Harrisons: Introduction To Infectious Diseases

Introduction to Infectious diseases: Host Pathogen Interactions pg.695-699 With the advent of antimicrobials as a defense to infectious agents we believed that soon these agents will be eliminated , but microbes developed resistance to these antimicrobial (antibiotic resistance) Ex. Pnemococci- penicillin Enterococci and Staph.- Vancomycin 1999 outbreak in N.Y. of encephalitis due to West Nile virus 2003 SARS was first recognized, caused by corona virus. The role of infectious agents in the etiology of a disease once believed to be non infectious H.pylori- peptic ulcer and gastric malignancy Papilloma- most impt. cause of invasive cervical cancer Herpes virus type 8- Kaposis sarcoma EBV- Lymphoma and Hodgkins disease. Other possible diseases of unknown cause but may have infectious etiology Rheumatoid arthritis Sarcoidosis Inflam. Bowel dse Emergence of infectious dse due to Increase in population Immunocompromised host- to prevent transplant rejection and treat ca. and inflammatory dse. -some infections like HIV, Influenza and Syphilis AIDS has brought to prominence once-obscure organism Pneumocyctis, C. parvum and M. avium. Host factors in infection For infectious process to occur ther must be a susceptible host and a virulent organism There are many host factors to be considered like -age, immunizations, prior/coexisting illness, nutrition, preg., emotional state, level of host defense (immune system) - Medical care -1) contact with pathogen during hospitalizations 2) breaching of skin or mucosal surface 3) intro of foreign bodies 4) alteration of natural flora with the use of antibiotics and 5)treatment with immunosuppressive drugs. The immune response Innate immunity

-exploit molecular patterns found specifically in pathogenic org. (pattern signatures) these are recognized by host molecules that directly interfere with the pathogen. Innate immunity serves to protect the host without prior exposure to an agent, it also functions as a warning system that activates component of adaptive immunity. Ex. Defensins- simple peptides found on the skin and mucosal surfaces Macrophages- engulf and kill microbes Complement system Example of response Lipopolysaccharide (LPS)- even minute amount are detected by LPS binding proteins, CD4 and toll-like receptor 4, there would also be production of cytokines by macrophages via transcriptional activator NFkB. This would lead to inflammation and secretion of enzymes that enhance clearance of microbes. It also initiates specific or adaptive immune response. Adaptive immunity Cellular immunity T-lymphocytes, macrophages, NKcells - primarily recognize and combats micro. that proliferate intracell. Ex.-Bacteria (Mycoplasma, Chlamydia, Listeria, Salmonella and Mycobactria) Parasites (Trypanosoma, Toxoplasm and Leishmania) and Fungi (Histoplasma, Cryptococcus and Coccidiodes) T-lymphocytes- activated by macrophage and B-lymphocytes, w/c serves antigen presenting cells -once activated it may act as Cytotoxic t-cell directly attacking the organism or Helper t-cell w/c stimulates the prolif of b-cells and the procuction of Ig. T-cell and B-cell communicate with each other Ex. Stimulation ofCD40-↑ B-cell response Stimulation of B7-CD28 activation of CD4- helper T-cell -elaborate cytokines (interferon) tat inhibit growth of pathogen or stimulate killing by macrophages and cytoxic T-cells. Cytokines also augment immunity by stimulating inflammatory response

(fever, acute phase reactants and prolif of WBC) adverse effect of cytokinesSeptic and toxic shock. Reticuloendothelial system (RES) Comprised of monocyte derived phagocytic cells found in: Liver- Kupffer cells Lungs- Alveolar macrophage Spleen and Kidney- Mesangial Brain- Microgial Lymphnode They clear organism by killing them but they work more efficiently when pathogen are first opsonized by complement system such as C3b and/or antibodies. Humoral immunity Composed of Antibodies, Complement cascades and phagocytic cells- targets extracellular pathogens including most of the encapsulated organism(complex polysaccharide coat) Antibodies- Ig- are complex glycoproteins that are produced by mature B-cells that circulate in body fluids, and are secreted on mucosal sufaces. - they specifically recognize and bind to foreign antigens and not reacting with self. Classes of Ig Ig G- predominates and persist Ig M- earliest Ig A Secretory- found mucosal surfaces Ig A Monomeric- found in serum Ig E- allergy and parasitic Function Directly impede pathogen Neutralize secreted toxin and enzymes Facilitate removal of antigen Participate in cell mediated immunity by promoting antibody dependent cell cytotoxicity Promote deposition of complement components on the surface of org. Complement system- consist of group of serum proteins that function cooperatively, self regulating enzymes that adhere to-, disrupt- surface of pathogen. Adherent protein like C3b can act as opsonin. The terminal components C78&9 can directly kill pathogen (esp. Neisseria) by forming the Membrane Attack Complex (MAC) and disrupting the integrity of pathogens membrane. Another

component the C5a- act as a chemoattractant for PMN. Complement activation Classical- activated primarily by immune complexes (antibody bound to antigen) Alternative- activated by microbial component, frequently in the absence of antibody. PMN’s- short lived WBC that engulf and kill invading microbes, are first attracted to inflammatory sites by C5a. they localize to the site by adhering to cellular adhesion molecules expressed in the endothelial cells (selectinsCD62, ELAM-1)in response to inflamm. Cytokines like TNFα and interleukin-1.Cytokine mediated upregulation and expression of ICAM-1 on endothelial cell then later this receptor binds to β2 integrins on PMN thereby facilitating diapedesis Laboratory investigation Should be directed at est. an etiologic dx. In the shortest possible time, lowest cost and least discomfort to the patient. Cultures must be performed in manner that minimizes contamination to maximize the yield. Gram staining should be interpreted carefully and should correspond to the culture result. In case where a diagnosis appears difficult, serum should be stored during the acute phase of the illness for detection of antibody titer. Bacterial and fungal antigens can sometimes be detected in body fluids. PCR for amplification of minute amounts of forign nucleic acids. Treatments Life threatening conditions –such as Bacterial meningitis or sepsis, Viral encephalitis, or malaria(falciparum ) must be treated immediately, often before a specific causative agent is identified. Antimicrobials must be chosen empirically and must be active against the range of potential agent. Direct toxicity of animicrobials Ex. Ototoxicity- aminoglycosides Lipodystrophy-anti-retroviral Hepatotoxicity- Isoniazid and Rifampicin Allergic reaction are common and can be serious Tharapy should be directed toward as narrow a spectrum of infectious agents

as possible to prevent superinfection and eradication of normal flora. In case of abscess it requires surgical or percutaneous drainage for treatment Surgical removal in cases of foreign body, necrotizing fasciitis peritonitis due to perforated organ, gas gangrene and chronic osteomyelitis. Glucocorticoids- H.influenza meningitisin children and Pneumocystis pneumonia in patients with AIDS Activated C proteins- is the first immunomodulatory agent for treatment of sepsis. Other agents are Prostaglandin inhibitors, lymphokines, and TNF inhibitors. Specific antibody- Rabies and Tetanus. Also CMV Perspective The genetic simplicity of many infectious agents allows them to undergo rapid evolution. Plus the changes in the environment and host can predispose to a particular infection. Environmental changes, rapid global travel, population movements and medications all increases the impact of infectious dse. Development of new vaccine, antibiotics and modalities of treatment and prevention, however pathogenic microbes will also continue to develop new strategies of their own presenting us with UNENDING and DYNAMIC CHALLENGE!!!!!!!!!!!!!!!!!!!!!! HEHEHEHEHEHEHEHEHEHEHEHEHEHE!!!