Touro PA Microbiology Lecture 15 Fall 2023.pptx

Immunodeficiencies Immunodeficiencies • Congenital: due to defective or missing genes • Acquired: develop during an individual’s life • Due to drugs, cancers, and infections Immunodeficiencies Disease Cells Affected AIDS Selective IgA immunodeficiency TH (CD4+) cells B, T cells B, T cells (de...

Immunodeficiencies Immunodeficiencies • Congenital: due to defective or missing genes • Acquired: develop during an individual’s life • Due to drugs, cancers, and infections Immunodeficiencies Disease Cells Affected AIDS Selective IgA immunodeficiency TH (CD4+) cells B, T cells B, T cells (decreased immunoglobulins) poorly understood B, T, and stem cells B, T, and stem cells Common variable hypogammaglobulinemia Reticular dysgenesis Severe combined immunodeficiency Thymic aplasia (DiGeorge syndrome) Wiskott-Aldrich syndrome X-linked infantile (Bruton’s) agammaglobulinemia T cells (defective thymus) B, T cells B cells (decreased immunoglobulins) Immunodeficiency Disorders • Develop when the body cannot initiate or sustain an immune response • People with immunodeficiencies tend to have repeated infections • Types of infections depend on which part of the immune system is affected • For example, a B-cell deficiency will result in less antibody production and more infections by bacteria that travel in the bloodstream 4 Primary Immunodeficiencies • Present from birth; generally rare • May affect B cells, T cells, natural killer (NK) cells, phagocytes, or complement components Antibody deficiencies • Selective IgA deficiency is most common • Little or no IgA is produced • Affected people appear healthy, but develop repeated infections of the respiratory, gastrointestinal, and genitourinary tracts, where IgA normally protects against pathogens • Another antibody deficiency is agammaglobulinemia, a disease in which few or no antibodies are produced 5 Primary Immunodeficiencies 2 Lymphocyte Deficiencies Severe combined immunodeficiency (SCID) • Hematopoietic stem cells do not produce functional lymphocytes; infection kills at early age • The only cure was a stem cell transplant but gene therapy is now promising DiGeorge syndrome • Thymus fails to develop; cell-mediated immunity is deficient • May be treated with a transplant of thymus tissue • Affected people are susceptible to a variety otherwise uncommon infections 6 Primary Immunodeficiencies • Defects in phagocytic cells • Chronic granulomatous disease (CGD) • Phagocytes fail to produce reactive oxygen species (ROS) within a phagolysosome • Patients can mount an immune response to most infections • Cannot respond effectively to a few common pathogens such as Staphylococcus aureus or molds of the genus Aspergillus • Also produce an abundance of non-functional phagocytes, forming granulomas • Treatments include using antibiotics to reduce the chance of infection and giving interferons to boost the immune response 7 Secondary Immunodeficiencies Develop after birth Cancers involving lymphatic system • Decrease effective antibody-mediated immunity • Multiple myeloma is cancer of a single plasma cell; produces a single type of immunoglobulin at expense of others needed to fight infections • Some viral infections deplete certain immune cells • Measles replicates in lymphoid cells and destroys them • HIV destroys helper T cells, results in AIDS • Highly susceptible to opportunistic infections 8 AIDS • 1981: in United States, cluster of Pneumocystis pneumonia and Kaposi’s sarcoma discovered in young homosexual males from New York and San Francisco. • These patients presented with unexplained opportunistic infections, such as Pneumocystis carinii and Kaposi’s sarcoma • The men showed loss of immune function • 1983: discovery of virus causing loss of immune function Initially To Clinical Latency • Primary HIV infection is difficult to diagnose • symptoms such as fever, lethargy, malaise, sore throat, lymphadenopathy and maculopapular rash are non-specific • And these symptoms often precede the humoral immune response to HIV • Clinical Latency: lasting several years Types of microorganisms. CD4+ T cell HIVs The Origin of AIDS • Crossed the species barrier into humans between 1884 and 1924 • Patient who died in 1959 in Congo is the oldest known case • Spread worldwide through modern transportation and unsafe sexual practices • Norwegian sailor who died in 1976 is the first known case in Western world HIV structure and attachment to receptors on target T cell. Glycoprotein spike: gp120 gp41 transmembrane glycoprotein Envelope Reverse transcriptase enzyme Envelope RNA Core with protein coat Capsid Structure of HIV and infection of a CD4+ T cell. The gp120 glycoprotein spike on the membrane attaches to a receptor on the CD4+ cell. The gp41 transmembrane glycoprotein probably facilitates fusion by attaching to a proposed fusion receptor on the CD4+ cell. HIV structure and attachment to receptors on target T cell. CCR5 or CXCR4 coreceptor CD4 receptor gp41 gp120 CD4+ T cell Attachment. The gp120 spike attaches to a receptor and to a CCR5 or CXCR4 coreceptor on the cell. . HIV structure and attachment to receptors on target T cell. 2 Viral envelope Fusion. The gp41 participates in fusion of the HIV with the cell. HIV structure and attachment to receptors on target T cell. Envelope remains behind Entry. Following fusion with the cell, an entry pore is created. After entry, the viral envelope remains behind and the HIV uncoats, releasing the RNA core (see Figure 19.14b) for directing synthesis of the new viruses. Latent and active HIV infection in CD4+ T cells. Provirus Viral RNA mRNA Core with viral RNA Progeny HIV Envelope Virus beginning to bud from T cell (b) Active infection. The provirus is activated, allowing it to control the synthesis of new viruses, which bud from the host cell. Final assembly takes place at the cell membrane, taking up the viral envelope proteins as the virus buds from the cell. Latent and active HIV infection in macrophages and dendritic cells. Provirus mRNA Viral RNA Core with viral RNA Activated macrophage. New viruses are produced from provirus. Completed virions are either released or persist in the macrophage within vacuoles. Latent and active HIV infection in CD4+ T cells. CD4 receptors CCR5 or CXCR4 receptors CD4+ T Cell Chromosomal DNA Provirus (a) Latent infection. Viral DNA is integrated (via integrase) into cellular DNA and forms a provirus that can later be activated to produce infective viruses. Latent and active HIV infection in macrophages and dendritic cells. Provirus Macrophage Chromosomal DNA Vacuole Insert Fig 19.15a HIV Latently infected macrophage. HIV can persist either as a provirus or as a complete virion in vacuoles. The Stages of HIV Infection • Phase 1: asymptomatic or chronic lymphadenopathy • Phase 2: symptomatic; early indications of immune failure • Phase 3: AIDS indicator conditions The Progression of HIV Infection HIV Transmission • HIV survives 6 hours outside a cell • HIV survives less than 1.5 days inside a cell • Infected body fluids transmit HIV via: • • • • • • • Sexual contact Breast milk Transplacental infection of fetus Blood-contaminated needles Organ transplants Artificial insemination Blood transfusion Diseases Associated with AIDS • Recurrent bacterial infections • recurrent pneumonia • esophageal Candidiasis • Candidiasis of bronchi, trachea or lungs • Toxoplasma gondii • Kaposi’s sarcoma • Cytomegalovirus • Herpes simplex virus with chronic ulcers for longer duration • Varicella-zoster virus • Mycobacterium tuberculosis • M. avium-intracellulare Survival with HIV Infection • Exposed, but not infected • CCR5 mutation • Long-term nonprogressors • Low viral load • Effective humoral and CTLs responses Diagnostic Methods • Seroconversion takes up to 3 months • HIV antibodies detected by ELISA • Viruses detected by: • Western blotting • Plasma viral load (PVL) is determined by PCR Reported AIDS cases in the United States. 120,000 Second 250,000 cases First 250,000 cases Third 250,000 cases Fourth 250,000 Cases Number of cases 100,000 80,000 Expansion of surveillance case definition 60,000 40,000 Insert Fig 14.4 20,000 0 1979 1983 1987 1991 1995 Year 1999 2003 2007 AIDS Worldwide • Heterosexual intercourse (85%) • Women comprise 42% of infected • Injected drug use (IDU) (eastern Europe, central and southeast Asia) Distribution of HIV infection and AIDS in regions of the world. NORTH AMERICA EASTERN EUROPE & CENTRAL ASIA EAST ASIA* WESTERN EUROPE 1.5 million CARIBBEAN 240,000 1.4 million 770,000 820,000 SOUTH & NORTH AFRICA & THE MIDDLE EAST SOUTHEAST ASIA* 460,000 SUB-SAHARAN Insert Fig 19.17AFRICA LATIN AMERICA 4.1 million AUSTRALIA, NEW ZEALAND & OCEANIA 1.4 million 57,000 22.5 million = 100,000 persons living with HIV/AIDS * Estimates are that India now has about 2.4 million cases; China is estimated to have less than 1 million cases. Preventing AIDS • Use of condoms • Use of sterile needles (IDUs) • Health care workers use universal precautions • Wear gloves, gowns, masks, and goggles • Do not recap needles • Risk of infection from infected needlestick injury is 0.3% Vaccine Difficulties • Mutations • Clades • Proviruses • Latent viruses Chemotherapy • Reverse transcriptase inhibitors • Nucleoside reverse transcriptase inhibitors • Tenofovir • Non-nucleoside reverse transcriptase inhibitors • Efavirenz Chemotherapy • Protease inhibitors • Atazanavir, indinavir, and saquinavir • Cell entry inhibitors • Block fusion • Enfuvirtide and maraviroc • Integrase inhibitors • Enzyme to form HIV provirus • Raltegravir HAART • Highly active antiretroviral therapy • Combinations of nucleoside reverse transcriptase inhibitors plus • Non-nucleoside reverse transcriptase inhibitor or • Protease inhibitor