Immune Response to Bacteria PDF

Immune Response to Pathogens ▪ Pathogen: a bacterium, virus, or other microorganism that can cause disease ▪ Opportunistic Pathogen: a bacterium, virus, or other microorganism that can cause disease in people with impaired immunity but not in normal (healthy) individuals ▪ Being a patho...

Immune Response to Pathogens ▪ Pathogen: a bacterium, virus, or other microorganism that can cause disease ▪ Opportunistic Pathogen: a bacterium, virus, or other microorganism that can cause disease in people with impaired immunity but not in normal (healthy) individuals ▪ Being a pathogen means that the organism does something to evade innate immunity and cause damage Evasion of Immunity ▪ The immune system is finely tuned to fight off invading organisms ▪ However: Mammals first appeared around 210 million years ago First prokaryote appeared about 4 billion years ago ▪ “Never underestimate an adversary with a 3.5-billion-year head start.” – Dr. Abigail Salyers Immune Response to Pathogens ▪ Non-pathogen: Most E. coli strains are harmless and are frequent residents of the mammalian microbiota E. coli K12 – Synthesizes vitamin B6 and coenzyme B12 – No toxins, no virulence factors ▪ Pathogen: Enteropathogenic and Enterotoxigenic Escherichia coli (EPEC and ETEC) Can cause diarrheal diseases in dogs and cats (and people) ETEC has multiple toxins EPEC has virulence factors for colonization at host epithelial cells Innate Immunity and the Microbiota ▪ Mammals are colonized by hundreds to thousands of species of bacteria that live in symbiosis with us ▪ In the colon, there are about 1012 bacterial cells These can breach the mucosal barrier Innate immunity responds and controls before adaptive immunity is needed Inflammatory bowel disease is an adaptive immune response to microbiota Immune Response to Pathogens ▪ Pathogens cause direct damage to tissues by killing host cells and release of toxins ▪ Immune responses to these pathogens can indirectly contribute to tissue damage and disease as well. How Does the Immune System Respond To: 1. Non-pathogens 2. Intracellular bacterial pathogens 3. Extracellular bacterial pathogens 4. Fungal pathogens How Does the Immune System Respond To: 1. Non-pathogens a. Complement b. Phagocytosis c. Adaptive Response to Microbiota How Does the Immune System Respond To: 1. Non-pathogens a. Complement b. Phagocytosis c. Adaptive Response to Microbiota Pathogens Evade These Responses ▪ How do they do this? 1. Antigenic or Phase Variation 2. Antigenic Drift 3. Molecular Mimicry 4. Virulence Factors Agents that cause damage Can have an array of functions Pathogens Evade These Responses 1. Antigenic or Phase Variation Change in arrangement of promoter leads to differential expression of flagellin protein in Salmonella Heather R. Bonifield, and Kelly T. Hughes J. Bacteriol. 2003;185:3567-3574 Pathogens Evade These Responses 1. Antigenic or Phase Variation Pili Functions: Attachment to host cells Motility Made of protein called pilin Should be highly antigentic Neisseria species Expresses pilE – single copy of functional pilin gene Carries 10 to 20 silent copies of pilS – no promoter Vink et al. 2012. FEMS Microbiology Reviews Pathogens Evade These Responses 2. Antigenic Drift Natural mutations over time lead to changes in structure of proteins that may be targeted by antibodies Mutation rate of a wild-type E. coli is ∼1 × 10−3 per genome per generation Pathogens Evade These Responses 3. Molecular Mimicry Sequence similarities between foreign and self-peptides – Can result in lack of antibody response to antigen – Can result in cross-reactive immune response Campylobacter jejuni Infection and Immunity Nov 2006, 74 (12) 6517-6527 Pathogens Evade These Responses 4. Virulence Factors Borrelia burgdorferi – Lyme disease Resists complement mediated phagocytosis – Produces Osp proteins in outer membrane that binds complement protein factor H » When C3b binds to factor H, it is inactivated Other Evasive Strategies ▪ Most use many mechanisms Possession of a capsule to resist phagocytosis and inhibit complement activation. Capsules are important virulence factors for some extracellular bacteria – E.g., Streptococcus suis Secretion of sIgA proteases that cleave IgA at the hinge regions Several bacteria secrete IgA proteases that inactivate sIgA Fab and Fc fragments have a short half life and are ineffective at the mucosal surface How Does the Immune System Respond To: 2. Intracellular Bacteria Listeria monocytogenes – causes gastroenteritis in many mammals Produces Listeria lysin O, or LLO – Degrades phagosomal membrane Replicates in cytoplasm and makes ActA Hijacks host cell actin filaments and uses to propel to new cell How Does the Immune System Respond To: 2. Intracellular Bacteria Immune response: Innate response to intracellular bacteria includes phagocytosis and NK cell activity – Most intracellular organisms survive in the macrophage – Macrophages secrete IL-12 in response to ingested microorganisms that they are unable to kill intracellularly How Does the Immune System Respond To: 2. Intracellular Bacteria Immune response: IL-12 activates NK cells. Activated NK cells function by: – Secreting IFN-γ to activate macrophages increase production of reactive oxygen species and lysosomal enzymes – Directly killing infected cells if the bacterium caused downregulation of Class I MHC molecules How Does the Immune System Respond To: 2. Intracellular Bacteria Immune response: Adaptive response is primarily cell-mediated immunity – IL-12 from phagocytes stimulates a TH1 cell response, resulting in secretion of IFN-γ and expression of CD40L to activate macrophages » Activated macrophages have increased killing power How Does the Immune System Respond To: 2. Intracellular Bacteria Immune response: CD8 T cells (cytotoxic T cells) – Activated CTLs can kill cells displaying bacterial antigens on Class I MHC molecules – CTLs kill infected cells via perforin and granzymes or Fas-FasL interaction How Does the Immune System Respond To: 2. Intracellular Bacteria Immune response: Antibodies – Play a minor role against intracellular bacteria – Binding to bacterial antigens displayed on the surface of infected cells can initiate ADCC – Can activate complement or can serve as opsonins for phagocytosis How Does the Immune System Respond To: 2. Intracellular Bacteria Avoiding the Immune response: Escape the phagosome – Listeria monocytogenes Prevention of phagosome-lysosome fusion – Mycobacterium tuberculosis Resistance to lysosomal enzymes – Corynebacterium pseudotuberculosis How Does the Immune System Respond To: 3. Extracellular Bacteria Mechanisms of pathogenesis Release of toxins – Endotoxin (LPS) – activator of macrophages, causes the release of cytokines, activates the alternative complement » Component of gram-negative bacterial cell walls » Gram-positive bacterial cell walls can have lipoteichoic acid – Exotoxins either stimulate cytokine release or are cytotoxic to certain cells How Does the Immune System Respond To: 3. Extracellular Bacteria - Exotoxins Atrophic rhinitis in swine Bordetella brontisceptica Pasteurella multocida – PMT » Disrupts cell signaling » Leads to bone resorption and disrupted bone formation How Does the Immune System Respond To: 3. Extracellular Bacteria Immune response: Innate response to intracellular bacteria includes – Physical barriers (skin, mucosal membranes) – Antimicrobial peptides » Lysozyme » Defensins How Does the Immune System Respond To: 3. Extracellular Bacteria Immune response: If they invade the tissues, the innate responses include inflammation, activation of complement, and phagocytosis Anaphylatoxins, pro-inflammatory cytokines from phagocytes as well as other substances (both host-derived & bacterial) promote inflammation How Does the Immune System Respond To: 3. Extracellular Bacteria Adaptive Response Antibodies are the primary response to extracellular organisms – Antibodies are protective against bacterial cells as well as proteins (toxins) secreted by the pathogen How Does the Immune System Respond To: 4. Fungal pathogens Disease caused by fungi occurs primarily by the same mechanisms as for bacteria: Persistence within phagocytes – Survival of the organisms within the phagocytes, leading to increased replication and potential spread of the organism Inflammation – Resulting in tissue destruction at the site, along with any systemic responses CTL cell activity – Cytotoxic activity by cell-mediated immune responses damages the tissues How Does the Immune System Respond To: 4. Fungal pathogens Dectin-1 TLR2 ▪ The principal mediators of innate response are neutrophils, Y Y Dectin-2 macrophages, and dendritic cells YY YY DC Sentinel macrophages and dendritic cells express PRRs, such as TLRs and Dectins (a type of C-type lectin receptor) that recognize fungal cell wall components Innate Secrete cytokines that recruit and activate neutrophils Effector Cell Neutrophils can phagocytose fungal cells; can also release ROIs, Th1/17 lysosomal enzymes, and NETs A dendritic cell expressing anti-fungal PRRs. Upon recognition of fungi through these receptors, signaling results in activation of innate effector cells and generation of Th1/17 adaptive immune responses. Modified from https://www.immunology.org/public- information/bitesized-immunology/pathogens-and- disease/immune-responses-fungal-pathogens\ https://www.crick.ac.uk/research/a-z- researchers/researchers-p-s/venizelos- papayannopoulos/ How Does the Immune System Respond To: Dectin-1 TLR2 Y Y Dectin-2 4. Fungal pathogens DC Y YYY Adaptive Response is cell mediated, stimulated by cytokines from dendritic cells Innate Effector Cell Th1/17 A dendritic cell expressing anti-fungal PRRs. Upon recognition of fungi through these receptors, signaling results in activation of innate effector cells and generation of Th1/17 adaptive immune responses. Modified from https://www.immunology.org/public- information/bitesized-immunology/pathogens-and- disease/immune-responses-fungal-pathogens ◼ Intracellular fungi: Th1 & CTLs, same as for intracellular bacteria (see slides 19-20). ◼ Extracellular fungi: Th17 responses, stimulating inflammation & recruitment of neutrophils. How Does the Immune System Respond To: 4. Fungal pathogens Antibodies are made and similarly as with extracellular bacteria Neutralization Opsonization Activation of complement ADCC How Does the Immune System Respond To: 4. Fungal pathogens – Evasion tactics Biofilm formation to facilitate colonization and resist phagocytosis. Composition and organization of the cell wall to mask antigens from the immune system. Synthesis of structures that hinder the immune system (fungal dimorphism, presence of capsules) Ability to obtain nutrients, such as iron and zinc Secretion of proteins that inactivate antimicrobial peptides How Does the Immune System Respond To: ▪ Summary of the response to pathogens