the disease. 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 (vCJD) Hendra virus Nipah virus Vibrio cholerae 0139 Cryptosporidium Cyclospora Severe acute respiratory syndrome (SARS) associated coronavirus Epizootic avian influenza H5N1 Human T-cell lymphotropic virus 3 (HTLV-3) HTLV-4 Xenotropic MuLV-related virus While we have developed treatments for various infectious diseases, new infections have also been identified in the past 20 years Developed as part of the RCSB Collaborative Curriculum Development Program 2014

Microorganism : Host Relationships Pathology - Infectious Disease Lecture - 1-27-2012 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 Different types of relationships of microbes and human (or other organisms) as their hosts. The parasitic relationships are most harmful and should activate an immune response - the subject of this discussion. Developed as part of the RCSB Collaborative Curriculum Development Program 2014

Categories of Infectious Agents Pathology - Infectious Disease Lecture - 1-27-2012 Categories of Infectious Agents Bacteriophages, Plasmids, Transposons Bacteria Extracellular Intracellular Chlamydiae, Rickettsiae, Mycoplasmas Fungi Parasites Helminths Ectoparasites Prions Protozoa Viruses The pathogens colored in blue are discussed further in the following slides 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 Innate and adaptive immune responses Developed as part of the RCSB Collaborative Curriculum Development Program 2014

Evasion of Host Barriers Pathology - Infectious Disease Lecture - 1-27-2012 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 How do pathogens evade the immune system at various sites – skin, GI tract, Respiratory tract, UG tract. Developed as part of the RCSB Collaborative Curriculum Development Program 2014

Immune Evasion By Microbes Pathology - Infectious Disease Lecture - 1-27-2012 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 How do pathogens hide from immune cells and immune system molecules Developed as part of the RCSB Collaborative Curriculum Development Program 2014

Immune Evasion by Microbes Pathology - Infectious Disease Lecture - 1-27-2012 Immune Evasion by Microbes How do pathogens hide from immune processes 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? Pathology - Infectious Disease Lecture - 1-27-2012 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 Pathogens cause pathogenesis or disease in the above ways Developed as part of the RCSB Collaborative Curriculum Development Program 2014 12

Bacterial Infections Pathogen Innate immunity Adaptive immunity Pathology - Infectious Disease Lecture - 1-27-2012 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 -Phagocytosis/intracellular killing resistant -Adapted to survive within host cells Mycobacterium tuberculosis Bacterial infections – to treat infections antibiotics may have to be used Developed as part of the RCSB Collaborative Curriculum Development Program 2014

Viral Infections Pathogen Innate immunity Adaptive immunity Pathology - Infectious Disease Lecture - 1-27-2012 Viral Infections Pathogen Innate immunity Adaptive immunity Evasion of immunity Example Virus - Type 1 IFNs - NK cells - Antibodies block viral binding to and entry into cells, Promote viral elimination, activate the complement system and block the spread of viruses from infected cells - Cytotoxic T cells - Latent infections --HIV -Rubeola -Herpes Simplex Virus 1 and 2 Viral infections – when immune system fails to check the infection drugs that destroy the virus lifecycle have to be used. Antibiotics are not effective. Gingivostomatitis (Herpes) Developed as part of the RCSB Collaborative Curriculum Development Program 2014

Parasitic Infections Pathogen Innate immunity Adaptive immunity Pathology - Infectious Disease Lecture - 1-27-2012 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 Schistosomiasis Parasitic infections – when immune system fails, specific medications to disrupt the parasite’s life cycle may be used to treat the infection Developed as part of the RCSB Collaborative Curriculum Development Program 2014

Summary Infectious diseases understood as recently as 19th 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