General Pathology: Pathogenicity

General Pathology of Infectious Disease Pathogenicity Virulence Host Location How Microorganisms Cause Disease Directly cause cell death Toxins or enzymes Immune-mediated mechanisms Induce host cellular responses: additional tissue damage Mechanisms of Viral Injury Direct damage (Viral tropism) 1) Host cell receptors for the virus (major) 2) Cellular transcription factors 3) Anatomic barriers, Local temperature, PH and host defenses Viral receptors on the host HIV gp 120 →  CD4 on T cells  chemokine receptors (CXCR4) on T cells  chemokine receptors (CCR5) on macrophages Rhinovirus → binds to the same site on ICAM-1 as LFA-1 (integrin on surface of lymphocytes) Influenza virus: Host proteases → Breaks hemaglutinins and activates it Transcription fact or Ability of the virus to replicate inside some cells but not in others JC virus (leukoencephalopathy) → Oligodendroglia (viral enhancer and promoter DNA sequences) Physical barriers & Local temperature, PH and host defenses: Enteroviruses in the intestine Rhinoviruses→Upper respiratory tract How viruses can kill the cells or cause tissue damage? Lysis of host cells Influenza, yellow fever, polio, rabies Vir Viral killing of one cell type → death of other cells (poliovirus, nerve: muscle) Immune cell mediated killing HBV: (acute liver failure): FAS ligand of CTLs & FAS R on heptocytes (apoptosis) RSV: IL-4 &IL-5→mast cell & eosinophil activation→ wheezing & asthma Manipulation of apoptosis pathway Induce: HIV, adeno Vir, inhibit (proliferation, cancer): HBV, EBV Cause cell proliferation & transformation EBV,HBV,HPV,HTLV1→ cancer Inhibit host cell DNA, RNA or pr synthesis → poliovirus inactivates cap-binding protein (translation of mRNA) Damage to plasma membrane HIV, measles Vir, HSV Damage cells involved in host antimicrobial defense: Vir: damage to respiratry epithelium → secondary infections by S.pneum & H.influ ) HIV(↓CD4+ helper Lymph) PAP Smear Herpes virus Mechanisms of bacterial injury      Bacterial virulence Adherence Invasion Deliver toxins Depends on virulence genes Pathogenicity islands May present by increase in number Fibrilla, F pr & pili  Fibrillae lipoteichoic acid M-protein Protein F (gram positive, strep pyogen)  Fimbriae or pili (gram negative: E coli, gonococcus) Stalk→ repeating subunits Tips→ variable amino acids Bacterial Adherence to Host Cells Adhesins Virulence of intracellular bacteria Epithelial cells (shigella, enteroinvasive E.coli) Macrophages (M.tuberculosis, M.leprae) Both (S.typhi)  Entry:  Use the host immune response to gain entry into macrophages (Ab,C3b): M.tuberculosis→ binds CR3 on macrophages  Intracellular survival:  In the cytoplasm of epithelial cells:  Inhibit host protein synthesis →replicate rapidly and lyse the cell (shigella & E.coli)  Within macrophages  Blocks fusion of the phagosome with the lysosome (M.tuberculosis)  Escaping from the phagosome: pore forming protein (phospholipase) → lyse phagosome (L.monocytogenese) Bacterial Toxins Any bacterial substance that contributes to illness  Endotoxins Lipopolysaccaride (Cell wall): gram neg  lipid A + core suger chain + variable carbohydrate chain (O antigen) Adheres to CD 14 on Mac, PMN, Mono →Toll like R-4 signaling pathway→cytokine Endothelial: prothrombic state beneficial harmful : TNF, Il1, 12: RDS, DIC, Septic shock  Exotoxins→ secreted proteins, gram neg & pos  A variety of enzymes:  Protease (eg: protease of staph aureus)  Hyaluronidase  Coagulase  Fibrinolysin  Lecithinase (Colestridium perfringes)  Substances altering intracellular signaling or regulatory pathway A(active) + B(adhesion) subunits Bacillus anthracis Vibrio cholerae, E.coli: increase in cAMP  Neurotoxins→inhibit release of neurotransmitters → paralysis (C.botulinum, C.tetani)  Scarletiform rash: S. pyogen  Superantigens: bacterial toxins that bind to MHC II-TCR→ massive proliferation of T cells and cytokine release (TNF)→ capillary leak and shock (s.aureus and s.pyogen→TSS) Biofilm Colony Liquid - solid interface (valve, catheter) Activating genes Resistance to antibiotics Injurious effects of host immunity Cellular: Granulomatous inflammation: M. tuberculosis: tissue damage and fibrosis Parenchymal damage: HBV in liver Humoral: Cross-reaction of Abs: Cardiac pr react with Ab to M-pr of S.pyogen: Rheumatic fever Ag-Ab immune complex: B-Hemalytic Strep Kidney: Post streptococcal glomerulonephritis Immune Evasion by Microbes Important determinants of microbial virulence and pathogenicity  Remaining inaccessible to the host immune system  Varying or shedding antigens  Resisting innate immune defenses  Preventing T-cell activation or impairing effective T-cell antimicrobial responses by immunosuppression Inaccessible Propagate in the lumen of the intestine (C. Difficile), or gallbladder (S.typhi) Shedding from the luminal surface of epithelial cells (CMV in urine or milk and poliovirus in stool) Infect the keratinized epithelium (Pox Vir) Rapidly invading host cells (malaria sporozoites in liver cells, trichinella, T.cruzi in muscles) Form cysts covered by a dense fibrous capsule (larvae of tapeworm) Viral latency: Many of vir genes not express Covering by host prs Varying or Shedding antigens Neutralizing antibodies→Vaccination  HIV AIDS: RNA polymerase  Influenza V Influenza: Gene rearrangment  Schistosoma mansoni Schistosomiasis: Shedding  S.pneumonia Pneumonia  Borelli hermsii Relapsing fever  Borrelia burgdorferi Lyme dis  Rhinoviruse Colds  N.gonorrheae Gonorrhea  T. brucei African sleeping sickness  Giardia lamblia Giardiasis  P. falciparum Severe malaria Evading Innate Immune Defenses Escaping killing by phagocytes & complement o CAMP resistance: defensin o Carbohydrate capsule → shielding bacterial antigens & preventing phagocytosis by neutrophils (E.coli with K1 capsule) o Make toxic proteins that kill phagocytes, prevent their migration, diminish their oxidative burst (S.aureus protein A inhiits phagocytosis) o Secreting proteases (Neisseria, Haemophilus, Streptococcus)→ degrade antibodies o Replicating within phagocytes (Vir, rich, bac) o Inhibit innate immunity by producing proteins that block complement activation (HSV, poxV) o Viruses can combat interferons (IFN) o Produce homologues of chemokines/CRs (vir) o Immunosuppressive cytokine (Il10) (EBV) Inhibiting adaptive immunity: o Decrease recognition of infected cells by CD4+ & CD8+ cells CMV,EBV can bind to or alter localization of MHC class I proteins HSV target MHC class II molecules , degradation, impairing Ag presentation to CD4+ helper cells o Directly infect lymphocytes (HIV→CD4+ helper cells, macrophages, dendritic cells and EBV infects B lymphocytes) Infections in Immunosuppressed Hosts Genetic (primary) Acquired (secondary) Genetic:  Antibody deficiency (X-linked agammaglobulinemia) → extracellular bacterial infections (S.pneumoniae, H.influenza, S.aureus & few viral infections: rotavirus, enteroviruse)  T- cell: intracellular bacteria & vir  Deficiencies in complement proteins→ S.pneumoniae, H.influenza, N.meningitidis  Deficiencies in neutrophil function→ S.aureus, some gram neg bacteria & fungi Disease of organ systems:  Cystic fibrosis→P.aeroginosa, S.aureus, B.cepacia  Sickle Cell Disease (Lack of splenic function) → encapsulated bacteria: S.pneumonia Acquired:  Acquired immunodeficiencies: HIV→infects and kills CD4+ helper T-cells→ cryptococcus, pneumocystis, HHV-8  Leukemia: (Impaired production of leukocytes) →opportunistic infections  Burns: P. aeroginosa  Iatrogenic: drugs Therapy to prevent organ transplant rejection (BM transplants→ Aspergillus, pseudomonas spp)  Malnutrition: impair immune response Morphology Scant inflammatory response: culture, stain, inclusion No granlumatous inflammtion: MAC Copious organisms: Lepromatous lepresy