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Transcript
HOST and the MICROBE Rontgene M. Solante, M.D. Internal Medicine- Infectious Disease Specialist Department of Medicine Section of Infectious Diseases- UERMMMC Definitions 1. Infection: establishment of a microorganism on or within a host; may be short-lived, most often asymptomatic, or subclinical signs of altered pathophysiology 2. Infectious Diseases: an interaction of the microbe with the host, causing damage and altered physiology on the host, resulting in clinical signs and symptoms of the disease 3. Pathogen: any microorganism that has the capacity to produce disease (not all pathogens has the capacity to cause disease in the same populations). Definitions 1. Principal pathogens: microbes that regularly causes disease in some proportions of susceptible individuals with apparently intact defense systems e.g. Streptococcus pneumoniae Staphylococcus aureus 2. Potentially pathogenic microbes: = non-commensals = doesn’t usually cause disease in those with intact immune system = cause severe disease in hospitalized or immunocompromised host e.g. Pseudomonas aeruginosa Microbial Pathogenicity 1. Virulence: quantitative measure of pathogenicity or the likelihood of causing disease e.g. encapsulated pneumococci are more virulent than noncapsulated 2. Virulence factors refer to the properties of a microbe that enable itself to establish within a host and enhance its potential to cause disease Microbial Pathogenicity 3. Opportunist organisms = microbes with a capacity for sustained multiplication in human, and cause disease to individuals with underlying chronic disease or compromised immune status = outcome is determined by the status of the host = ability to be transient pathogens in a normal host (“just passing through’) e.g. a. fungal infections (Candida albicans) = immunosuppresive cancer chemotherapy b. protozoal infections (Pneumocystis carinii)= HIV (+) individuals “Normal Flora” Advantages Prevent overgrowth of pathogenic organisms Skin: fatty acids Gut: release bacteriocins, colicins and metabolic waste; compete with others for living space, produce vitamins B and K Vagina: lactobacilli maintain acid ph “Normal Flora” Disadvantages Potential for spread during procedures or trauma: intestinal perforation, skin breaks, dental extraction Person is vulnerable during periods of decreased immunity, change in environmental conditions Attributes of Microbes to be Pathogenic 1. Microbes have an interractive group of complementary genetic properties that promote interaction to its host. This is in the form of “genetic traits” called phenotypes. 2. Microbes should have the capacity to breach normal host anatomic, cellular, or biochemical barrier that ordinarily prevent entry by other microrganisms. = motility = chemotactic properties, adhesive structures Attributes of Microbes (Pathogens) 3. Microbes is be able to pass thru the “normal host defense” mechanism thru the following microbial factors: = antiphagocytic capsule = elaboration of toxins and enzymes = immune specific proteases and iron (e.g. IgA proteases of Haemophilus influenzae) = iron sequestration mechanisms (N. gonorrehae) Attributes of Microbes (Pathogens) 4. Microbes has the ability to multiply upon reaching its specific niche (blood, lungs, tissues, etc) and the potential to be transmitted to a new susceptible host. - this determine the outcome of the events, either in the form of alteration of host physiology and tissue damage or death of the host Pathogens/microbes= Complex and highly adapted organisms? Microbial Adherence Initial interaction of a pathogen w/its host Route to invasion by intracellular parasites First step in host cell killing and toxin delivery Microbial Adhesins Surface structures that anchor the microorganism to tissue, promote cellular entry and elicit host responses Pili (fimbriae) Flagella Hemagglutinin Surface glycoprotein Glycosaminoglycans Viral capsid protein Lectins Lipids Avoidance of Phagocytosis of Microbes Release toxin that destroys phagocyte Prevent opsonization by releasing protein Prevent contact by capsule, etc. Inhibit fusion of phagolysosome Organism escapes into the cytoplasm and replicates within the phagocyte Resists killing by producing antioxidants, etc. EVASION STRATEGIES OF PATHOGENS Strategy Elicit minimal response Example HSV latent stage Evade effects of response Depress host response Mycobacteria in granulomas HIV destroys T cells Antigenic change Viruses, spirochetes Rapid replication Viruses, bacteria, protozoa Survive in weakly responsive persons Genetic heterogeneity Mediators of Tissue damage and disease Viruses: down-regulate MHC molecule production, make proteins that interfere with interferon, decrease cytotoxic T cell recognition of infected cells, etc. Bacteria: toxins (enterotoxin, exotoxin, endotoxin) Survival of microbe in host Concealment of antigen Privileged sites (CNS, joints, testes, placenta, cysts, host DNA) Mimicry (e.g., streptococci and cardiac muscle) Antigen uptake infection during embryonic life, production of large amts of antigen, exploit gaps in immune repertoire, upset balance between antibody and TH1 and TH2 Tolerance: Microbial biofilms Matrix enclosed bacterial populations that adhere to a surface, interface or each other Responsible for dental plaque, clogged water pipes, form on synthetic medical implants Leads to altered metabolism, production of extracellular virulence factors Decreased susceptibility to antibiotics by forming an exclusion barrier or directly complex with them HOST FACTORS in INFECTIONS 1. There are specific host factors that influence likelihood of acquiring infectious diseases. a. b. c. d. e. f. Age= elderly and infants (altered immune response) immunization history prior and coexisting illnesses (e.g. diabetes) level of nutrition (e.g. malnutrition) pregnancy state emotional state (e.g. depression) HOST FACTORS in INFECTIONS 2. External host factors such as environment, geography and behavior. Examples: a. geography/environment = P. falciparum malaria bearing Aedes mosquito in mountainous and coastal areas b. geography= antibiotic-resistant malaria are common in highly endemic areas (Phils, Africa, Indonesia) c. behavior = acquisition of sexually transmitted diseases, IV drug use hepatitis B and C HOST FACTORS in INFECTIONS 3. Medical care (hospital, healthcare facilities) and medical devices a. contact of pathogens during hospitalization b. breach of the skin during insertion of intravenous devices and surgical incisions c. alteration of the normal flora or commensals with use of antibiotics d. treatment with immunosuppressive drugs such as cancer chemotherapy HOST FACTORS in INFECTIONS 4. Genetics: e.g., MHC genes (class II and leprosy), sickle cell gene and malaria Host Receptors Host molecules or ligands that microbial adhesins bind to for adherence Sugars Ig superfamily Growth factors Integrins Extracellular matrix component Transport proteins Complement receptor Host response Cellular immunity Humoral immunity: Antibodies: recognize and bind to foreign antigens, impede function of organism, facilitate its removal Complement: adhere and disrupt Phagocytic cells: engulf, kill and digest Reticuloendothelial system: monocyte derived phagocytic cells that clear circulating organisms in liver, spleen, kidney, LN, brain Interaction with phagocytes Activation of phagocytes is a key step in initiating inflammation and migration of additional phagocytes into affected sites Microbial factors that interact w/ phagocytes: LPS of gram (-) bacteria, lipoteichoic acid of gram (+), etc. 1. Attachment by nonspecific receptors 3. Lysosome fusion & killing 2. Pseudopodia forming a phagosome 4. Release of microbial products Phagocytosis Macrophages Produced in bone marrow, tissues Killing mechanism: oxidative, nitric oxide, cytokines Activated by TNF, IFNγ, IL-4, GM-CSF, microbial products Secretes lysozyme, cytokines, etc. Neutrophils Produced in the bone marrow Killing mechanism: oxidative and nonoxidative Activated by TNF Secretes lysozyme Deficient states: CGD, myeloperoxidase, chemotactic, Chediak-Higashi T helper (TH) cells TH1 subset: mediate chronic inflammatory reactions (e.g., tuberculosis) IL-2, IFNγ TH2 subset: help B cells make antibody IL-4, IL-5, IL-6 Cytotoxic T lymphocyte Carries out both antigen specific recognition and killing of target cell Recognition is associated with Class 1 MHC Killing mechanism: leakage due to insertion of perforin, DNA fragmentation, apoptosis Extracellular Killing Natural killer cells: cytotoxic cells that attach to the surface of virally infected cells and release granules that enter cells through pores and lead to programmed cell death or apoptosis Eosinophils: important against helminths, produce major basic protein, perforins and O2 metabolites that damage the cells Febrile response a complex physiologic reaction to disease involving a cytokine mediated rise in the core temperature, generation of acute phase reactants, activation of numerous physiologic, endocrinologic and immunologic systems. Due to infection, malignancy, collagen vascular disease, etc. Host response to infection Outcome of infection depends on the balance between an effective response that eliminates a pathogen and an excessive inflammatory response Cytokine production: stimulate inflammatory response Abscess or granuloma formation Local or systemic inflammation Acute inflammatory response Opsonization: engulfment by phagocytic cells facilitated by opsonins (C3B) Margination: PMNs align alongside blood vessel wall Chemotaxis: marginated PMNs attracted to site of C3B coated bacteria bacterium C3B C3bBb C5 C3b C5a/C3a MC C3b receptor Chemotactic factors Vascular permeability mediators Acute inflammatory reaction C3 RESPONSE TO PATHOGENS, “CROSS-TALK” AMONG CELLS BACTERIA DENDRITIC CELL NEUTROPHIL MACROPHAGE NECROTIC CELL NECROTIC CELL APOPTOTIC CELL INFLAMMATORY PRODUCTS APOPTOTIC CELL CD4 T CELL ANERGY ANERGY Th1 Th1 Th 2 Th 2 - Hotchkiss. N Engl J Med 2003; 348(2):135-50 Innate immune system Soluble factors Lysozyme, complement, acute phase reactants Cells Phagocytes, NK cells Adaptive immune system Antibody T lymphocytes Response to microbial infection 1st contact 2nd contact + +, nonspecific, no memory + +++, specific memory, resistance improved by repeated contact HOST and MICROBES : Symbiosis or Opportunistic Relationship?