NURS 7053 Advanced Pathophysiology I - Infection Class Notes PDF

NURS 7053 Advanced Pathophysiology I for DNP Students Infection - Class Notes Viruses and Viral Infections Overview Viruses have genetic information in D...

NURS 7053 Advanced Pathophysiology I for DNP Students Infection - Class Notes Viruses and Viral Infections Overview Viruses have genetic information in DNA or RNA (single or double strand, linear or circular) contained within a capsule or capsid Viruses (virus particles or virions) consist of just the genetic material (nucleic acids) and the capsid, or may have an outer envelope/membrane Use the host’s cellular replication machinery for viral replication Viral Transmission Inhaled droplets (rhinovirus) Oral transmission (hepatitis A) Direct transfer from other hosts (HIV, HPV) Bites of vector arthropods (zika virus, dengue) Infection of Host Cells Recognition and attachment of virus to host receptor or cell wall molecule Penetration by fusion or endocytosis Uncoating of viral genome within cell cytoplasm Replication of viral genome using host viral transcriptases and polymerases 1  NURS 7053 Advanced Pathophysiology I for DNP Students Infection - Class Notes Translation with viral structural protein synthesis in host cell endoplasmic reticulum and Golgi apparatus Assembly of virus Release of virus – budding, exocytosis, host cell lysis Viral Replication Involves synthesis of messenger RNA (mRNA) leading to viral genome replication (replication of nucleic acid core and protein shell). DNA Viruses mRNA is formed using host’s DNA polymerase This new mRNA is used to synthesize enzymes needed to make new viral DNA RNA Viruses RNA viruses must make their own RNA polymerase in order to form mRNA Retroviruses: RNA is made into DNA using the viral reverse transcriptase enzyme, then the new DNA is inserted into the host cell nucleus and integrated into the host cell genome. Outcomes of Viral Replication Synthesis of viral proteins (e.g., enzymes, regulatory molecules) 2  NURS 7053 Advanced Pathophysiology I for DNP Students Infection - Class Notes Lytic infections: Release of new virus particles causes host cell lysis (poliovirus, influenza virus) Persistent infections: Virus remains continually present; viral genetic material exists in the host cell (herpes simplex virus) Latent infections: Replication does not occur until a signal triggers a release from latency (e.g., stress and herpes simplex infection) Principles of Antiviral Therapy For most viral infections there is no treatment. Current drugs interfere with an aspect of viral replication. Examples DNA polymerase inhibitors (acyclovir, ganciclovir) Drug action only affects infected cells because activation of the drug requires phosphorylation by a viral kinase Inhibits viral DNA polymerase, but doesn’t affect cellular DNA polymerase Reverse transcriptase inhibitors (AZT + other HIV drugs) Blocks reverse transcription in retroviruses and blocks the formation of viral DNA Protease inhibitors Protease inhibitors affect the synthesis of a protease required for replication of the HIV Neuraminidase inhibitors (oseltamivir) Competitive inhibitor of influenza’s neuraminidase enzyme 3  NURS 7053 Advanced Pathophysiology I for DNP Students Infection - Class Notes Issues Incubation period for viral infections is often 1 week or more and by the time symptoms appear, viral replication has already taken place. Latent viral infections are not affected by antiviral medications Viruses have high rates of mutations and easily develop resistance to antiviral medications Bacteria and Bacterial Infections Overview Bacteria are single celled organisms with a double circular strand of DNA (no distinct nucleus) Most bacteria have a cell wall and have other cellular structures such as capsules, flagella, and pili (rigid flagellae) Some bacteria can create form endospores that enable it to survive in adverse conditions Bacteria Classification Gram Positive vs. Gram Negative Bacteria Gram staining laboratory technique is used to detect and identify bacteria Gram positive bacteria Have a thicker peptidoglycan coat to the bacterial cell wall which stains purple Peptidoglycan coat is hydrophilic and can resist the activity of bile in the small intestine 4  NURS 7053 Advanced Pathophysiology I for DNP Students Infection - Class Notes Common genus categories for gram positive bacteria Staphylococcus Streptococcus Clostridium Common genus categories for gram positive bacteria (continued) Corynebacterium Bacillus Listeria Mycobacteria have a waxy outer coat that affects staining (acid-fast bacteria) and provides resistance to drying Gram negative bacteria Have a thinner peptidoglycan coat to the bacterial cell wall which stains pink Also have an outer membrane made of lipopolysaccharides and lipoproteins A lipopolysaccharide (LPS) component of the outer membrane forms endotoxin (specifically LPS A) when the bacteria dies Common genus categories for gram negative bacteria Escherichia Neisseria 5  NURS 7053 Advanced Pathophysiology I for DNP Students Infection - Class Notes Bordatella Pseudomonas Yersinia Proteus Common genus categories for gram negative bacteria (continued) Klebsiella Enterobacter Salmonella Shigella Aerobes vs. Anaerobes Aerobic bacteria Require oxygen for cellular respiration (metabolism) Anaerobic bacteria Can tolerate low oxygen concentrations Produce enzymes that destroy surrounding tissue and some produce potent paralytic toxins 6  NURS 7053 Advanced Pathophysiology I for DNP Students Infection - Class Notes Often cause abscess formation, tissue necrosis, and gas formation Examples: Bacteroides (gram negative), Clostridium and others Outcomes of Bacterial Infection Release of exotoxins leading to: Inhibition of protein synthesis (diphtheria) Host cell injury (Staphylococcus aureus, Bordatella pertussis, etc.) Host cell malfunction (Clostridium botulinum, Clostridium tetani, etc.) Release of exotoxins that stimulates cell processes that are harmful to the body such as fluid loss from intestinal cells (Cholera, E. coli) Release of enzymes that break down cells and tissues and allow the infection to spread (enzymes include collagenase, hyaluronidase, streptokinease, DNAase, etc) Release of endotoxin (LPS) from gram negative bacteria LPS is a pyrogen and stimulates a fever through the release of prostaglandins in the hypothalamus Molecules that are part of the LPS complex are very immunogenic and can stimulate a systemic inflammatory response if released in the bloodstream 7  NURS 7053 Advanced Pathophysiology I for DNP Students Infection - Class Notes Targets for Antibacterial (Antibiotic) Therapy Cell wall Peptidoglycan synthesis is interrupted These antibiotics can make others more effective (e.g., penicillin allows aminoglycosides to penetrate the cell wall) Examples: penicillin (b-lactam antibiotics), cephalosporins Cell membrane Disrupt LPS causing membrane damage Greater effect on gram negative bacteria Example: polymixins – e.g., polysporin Bacterial enzymes Interfere with essential enzyme activity Example: quinolones, sulfonamides, rifamycins, lipiarmycins Bacterial protein synthesis These drugs are generally bacteriostatic, rather than bacteriocidal (except aminoglycosides) Example: macrolides, lincosamides, tetracyclines 8  NURS 7053 Advanced Pathophysiology I for DNP Students Infection - Class Notes Antibiotic Resistance Widespread use of antibiotics has resulted in the survival of the bacteria able to resist them Resistance can develop from spontaneous genetic mutations – for example, alteration of a single protein could provide resistance to the effects on an antibiotic Acquired resistance can develop from transmissible plasmid mutations (DNA separate from the chromosomal DNA) which often confers resistance to multiple drugs Mechanisms of resistance Antibiotic target site on bacteria is altered Uptake of antibiotic into bacteria is altered Bacteria produce enzymes that inactivate or destroy the antibiotic Superbugs: emergence of bacterial strains that are resistant to available antibiotic therapy Example: multidrug resistant tuberculosis (MDR-TB) 9  NURS 7053 Advanced Pathophysiology I for DNP Students Infection - Class Notes Human Immunodeficiency Virus and Acquired Immune Deficiency Syndrome Strains of HIV A retrovirus with a capsid within the lentivirus genus. HIV1 Most common and pathogenic strain of HIV 4 groups (M, N, O, P) and multiple subtypes HIV1 has continually evolving viral diversity HIV2 Not commonly seen outside of Africa (mainly West Africa) 8 groups (A-H), but only two have grown to epidemic proportions (A & B) Epidemiology Over 39 million people worldwide living with HIV. 1.3 million new cases in 2022 36,136 new cases in 2021 in U.S. (declining from 41,800 in 2010) Over 2.2 million diagnoses and 700,000 deaths in the U.S. since 1981 Worldwide, 53% of cases located in eastern/southern Africa, 12% in western/central Africa, 17% in Asia and the Pacific, and 6% in Western and Central Europe and North America 1 in 25 individuals in WHO Africa region infected with HIV 67% of new cases in U.S. due to male-to-male sexual contact 22% of new cases in U.S. due to high-risk heterosexual activity 7% of new cases due to injected drug abuse Worldwide, most cases transmitted heterosexually 10  NURS 7053 Advanced Pathophysiology I for DNP Students Infection - Class Notes Viral Transmission Primary transmission via blood (IV drug use, blood/blood product transfusions) or sexual intercourse (semen, pre-ejaculate, and vaginal fluid); also in utero placental spread, during vaginal delivery, and through breast milk Viral load is predictive of transmission risk Co-infections with other sexually transmitted diseases in asymptomatic HIV infected people can increase viral shedding Pathogenesis HIV Retrovirus Carry genetic information in form of RNA Use reverse transcriptase to convert RNA into double-stranded DNA Genetic material is encapsulated in a lipid envelope derived from the host cell membrane P24 antigen readily detectable early in disease, but becomes less detectable with time Cellular Targets Cells with CD4 – acts as a binding site for the gp120 envelope glycoprotein for HIV Helper T cells (Th) Dendritic cells (skin and genital mucosa) Monocytes, macrophages 11  NURS 7053 Advanced Pathophysiology I for DNP Students Infection - Class Notes Other targets include CD8+ cells (cytotoxic T cells), microglial cells in CNS, thymus, GI epithelium, lung, bone marrow, lymphocytes in blood and lymph nodes HIV produces a fusion protein (GP41) that allows fusion with host cell and allows release of viral capsid into host cell’s cytoplasm HIV Infection and Replication Cycle HIV enters body and first infects CD4+ cells (Th cells, dendritic cells, and macrophages) HIV gp120 protein binds to CD4 molecule creating fusion Viral core enters the cytoplasm of the target cell RNA genome of HIV undergoes reverse transcription leading to the formation of viral DNA As the target cells divide, the HIV DNA is integrated into its own DNA (i.e., the host genome) creating what’s called the provirus The provirus may end up locked in the host chromosome for months or years creating a period of latency Activation of the host cell by cytokines causes transcription of the provirus DNA which leads to the formation of new viral particles (nucleic acids & capsid) The newly formed virion is shed from the host cell through a process called budding where the cell’s plasma membrane becomes the outer envelope of the new virus 12  NURS 7053 Advanced Pathophysiology I for DNP Students Infection - Class Notes Mechanisms of Immunodeficiency Eventually see lysis of infected CD4+ caused by HIV virion production In early phases of infection, the bone marrow replaces the dying Th and other CD4+ cells The lymphoid tissues become a reservoir of infected cells which gradually destroys the architecture of these tissues and precursor CD4+ cells See significant apoptosis of uninfected CD4+ cells (mechanism unknown) End result is a decrease in the production of Tc cells and plasma cells (activated B lymphocytes) and an associated increased susceptibility to infection Note: Also see reductions in monocyte counts and macrophage activity, and defects in their function Disease Progression Acute infection (acute HIV) Relatively mild symptoms similar to influenza (also see night sweats, swollen lymph glands, diarrhea, fatigue, rash, etc) Clinical latency Viral incubation can last from 3 to 20 years (average 8 years) Generally asymptomatic, although lymphadenopathy and other symptoms become pronounced towards the end of latency 13  NURS 7053 Advanced Pathophysiology I for DNP Students Infection - Class Notes AIDS CD4+ T cell counts below 200 cells/mm Opportunistic infections Protozoal infections (e.g., pneumocytosis or toxoplasmosis pneumonia) Fungal infections (e.g., candidiasis, cryptococcsis, histoplasmosis) Atypical bacterial infections (e.g., mycobacteriosis) Viral infections (e.g., CMV, HSV, varicella-zoster) Secondary neoplasms (25-40%) Kaposi sarcoma B-Cell non-Hodgkin lymphomas Primary lymphoma of the brain Neurological dysfunction (40-60%) Peripheral neuropathies Meningoencephalitis Progressive encephalopathy (AIDS-related dementia) 14