Pathology Infectious Diseases - CM 109 PDF

CM 109: INTEGRATED BASIC SCIENCES II (PATHOLOGY) INFECTIOUS DISEASES ROSA MIA D. GOMEZ, MD, DPSP | 09 NOVEMBER 2024 TABLE OF CONTENTS Rabies virus, poliovirus, and varicella-zoster virus...

CM 109: INTEGRATED BASIC SCIENCES II (PATHOLOGY) INFECTIOUS DISEASES ROSA MIA D. GOMEZ, MD, DPSP | 09 NOVEMBER 2024 TABLE OF CONTENTS Rabies virus, poliovirus, and varicella-zoster virus → Spread to the central nervous system (CNS) by infecting I. GENERAL PRINCIPLES OF MICROBIAL PATHOGENESIS 1 peripheral nerves and then traveling along axons A. HOW MICROORGANISMS CAUSE DISEASE 1 Through the bloodstream → Most common and efficient mode of microbial dissemination B. HOST-PATHOGEN INTERACTIONS 2 → Organism can reach all organs C. HOST DAMAGE BY MICROBES 2 D. SPECTRUM OF INFLAMMATORY RESPONSES TO INFECTION 3 II. VIRAL INFECTIONS 3 A. ACUTE (TRANSIENT) INFECTIONS 3 B. LATENT INFECTIONS 5 C. CHRONIC PRODUCTIVE INFECTIONS 7 D. TRANSFORMING VIRAL INFECTIONS 7 III. BACTERIAL INFECTIONS 8 A. GRAM-POSITIVE BACTERIAL INFECTIONS 8 B. GRAM-NEGATIVE BACTERIAL INFECTIONS 10 C. MYCOBACTERIAL INFECTIONS 11 IV. FUNGAL INFECTIONS 14 A. YEAST INFECTIONS 14 B. MOLD INFECTIONS 14 V. PARASITIC INFECTIONS 15 A. PROTOZOAL INFECTIONS 15 VI. SEXUALLY TRANSMITTED INFECTIONS 16 VII. EMERGING INFECTIOUS DISEASES 16 A. AGENTS OF BIOTERRORISM 16 IV. REFERENCES 16 I. GENERAL PRINCIPLES OF MICROBIAL PATHOGENESIS How microorganisms cause disease Host-pathogen interactions Host damage by microbes Spectrum of inflammatory responses to infection A. HOW MICROORGANISMS CAUSE DISEASE Most infectious disease are caused by pathogenic organisms → Exhibit a wide range of virulence → Acquired from a variety of sources Figure 1. Routes of entry and dissemination of microbes. ▪ People, animals, insect vectors, and the environment Retrieved from Dr. Gomez’s PPT (2024) ▪ They are not found in the normal microbiota of healthy Note: Information was directly taken from Dr. Gomez’s PPT (2024). people → their presence is diagnostic of an infection Microbes penetrate epithelial or mucosal barriers to enter the body Humans and other animals harbor a complex ecosystem of microbes Infection may remain localized at the site of entry or spread to (the microbiome) that has important roles in health and disease other sides in the body → Most commensal organisms coexist peacefully with their human Most common microbes (selected examples are shown) hosts → Spread through the lymphatics or bloodstream → However, if normal host defenses are breached or attenuated ▪ Freely or within inflammatory cells ▪ Commensal microbiota may cause symptomatic infections Certain viruses and bacterial toxins may also travel through nerves Routes of Entry of Microbes Microbes can enter the host by breaching epithelial surfaces, Release from the body and transmission of microbes inhalation, ingestion, or sexual transmission Microbes use a variety of exit strategies to ensure their transmission → Release may be accomplished by: Note: See Table 1. Routes of Microbial Infection in the appendix ▪ Skin shedding ▪ Coughing Vertical Transmission ▪ Sneezing Transmission from mother to fetus or newborn child ▪ Voiding of urine or feces Placental-fetal transmission ▪ Sexual contact → Most likely to occur when the mother becomes infected with a ▪ Insect vectors pathogen during pregnancy Some pathogens → Some resulting infections interfere with fetal development, and → Released for only brief periods of time or periodically during the degree and type of damage depend on the age of the fetus at disease flares the time of infection → May be shed for long periods by asymptomatic carrier hosts ▪ Rubella virus infection during the first trimester Most pathogens are transmitted from person to person by − Can lead to heart malformations, intellectual disability, respiratory, fecal-oral, or sexual routes cataracts, or deafness Other routes of transmission ▪ Rubella virus infection during the third trimester → Saliva is responsible for transmitting viruses that replicate in the − Has little effect salivary glands or the oropharynx (e.g., EBV) Transmission during birth → Protozoa spread through blood meals taken by arthropod → Caused by contact with infectious agents during passage vectors (mosquitoes, ticks, mites) through the birth canal → Zoonotic infections are those transmitted from animals to → e.g., Gonococcal and Chlamydial conjunctivitis humans, either by: Postnatal transmission in maternal milk ▪ Direct contact (including animal bites) → Can transmit cytomegalovirus (CMV), human immunodeficiency ▪ Use of animal products virus (HIV), and hepatitis B virus (HBV) ▪ via an Invertebrate vector Spread and dissemination of microbes within the body B. HOST-PATHOGEN INTERACTIONS Some pathogens secrete enzymes that break down tissues The outcome of infection is determined by: → Allow organisms to spread contiguously in tissue → Virulence of the microbe Organisms that disseminate → Nature of the host immune response → Often travel through the lymphatics to regional lymph nodes, to ▪ May eliminate the infection or, in some cases, exacerbate or reach the bloodstream cause tissue damage Trans # 13 SGD A5 & A6 TH: Fabila 👑 1 of 18  Immune Evasion by Microbes Resistance to cytokine-, chemokine- and complement-mediated Most pathogenic microbes have developed one or more strategies to host defense evade host defenses Some viruses interfere with interferon (IFN) function → Producing soluble homologues of IFN-α/β or IFN-γ receptors that function as "decoys" ▪ Inhibit the actions of secreted IFNs → Producing proteins that inhibit the JAK/STAT cytokine receptor signaling pathway → Producing proteins that inactivate or inhibit double-stranded RNA-dependent protein kinase (protein kinase R [PKR]), through which IFNs inhibit viral replication Evasion of recognition by CD8+ Cytotoxic T lymphocytes (CTLs) and CD4+ Helper T cells T cells recognize microbial antigens presented by MHC molecules → Class I for CTLs → Class Il for CD4+ cells Several DNA viruses bind to or alter localization of MHC class I proteins → Impairing peptide presentation to CD8+ T cells → Examples: ▪ Herpes Simplex Virus (HSV) ▪ Cytomegalovirus (CMV) ▪ Epstein-Barr Virus (EBV) Herpesviruses target MHC class Il molecules for degradation → Impairing antigen presentation to CD4+ T-helper cells Immunoregulatory mechanisms to downregulate antimicrobial T-cell response Figure 2. An overview of mechanisms used by viral and bacterial pathogens T-cell exhaustion to evade innate and adaptive immunity. → Loss of T cell potency over time Retrieved from Dr. Gomez’s PPT (2024). → Feature of chronic infections by HIV, hepatitis C virus (HCV), and Antigenic variation hepatitis B virus (HBV) To escape recognition, microbes have strategies that allow them to Programmed cell death protein 1 (PD-1) "change their coats" by expressing different surface antigens → Immune checkpoint cell surface receptor PD-1 pathway Table 2. Mechanisms of Antigenic Variation → Functions to maintain T-cell tolerance to self-antigens Type Example Disease → Important mediator of T-cell exhaustion during chronic viral infection High Mutation Rate Human Immunodeficiency AIDS Virus (HIV) Establishing a state of latent infection Few, if any, viral genes are expressed, until reactivation Influenza Virus Influenza → Latent infection of neurons by HSV and varicella-zoster virus → B lymphocytes by EBV Genetic reassortment Influenza virus Influenza Pathogens can infect immune cells and interfere with their Rotavirus Diarrhea function Genetic Borrelia burgdorferi Lyme disease HIV - infects and destroys CD4+ T cells rearrangement Infections in People with Immunodeficiencies (e.g., gene Neisseria gonorrhoeae Gonorrhea Inherited or acquired defects in innate and adaptive immunity often recombination, Trypanosoma brucei African sleeping impair the immune system, rendering the affected individual gene conversion, sickness susceptible to infections site-specific Opportunistic inversion) Plasmodium falciparum Malaria → Organisms that cause disease in immunodeficient individuals but not in people with intact immune systems Large diversity of Rhinoviruses Colds → e.g., Aspergillus spp. and Pseudomonas spp serotypes Decline of immune responses can result in reactivation of latent Streptococcus Pneumonia and pneumoniae meningitis infection (e.g., Herpesviruses and Mycobacterium tuberculosis) Age-related decline in immune function may increase infections in Resistance to antimicrobial peptides the elderly Shigella spp., Staphylococcus aureus, Candida spp. Non-immune diseases or injuries also increase susceptibility to Use strategies to avoid killing by cationic antimicrobial peptides infection → Changes in net surface charge and membrane hydrophobicity → Pseudomonas aeruginosa and Burkholderia cepacia in cystic ▪ Prevent antimicrobial peptide insertion and pore formation fibrosis due to defective transmembrane conductance regulator → Secretion of proteins → S. pneumoniae in people with sickle cell disease due to loss of ▪ Inactivate or degrade the peptides splenic macrophages → Pumps → P. aeruginosa in burns due to barrier disruption ▪ Export the peptides Malnutrition can impair immune defenses Resistance to killing by phagocytes C. HOST DAMAGE BY MICROBES The carbohydrate capsule on the surface of many bacteria prevents Infectious agents establish infection and damage tissues by a few phagocytosis of the organisms by neutrophils mechanisms: → Streptococcus pneumoniae → Can contact or enter host cells and cause cell death directly, or → Neisseria meningitidis cause changes in cellular metabolism and proliferation that can → Haemophilus influenzae eventually lead to transformation S. aureus expresses protein A → Release toxins that kill cells at a distance → Binds the Fc portion of antibodies → Release enzymes that degrade tissue components → Inhibits phagocytosis by competitively reducing binding of the → Damage blood vessels and cause ischemic necrosis antibodies to phagocytose Fc receptors → Induce host immune responses that, though directed against Some pathogens are resistant to intracellular killing in phagocytes the invader, cause additional tissue damage → Mycobacteria: inhibit phagosome-lysosome fusion Mechanisms of Viral Injury → Listeria monocytogenes: disrupts the phagosome membrane and Viruses can directly damage host cells by entering them and escapes into the cytosol replicating at the cell's expense → Cryptococcus neoformans → Protozoa (e.g., Leishmania spp., Trypanosoma spp., Toxoplasma Tropism gondii) Predilection for viruses to infect certain cells and not others Evasion of apoptosis and manipulation of host cell metabolism Major determinant - presence of viral receptors on host cells → Viruses bind to proteins found on the surface of host cells that Some viruses produce proteins that interfere with apoptosis of the normally function as receptors for host factors host cell, buying time to replicate, enter latency, or even transform → e.g., HIV glycoprotein gp120 binds to: infected cells ▪ CD4 on T cells Microbes that replicate intracellularly (viruses, some bacteria, fungi, ▪ Chemokine receptors CXCR4 (mainly on T cells) and protozoa) also express factor that modulate autophagy, thus ▪ CCR5 (mainly on macrophages) evading degradation CM 109 Infectious Diseases 2 of 18  Physical barriers can contribute to tissue tropism Communities of bacteria form biofilms → Enteroviruses replicate in the intestine in part → Organisms live within a viscous layer of extracellular ▪ Can resist inactivation by acids, bile, and digestive enzymes polysaccharides that adhere to host tissues or devices such as → Rhinoviruses infect host cells within the upper respiratory tract intravascular catheters and artificial joints ▪ They replicate optimally at the lower temperatures found in Bacterial adherence to host cells sites exposed to the ambient atmosphere Adhesins are bacterial surface proteins that bind the organisms to Mechanisms that viruses use to damage or kill host cells host cells or extracellular matrix Direct cytopathic effects → e.g., Streptococcus pyogenes → Some viruses kill cells by preventing synthesis of critical host ▪ Adheres to host tissues using the adhesins protein F and macromolecules (e.g., host cell DNA, RNA, or proteins), or by teichoic acid, which project from the bacterial cell wall and bind producing degradative enzymes and toxic proteins to fibronectin on the surface of host cells and in the ▪ Poliovirus inactivates cap-binding protein, which is essential extracellular matrix for translation of host cells mRNAs but leaves translation of Pili are filamentous structures on the surface of bacteria that act as poliovirus mRNAs unaffected adhesins ▪ Viruses can induce cell death by: → Stalks of pili - composed of conserved repeating protein subunits − Activating so-called death receptors on the plasma → Variable tip fibrillum - determines the tissue-binding specificity of membrane the bacteria − By triggering the intracellular apoptotic machinery Intracellular bacteria ▪ Large amounts of viral proteins are synthesized in infected M. tuberculosis uses host receptors for opsonins (antibodies and cells, including unfolded or misfolded proteins that activate: C3b) as well as poorly defined nonopsonic receptors on − ER stress response macrophages − Pro-apoptotic pathways Some gram-negative bacteria use a type Ill secretion system to ▪ Some viruses encode proteins that are pro-apoptotic, such as enter epithelial cells the HIV viral protein R (Vpr) → Consists of needle like structures projecting from the bacterial surface that bind to host cells → These proteins then form pores in the host cell membrane and inject bacterial proteins that mediate the rearrangement of the host cell cytoskeleton Shigella spp. and E. coli → Inhibit host protein synthesis, replicate rapidly, and lyse the host cell within hours M. tuberculosis → Blocks fusion of the lysosome with the phagosome, allowing it to proliferate unchecked within the macrophage L. monocytogenes → Produces a pore-forming protein called listeriolysin O and two phospholipases that degrade the phagosome membrane, allowing the bacterium to escape into the cytoplasm Bacterial toxins Endotoxin: a lipopolysaccharide (LPS) in the outer membrane of gram-negative bacteria that both stimulates host immune responses and injures the host → Lipid A - the part of LPS that anchors the molecule in the host cell membrane, has the endotoxin activity of LPS Exotoxins: secreted bacterial proteins that cause cellular injury and disease → Enzymes - bacteria secrete a variety of enzymes (proteases, hyaluronidases, coagulases, fibrinolysins) that act on substrates in host tissues or on host cells → Toxins that alter intracellular signaling or regulatory pathways ▪ Active (A) subunit with enzymatic activity ▪ Binding (B) subunit that binds to receptors on the cell surface and delivers the A subunit into the cell cytoplasm → Superantigens ▪ Bacterial toxins that stimulate several T lymphocytes by binding to conserved portions of the T-cell receptor − Lead to massive T-lymphocyte proliferation and cytokine release → SIRS Figure 3. Mechanism by which viruses cause injury to cells. D. SPECTRUM OF INFLAMMATORY RESPONSES TO Retrieved from Dr. Gomez’s PPT (2024) INFECTION Many pathogens produce similar reaction patterns, and few features Antiviral Immune Response are unique or pathognomonic for a particular microorganism → Host lymphocytes can recognize and destroy virus-infected cells → CTLs also can be responsible for tissue injury Note: See Table 3. Spectrum of Inflammatory Responses to Infection Transformation of infected cells in the appendix → Oncogenic viruses can stimulate cell growth and survival by a variety of mechanisms: II. VIRAL INFECTIONS ▪ Expression of virus-encoded oncogenes A. ACUTE (TRANSIENT) INFECTIONS ▪ Expression of viral proteins that inactivate key tumor The viruses that cause transient infections are suppressors → Structurally heterogeneous ▪ Insertional mutagenesis, in which expression of host genes is → But all elicit effective immune responses that eliminate the altered by the insertion of viral genes into host genes or pathogens, limiting the durations of these infections flanking sequences However, specific viruses exhibit widely differing degrees of genetic Mechanisms of Bacterial Injury diversity Bacterial virulence → Variable that has an important impact on the susceptibility of the Bacterial damage to host tissues depends on the ability of the host to reinfection bacteria to adhere to host cells, to invade cells and tissues, and to → Mumps virus: has only one genetic subtype and infects people deliver toxins only once Pathogenic bacteria have virulence genes that encode proteins Measles responsible for these properties An acute viral infection that affects multiple organs Plasmids and bacteriophages Causes a wide range of disease → Mobile genetic elements → Mild, self-limited infections to severe systemic manifestations → Can transmit functionally important genes to bacteria, including Pathogenesis genes that influence pathogenicity and drug resistance Measles virus is a single-stranded RNA virus of the Quorum sensing Paramyxoviridae family → Process used by many bacteria to regulate gene expression There is only one serotype within a large population Very efficiently transmitted by the airborne route via aerosolized → Allows bacteria to turn on gene expression and express specific respiratory secretions traits only when the organism grows to reach a high concentration CM 109 Infectious Diseases 3 of 18  Three cell-surface receptors have been identified for measles Mumps hemagglutinin protein An acute systemic viral infection usually associated with pain and → Signaling lymphocytic activation molecule family member 1 swelling of the salivary glands (SLAMF1) Pathogenesis ▪ Expressed on activated lymphocytes, dendritic cells, and monocytes A member of the Paramyxoviridae family ▪ Serves as the initial receptor for viral infection Two types of surface glycoproteins: → Nectin-4 → With hemagglutinin and neuraminidase activities ▪ Found on the basal surface of epithelial cells → With cell fusion and cytolytic activities ▪ Important for replication of the virus within the respiratory tract Enter the upper respiratory tract through inhalation of or contact with → CD46 respiratory droplets >> Spread to draining lymph nodes where ▪ First cell-surface receptor identified for measles virus they replicate in lymphocytes (preferentially in activated T cells) >> ▪ Used only by culture-adapted virus (including the vaccine Spread through the blood to the salivary and other glands strain), and not wild-type virus Infects salivary gland ductal epithelial cells >> Desquamation of Can replicate in a variety of cell types, including epithelial cells and involved cells, edema, and inflammation that leads to the classic leukocytes salivary gland pain and swelling Initially multiplies within the respiratory tract and then spreads to Can spread to other sites, including the CNS, testis, ovary, and local lymphoid tissues pancreas Replication of the virus in lymphatic tissue is followed by viremia and Aseptic meningitis: dissemination to many tissues, including the conjunctiva, skin, → Most common extra salivary gland complication of mumps respiratory tract, urinary tract, small blood vessels, lymphatic system, → Occurring in up to 15% of cases and CNS Morphology T-cell mediated immunity to measles virus Mumps parotitis → Most children develop this to control the viral infection and → Bilateral in 70% of cases produces the measles rash → Affected glands are enlarged, have a doughy consistency, and Malnourished children with poor medical care are moist, glistening, and reddish-brown on cross-section → Measles virus may cause croup, pneumonia, diarrhea and → Microscopic: gland interstitium is edematous and diffusely protein-losing enteropathy, keratitis leading to scarring and infiltrated by macrophages, lymphocytes, and plasma cells, which blindness, encephalitis, and hemorrhagic rashes compress acini and ducts Rare late complications Mumps orchitis → Subacute sclerosing panencephalitis → Testicular swelling may be marked, caused by edema, → Measles inclusion body encephalitis mononuclear cell infiltration, and focal hemorrhages Morphology → Because the testis is tightly contained within the tunica albuginea, Blotchy, reddish brown rash of measles virus infection parenchymal swelling may compromise the blood supply and → Found on the face, trunk, and proximal extremities cause areas of infarction → Produced by dilated skin vessels, edema, and a mononuclear ▪ Testicular damage can lead to scarring, atrophy, and if severe, perivascular infiltrate sterility Mumps encephalitis → Associated with perivenous demyelination and perivascular mononuclear cuffing Figure 4. Rashes from measles virus infection. Retrieved from Dr. Gomez’s PPT (2024) Ulcerated mucosal lesions in the oral cavity near the opening of the Stensen ducts (pathognomonic Koplik spots) → Marked by necrosis, neutrophilic exudate, and neovascularization Figure 7. Mumps. Retrieved from Dr. Gomez’s PPT (2024) Poliomyelitis Causes an acute systemic viral infection, leading to a wide range of manifestations → Mild, self-limited infections to paralysis of limb muscles and respiratory muscles A spherical, unencapsulated RNA virus of the Enterovirus genus Three serotypes of poliovirus → Most infections are caused by type 1 Figure 5. Lesions in the oral cavity. Vaccines Retrieved from Dr. Gomez’s PPT (2024) → Inactivated (injected) poliovirus vaccine ▪ Protects against ALL three serotypes Lymphoid organs typically have: → Attenuated (oral) poliovirus vaccine → Marked follicular hyperplasia ▪ Available in various combinations of one, two, or all three → Large germinal centers serotypes → Warthin-Finkeldey cells ▪ Although only formulations containing one or two serotypes are ▪ Randomly distributed multinucleated giant cells currently in use ▪ Have eosinophilic nuclear and cytoplasmic inclusion bodies → These vaccines has nearly eradicated polio ▪ Pathognomonic of measles ▪ Because poliovirus infects only humans, shows limited genetic variation, and is effectively neutralized by antibodies generated by immunization Pathogenesis Transmitted by the fecal-oral route The virus infects human cells by binding to CD155, molecule expressed on a variety of cell types, including epithelial cells, lymphocytes, and neurons Poliovirus is ingested >> Replicates in the mucosa of the pharynx and gut, including tonsils and Peyer patches in the ileum >> Spreads through lymphatics to lymph nodes >> Reaches the blood >> Produces transient viremia and fever About 1 in 100 infected persons Figure 6. Measles giant cells in the lung. Note the glassy eosinophilic → Poliovirus invades the CNS intranuclear inclusions. Retrieved from Dr. Gomez’s PPT (2024) → Replicates in motor neurons of the spinal cord (spinal poliomyelitis) or brainstem (bulbar poliomyelitis) CM 109 Infectious Diseases 4 of 18  Figure 9. The morphology of the brain from a two month old child with congenital Zika virus infection. Retrieved from Dr. Gomez’s PPT (2024) Note: Information was directly taken from Dr. Gomez’s PPT (2024). (A) Subcortical band of degenerating cells with prominent Figure 8. Life Cycle of Polio. calcifications Retrieved from Dr. Gomez’s PPT (2024) (B) Cortex with degenerating neurons (arrows) Viral Hemorrhagic Fever A severe-life threatening multisystem syndrome in which there is Dengue Virus vascular damage, leading to widespread hemorrhage and shock Flavivirus transmitted by Aedes mosquitoes in tropical and Caused by enveloped RNA viruses belonging to 4 different genera: subtropical regions → Arenaviridae Clinical Manifestations → Filoviridae Breakbone fever → Bunyaviridae → Fever with headache, macular rash and severe myalgias → Flaviviridae Severe dengue (dengue hemorrhagic fever) with bleeding, liver Can produce a spectrum of illnesses: failure, reduced consciousness, organ failure, and plasma leakage → Mild acute disease - characterized by fever, headache, myalgia, leading to shock and respiratory distress rash, neutropenia, and thrombocytopenia Severe dengue → Severe, life-threatening disease - sudden hemodynamic → Widespread hemorrhages throughout the body deterioration and shock → Hepatic necrosis Pass through an animal or insect host during their life cycles → Mononuclear infiltrates → Ranges are restricted to areas in which their hosts reside → Septal thickening Humans: Incidental hosts → Hyaline membrane formation in the lung → Infected when they come into contact with infected hosts (typically rodents) or insect vectors (mosquitoes and ticks) Four Serotypes Some viruses that cause hemorrhagic fever (Ebola, Marburg, and Infection with each serotype stimulates protective immunity against Lassa) can also spread from person to person that serotype, but also stimulates a cross-reactive antibody response that is weak and non-protective for other serotypes of the Zika Virus Infections virus A Flavivirus that was discovered in 1947 and was subsequently Severe dengue usually occurs in people who have had previous found to be widespread in Africa, Asia, and the Middle East infection with a different serotype than the one associated with In 2015, an outbreak of Zika virus from March until June in Brazil their severe illness caused up to 1.3 million suspected cases → Antibody-dependent enhancement → A marked increase in the occurrence of microcephaly in infants ▪ The cross-reactive antibodies enhance uptake of virus into born in Brazil was noted with 4300 cases reported macrophages via Fc receptors → Zika virus has now been clearly linked − Increase infectivity of virus & contribute to severe dengue Transmitted by Aedes mosquitoes, primarily Aedes aegypti In addition to mosquito-borne and perinatal transmission, the virus Novel Coronavirus SARS-CoV-2 (COVID-19) can also infect through blood transfusion and sexual contact First detected in Wuhan, China Reported to the WHO in December 2019 Clinical Manifestations End of March 2020 Adults - usually mild, non-specific flu-like illness → Infection was a worldwide pandemic Associated with a small number of cases of neurologic complications (> 800,000 cases and ~ 40,000 deaths) in adults, primarily Guillain-Barré syndrome Origin: Seafood and animal market in Wuhan Perinatal transmission - can result in fetal death or moderate to → Animal-to-human transmission (initially) severe brain defects in the fetus and newborn child → Person-to-person spread (after) Morphology Clinical manifestations ranged from mild to severe respiratory Most common adverse outcomes associated with Zika virus infection illness → Cerebral calcifications Severe and sometimes fatal illness with respiratory compromise, → Cerebral atrophy often associated with bilateral ground-glass opacities on chest → Ventricular enlargements imaging, occurs mainly in: → Hypoplastic cerebral structures → Older individuals Microcephaly occurred in a small number of infants → With comorbidities such as diabetes, COPD, and heart failure Ocular abnormalities are common, including: Genomic sequence shows COVID-19 is related to bat coronaviruses → Pigment mottling and the SARS coronavirus → Chorioretinal atrophy Histologic analysis of lung tissue → Optic nerve abnormalities → Diffuse alveolar damage and inflammation with mainly Common findings in newborn children (from small autopsy series): mononuclear cells → Microcephaly B. LATENT INFECTIONS → Ventriculomegaly Latency is defined as the persistence of viral genomes in cells that → Congenital joint contractures (arthrogryposis) do not produce infectious virus → Pulmonary hypoplasia Dissemination of the infection and tissue injury stem from ▪ Severe neuronal depletion and associated thinning of the brain reactivation of the latent virus parenchyma occurred, with microcalcifications and microglial Herpesviruses nodules → Large encapsulated viruses with double-stranded DNA genomes Zika virus infection is mostly neurological → Most frequently establish latent infections in humans → Cause acute infection followed by latent infection ▪ The viruses persist in a noninfectious form with periodic reactivation and shedding of infectious virus CM 109 Infectious Diseases 5 of 18  Herpesvirus Corneal lesions Eight types of human herpesviruses, belonging to three subgroups → Herpes epithelial keratitis that are defined by the type of cell most frequently infected and the ▪ Typical virus-induced cytolysis of superficial epithelium site of latency → Herpes stromal keratitis → α-group viruses ▪ Infiltrates of mononuclear cells around keratinocytes and ▪ Includes HSV-1, HSV-2, and VZV endothelial cells >> neovascularization, scarring, opacification ▪ Infect epithelial cells and produce latent infection in postmitotic of the cornea, and eventual blindness neurons − Damage is caused by an immunologic reaction to the HSV → β-group viruses infection ▪ Include CMV and human herpesviruses 6 and 7 (HHV-6 and Herpes simplex encephalitis HHV-7) Disseminated skin and visceral herpes infections ▪ HHV-6 and HHV-7 cause exanthem subitum → Hospital encounters of patients with underlying cancer or − Also known as roseola infantum, and sixth disease immunosuppression − A benign rash in infants, and also have been associated → Herpes esophagitis with encephalitis, pneumonitis, hepatitis, and myelitis on → Herpes bronchopneumonia reactivation → Herpes hepatitis → γ-group viruses ▪ Include EBV and Kaposi sarcoma-associated virus (KSHV/HHV-8) ▪ Produce latent infection mainly in lymphoid cells → Herpesvirus simiae (monkey B virus) ▪ Old World monkey virus that resembles HSV-1 ▪ Can cause fatal neurologic disease in animal handlers, usually resulting from an animal bite Herpes Simplex Virus (HSV) Infections HSV-1 and HSV-2 → Differ serologically but are closely related genetically → Cause similar set of primary and recurrent infections ▪ Cutaneous lesions ▪ Genital lesions → Both viruses replicate in the skin and the mucous membranes at the site of entry of the virus (usually oropharynx or genitals) ▪ They produce infectious virions and cause vesicular lesions of the epidermis Figure 10. Gingivostomatitis (left); Genital herpes (right); Herpes keratitis The viruses spread to sensory neurons that innervate these (bottom). Retrieved from Dr. Gomez’s PPT (2024) primary sites of viral replication and release Varicella zoster virus (VSV) Infections Viral nucleocapsids are transported along axons to the neuronal cell Acute: Chickenpox bodies, where the viruses establish latent infection Reactivation: Shingles (Herpes zoster) During latency the viral DNA remains within the nucleus of the neuron, and only latency-associated viral RNA transcripts (LATs) Chickenpox are synthesized Transmission: epidemic fashion → LATS may contribute to latency by: → Respiratory aerosols ▪ Conferring resistance to apoptosis → Hematogenous dissemination ▪ Silencing lytic gene expression through heterochromatin Vesicular skin lesion (widespread) formation Infects mucous membranes, skin, and neurons ▪ Serving as precursors for micro-RNAS that downregulate Causes primary infection (self-limited) in immunocompetent expression of critical HSV lytic genes individuals Reactivation Shingles → In HSV-1 and HSV-2: occurs repeatedly with or without symptoms Latent VSV is seen in neurons and/or satellite cells around neurons → Due to viral spread: neurons >> skin / mucous membranes in the dorsal root ganglia → Can occur in the presence of host immunity since HSV have Uncommon developed ways to avoid immune recognition → May occur many years after primary infection Can infect multiple cell types: → Rare: immunocompetent individuals (1-4% of infected) → Dendritic cells (important for antiviral immune response) Multiple recurrence Corneal Blindness → Immunosuppressed or older persons >> needs vaccination → HSV-1 is the major infectious agent Localized recurrence Sporadic encephalitis → Most frequent and painful in dermatomes innervated by the → Fatal case in the USA trigeminal ganglia where virus is more likely latent → HSV-1 is the major infectious agent Disseminated herpesvirus infections VSV: Morphology → Common in neonates and individuals with compromised cellular Chickenpox rash immunity → Occurs ~2 weeks after respiratory infection ▪ e.g., Secondary to HIV infection or chemotherapy → Multiple waves centrifugally: torso >> head and extremities Ulceration and dampening of immune response + HSV-2 → “Dewdrop on a rose petal” infection ▪ Each lesion progresses rapidly from macule to a vesicle → HIV transmission = four-fold increased in risk → Histology: intraepithelial vesicles → HIV acquisition = two-to threefold increased in risk ▪ With intranuclear inclusions in epithelial cells at the base of the vesicles Morphology → After few days, Cowdry type A ▪ Vesicles rupture >> crust over >> heal (regeneration, no scars) → HSV-infected cells containing large, pink to purple intranuclear → Bacterial superinfection inclusions ▪ Ruptured vesicles by trauma may lead to destruction of basal ▪ Consists viral replication proteins + virions (various assembly epidermal layer and residual scarring stage) Shingles − Push the host cell chromatin out to the edges of the nucleus → Latent VSV (in dorsal root ganglia) is reactivated and infects HSV-1 and HSV-2 sensory nerves that carry it to one or more dermatome → Cause lesions ranging from: → Vesicular lesions ▪ Self-limited cold sores and gingivostomatitis ▪ When VSV infects keratinocytes ▪ Life-threatening disseminated visceral infections and ▪ Radiculoneuritis: intense itching, burning, or sharp pain → In cell infusion − Severe pain when trigeminal nerves are involved ▪ Produces inclusion-bearing multinucleated syncytia → Histology Fever blisters or cold sores ▪ Sensory ganglia → Favor the facial skin around mucosal orifices (lips, nose) − With dense, mononuclear infiltrates (predominant) ▪ Distribution is frequently bilateral and independent of skin − With herpetic intranuclear inclusions within neurons and dermatomes their supporting cells Gingivostomatitis Other complications (immunosuppressed people): → Common in children → Interstitial pneumonia → Caused primarily by HSV-1 → Encephalitis Genital Herpes → Transverse myelitis, → More often caused by HSV-2 than by HSV-1 → Vasculopathy → Necrotizing visceral lesions CM 109 Infectious Diseases 6 of 18  CMV in Immunosuppressed Individuals Susceptible to severe CMV infection → New infections → Reactivation of latent CMV In the past, CMV was the most common opportunistic viral pathogen in AIDS → The frequency of serious CMV infection in HIV-positive people has been greatly reduced by antiretroviral treatment Figure 11. Chickenpox (left); Shingles (right). Recipients of solid-organ transplants (heart, liver, kidney) also may Retrieved from Dr. Gomez’s PPT (2024) contract CMV from the donor organ Primarily affect the lungs (pneumonitis) and gastrointestinal tract Cytomegalovirus (CMV) Infections (colitis) β-group herpesvirus → Pneumonitis: interstitial mononuclear infiltrate with foci of Can produce a variety of disease manifestations depending on the necrosis develops, accompanied by the typical enlarged cells with → Age of the host inclusions → Host's immune status (more important) → Colitis: intestinal necrosis and ulceration can develop and be Latently infects monocytes and their bone marrow progenitors extensive, leading to the formation of pseudomembranes and Can be reactivated when cellular immunity is depressed debilitating diarrhea May cause: → Asymptomatic or mononucleosis-like infection in healthy C. CHRONIC PRODUCTIVE INFECTIONS individuals In some infections the immune system is unable to eliminate the → Devastating systemic infections in neonates and in virus, and continued viral replication leads to persistent viremia immunocompromised people, in whom the virus may infect many The high mutation rate of viruses such as HIV and HBV may different cell types and tissue contribute to their escape from control by the immune system Mode of Transmission D. TRANSFORMING VIRAL INFECTIONS Transplacental transmission Some viruses can transform infected cells into benign or malignant → From a newly acquired or primary infection in a mother who does tumor cells (oncogenic viruses) not have protective antibodies (congenital CMV) → EBV, HPV, HBV, and HTLV-1 Neonatal transmission Epstein-Barr Virus (EBV) Infections → Cervical or vaginal secretions at birth Associated with the pathogenesis of several human tumors, most → Through breast milk from a mother who has active infection commonly certain lymphomas and nasopharyngeal carcinoma (perinatal CMV) Transmission through saliva Infectious Mononucleosis → May occur during preschool years, especially in daycare centers Caused by EBV infections → Toddlers readily transmit the virus to their parents Benign, self-limited lymphoproliferative disorder Transmission by the genital route Characterized by: → Dominant mode ≥15 years old → Fever ▪ May also occur via respiratory secretions and fecal-oral route → Sore throat Iatrogenic transmission → Generalized lymphadenopathy → Occur at any age through organ transplant or blood transfusion → Splenomegaly → Appearance in the blood of atypical activated T lymphocytes Morphology (mononucleosis cells) Infected cells are strikingly enlarged, often to a diameter of 40 μm Occurs principally in late adolescents or young adults among upper → Show cellular and nuclear pleomorphism socioeconomic classes in higher-income nations Prominent intranuclear basophilic inclusions In the rest of the world, primary infection with EBV occurs in → One-half of the nuclear diameter are set off from the nuclear childhood and is usually asymptomatic membrane by a clear halo Pathogenesis Congenital infections Transmitted by close human contact, frequently through the saliva Asymptomatic in 95% of cases during kissing Sometimes when the virus is acquired from a mother with primary EBV infects B cells and possibly epithelial cells of the oropharynx infection (who does not have protective antibodies), classic An EBV envelope glycoprotein binds CD21 (CR2), the receptor for cytomegalic inclusion disease develops the C3d component of complement, which is present on B cells → Resembles erythroblastosis fetalis Infection of B cells may take one of two forms: → Intrauterine growth restriction → In a minority of B cells, infection is lytic, leading to viral replication → Present with jaundice, hepatosplenomegaly, anemia, bleeding and eventual cell lysis accompanied by release of virions, which due to thrombocytopenia, and encephalitis may infect other B cells → Brain (fatal cases) → In most B cells, EBV establishes latent infection, during which ▪ Often smaller than normal (microcephaly) the virus persists as an extrachromosomal episome ▪ May show foci of calcification ▪ Uncontrolled, expanding polyclonal population of EBV-infected Perinatal Infections B cells secretes antibodies with many specificities, including Asymptomatic antibodies that recognize sheep or horse red cells → Due to protective maternal anti-CMV antibodies that are ▪ These so-called heterophile antibodies are detected in transmitted to the fetus diagnostic tests for mononucleosis Despite the lack of symptoms, many of these infants continue to ▪ May also produce auto-antibodies, for example against excrete CMV in their urine or saliva for months to years platelets, leading to transient immune-mediated Subtle effects on hearing and intelligence later in life have been thrombocytopenia reported Symptoms of infectious mononucleosis appear on initiation of the Much less commonly, infected infants develop: host immune response → Interstitial pneumonitis → Cellular immunity mediated by CD8+ CTLs and NK cells is the → Failure to thrive most important component of this response → Rash ▪ The atypical lymphocytes seen in the blood, characteristic of → Hepatitis this disease, are mainly EBV-specific CD8+ CTLs, but also include NK cells CMV Mononucleosis The reactive proliferation of T cells is largely centered in lymphoid Most common clinical manifestation in immunocompetent hosts tissues, which accounts for the lymphadenopathy and splenomegaly beyond the neonatal period An infectious mononucleosis-like illness, with the following Morphology symptoms: Major alterations involve the blood, lymph nodes, spleen, liver, CNS, → Fever and, occasionally, other organs → Atypical lymphocytosis Absolute lymphocytosis in peripheral blood → Lymphadenopathy → >60% of white blood cells are lymphocytes → Hepatitis (marked by hepatomegaly & abnormal liver function → Atypical lymphocytes (5 - 80%) tests) ▪ Large, 12 to 16 μm in diameter Most people recover without any sequelae, but the virus may ▪ Characterized by: continue to be excreted in body fluids for months to years − Abundant cytoplasm containing multiple clear vacuolations Irrespective of the presence or absence of symptoms, infected − Oval, indented, or folded nucleus individuals remain seropositive for life, and the virus is never cleared, − Scattered cytoplasmic azurophilic granules persisting in latently infected leukocytes Lymph nodes → Discrete and enlarged throughout the body, particularly in the posterior cervical, axillary, and inguinal regions → Histology: expansion of paracortical areas due to activation of T cells (immunoblasts) CM 109 Infectious Diseases 7 of 18  Spleen S. aureus toxins → Enlarged in most cases → Hemolytic (membrane-damaging) toxins → 300 to 500 g ▪ α-toxin: protein that intercalates into the plasma membrane of → Usually soft and fleshy, with a hyperemic cut surface host cells, forming pores that allow toxic levels of calcium to leak into cells ▪ β-toxin: sphingomyelinase ▪ δ-toxin: detergent-like peptide ▪ γ-toxin: lyses red cells ▪ Leukocidin: lyses phagocytes Exfoliative A and B toxins → Produced by S. aureus → Serine proteases that cleave the desmosomal protein desmoglein 1, which holds epidermal cells tightly together >> causes keratinocytes to detach from one another and from the underlying basement membrane >> Result in a loss of barrier Figure 12. Atypical Lymphocytes in Infectious Mononucleosis. function Retrieved from Dr. Gomez’s PPT (2024) Superantigens → Cause food poisoning and toxic shock syndrome (TSS) → Bacterial superantigens cause polyclonal T-cell proliferation by binding to conserved portions of MHC molecules and to relatively conserved portions of T-cell receptor β chains → Superantigens may stimulate up to 20% of T lymphocytes >> Release of cytokines such as TNF and IL-1, in such large amounts that they may trigger the systemic inflammatory response syndrome Morphology Whether the lesion is located in the skin, lungs, bones, or heart valves, S.aureus causes pyogenic inflammation that is distinctive Figure 13. Infectious mononucleosis. for its local destruction of host tissue Retrieved from Dr. Gomez’s PPT (2024) → Furuncle (boil) Note: Information was directly taken from Dr. Gomez’s PPT (2024). → Carbuncle (a) The paracortex of a lymph node is expanded by proliferation of → Hidradenitis (chronic suppurative infection of apocrine glands, immunoblasts. Hematoxylin and eosin, × 400 most often in the axilla) (b) In situ hybridization for EBER shows numerous positive cells, × 400 → Infections of the nail bed (paronychia) → Palmar side of the fingertips (felons) III. BACTERIAL INFECTIONS S. aureus lung infections → Have a polymorphonuclear infiltrate like that of S. pneumoniae A. GRAM-POSITIVE BACTERIAL INFECTIONS infections, but they cause much more tissue destruction Staphylococcal Infections → Arise from: S. aureus ▪ Hematogenous source - Infected thrombus → A pyogenic gram-positive coccus that forms clusters resembling ▪ Predisposing condition - Influenza bunches of grapes Staphylococcal scalded-skin syndrome (Ritter disease) → Skin lesions, abscesses, sepsis, osteomyelitis, pneumonia, → Most frequently occurs in children with S. aureus infection of the endocarditis, food poisoning, and toxic shock syndrome nasopharynx or skin S. epidermidis → Sunburn-like rash that spreads over the entire body and evolves → Coagulase-negative staphylococci into fragile bullae that lead to partial or total skin loss → Causes opportunistic infections in: → Desquamation of the epidermis in staphylococcal scalded-skin ▪ Catheterized patients syndrome occurs at the level of the granulosa layer ▪ Patients with prosthetic cardiac valves ▪ Intravenous drug users S. saprophyticus → Common cause of urinary tract infection in young women Figure 15. Staphylococcal abscess of the lung with extensive neutrophilic infiltrate and destruction of the alveoli. The inset shows the same area on Gram stain highlighting clusters of bacteria. Retrieved from Robbins & Cotran Figure 14. The consequences of staphylococcal infection. Retrieved from Dr. Gomez’s PPT (2024) Figure 16. Staphylococcal scalded skin syndrome. Retrieved from Dermnet.org Pathogenesis S. aureus virulence factors Streptococcal and Enterococcal Infections → Surface receptors for fibrinogen ("clumping factor") Streptococci → Polysaccharide capsule enabling attachment to artificial Gram-positive cocci that grow in pairs or chains materials and resulting in significant prosthetic valve and Cause suppurative infections of the skin, oropharynx, lungs, and catheter-associated infection and a resistance to host cell heart valves phagocytosis Responsible for some post-infectious syndromes: → Surface protein A, which binds the Fc portion Of → Rheumatic fever immunoglobulins, allowing the organism to escape → Poststreptococcal glomerulonephritis antibody-mediated killing → Erythema nodosum CM 109 Infectious Diseases 8 of 18  Typed according to their surface carbohydrate antigens: → S. pyogenes (group A) ▪ Causes pharyngitis, scarlet fever, erysipelas, impetigo, rheumatic fever, TSS, and glomerulonephritis → Streptococcus agalactiae (group B) ▪ Colonizes the female genital tract and causes sepsis and meningitis in neonates and chorioamnionitis in pregnancy → S. pneumoniae ▪ Most important α-hemolytic streptococcus ▪ Common cause of community-acquired pneumonia in older adults and meningitis in children and adults Figure 19. Corynebacterium diphtheriae. → Viridans-group streptococci Retrieved from Dr. Gomez’s PPT (2024) ▪ Include α-hemolytic and non-hemolytic streptococci Morphology ▪ Found in normal oral microbiota that are a common cause of Inhaled C. diphtheriae carried in respiratory droplets proliferate at the endocarditis site of attachment on the mucosa of the nasopharynx, oropharynx, → Streptococcus mutans larynx, or trachea ▪ Major cause of dental caries Release of exotoxin causes necrosis of the epithelium, Enterococci accompanied by an outpouring of a dense fibrinosuppurative Gram-positive cocci that grow in pairs and chains exudate → Difficult to distinguish from streptococci by morphology alone → The coagulation of this exudate on the ulcerated necrotic surface Often resistant to commonly used antibiotics creates a pseudomembrane Significant cause of endocarditis and urinary tract infection ▪ Tough, dirty, gray to black superficial membrane ▪ Not formed by viable tissue Morphology → Bleeding and asphyxiation may occur when the membrane Streptococcal infections are characterized by diffuse interstitial sloughs off its inflamed and vascularized bed neutrophilic infiltrates with minimal destruction of host tissues Erysipelas → Caused by exotoxins from superficial infection with S. pyogenes → Characterized by rapidly spreading, erythematous cutaneous swelling that may begin on the face or, less frequently, on the body or an extremity → The rash has a sharp, demarcated, serpiginous border and may form a "butterfly" Figure 20. Diphtheria Pseudomembrane. Retrieved from Dr. Gomez’s PPT (2024) Listeriosis Listeria monocytogenes → Gram-positive bacillus that causes gastroenteritis in most individuals who ingest it in sufficient quantity → Most are associated with contaminated dairy products or Figure 17. Streptococcal erysipelas. processed fruits and vegetables Retrieved from Robbins & Cotran Pregnant women, neonates, older adults, and immunosuppressed persons are particularly susceptible to severe L. monocytogenes infection → Pregnant women ▪ Amnionitis that may result in abortion, stillbirth, or neonatal sepsis → Newborns ▪ Disseminated disease (granulomatosis infantiseptica) → Immunosuppressed adults ▪ Disseminated disease, exudative meningitis Figure 18. Streptococcal erysipelas. Retrieved from Dr. Gomez’s PPT (2024) Streptococcal pharyngitis → Major antecedent of post-streptococcal glomerulonephritis → Marked by edema, epiglottic swelling, and punctate abscesses of the tonsillar crypts → Sometimes accompanied by cervical lymphadenopathy Scarlet fever → Associated with pharyngitis caused by S. pyogenes → Characterized by a punctate erythematous rash that is most prominent over the trunk and inner aspects of the arms and legs S. pneumoniae is an important cause of lobar pneumonia Diphtheria Figure 21. Listeria monocytogenes. Caused by Corynebacterium diphtheriae Retrieved from Dr. Gomez’s PPT (2024) → Slender gram-positive rod with clubbed ends → Spreads from person to person through respiratory droplets or Pathogenesis skin exudate Facultative intracellular pathogen Respiratory diphtheria Bacteria bind to receptors on host epithelial cells and macrophages → Causes pharyngeal or, less often, nasal or laryngeal infection and are phagocytosed Cutaneous diphtheria Bacteria escape from the phagolysosome using: → Causes chronic ulcers with a dirty gray membrane, but does not → Listeriolysin O (LLO) - pore-forming protein; and, cause systemic damage → Two phospholipases C. diphtheriae produces a phage-encoded A-B toxin that blocks Act A host cell protein synthesis → Found in the host cell cytoplasm A fragment → A bacterial surface protein → Catalyzes the covalent transfer of ADP-ribose to elongation → Binds to the Arp2/3 complex, an actin nucleating complex >> factor-2 (EF-2) → this inhibits EF-2 function, which is required Induces actin polymerization >> Generates force to propel the for the translation of mRNA into protein bacteria into adjacent, uninfected host cells CM 109 Infectious Diseases 9 of 18  Anthrax Characterized by necrotizing inflammatory lesions in the skin or gastrointestinal tract or systemically Caused by Bacillus anthracis → A large, spore-forming gram-positive rod-shaped bacterium → Found in environmental sources Livestock become infected by spores in their environment or feed Humans usually become infected by eating or handling meat or products from infected animals (e.g., wool or hides) Anthrax spores can be made into a fine powder, creating a potent Figure 24. Bacillus anthracis. Bacillus anthracis in the subcapsular sinus of biological weapon that is a potential bioterrorism threat a hilar lymph node of a patient who died of inhalational anthrax. Retrieved from Dr. Gomez’s PPT (2024). Three Major Forms Cutaneous anthrax B. GRAM-NEGATIVE BACTERIAL INFECTIONS → Makes up 95% of naturally occurring infections Neisseria spp. → Begins as a painless, pruritic papule that develops into a vesicle Aerobic, gram-negative diplococci within 2 days Pathogenic Neisseria spp. often can secrete single-stranded DNA for → As the vesicle enlarges, striking edema may occur around it, with transformation of other Neisseria spp. development of regional lymphadenopathy → Commensal Neisseria spp. usually lack this ability → After the vesicle ruptures, the remaining ulcer becomes covered N. meningitidis with a characteristic black eschar → A significant cause of bacterial meningitis ▪ Common among adolescents and young adults N. gonorrhoeae → An important cause of sexually transmitted infection (STI) → In men: urethritis → In women: usually asymptomatic >> untreated >> may lead to pelvic inflammatory disease, which can cause infertility or ectopic pregnancy → Like N. meningitidis, N. gonorrhoeae is much more likely to become disseminated in people who lack the complement proteins that form the membrane attack complex Figure 22. Cutaneous Anthrax. Retrieved from Dr. Gomez’s PPT (2024) Inhalational anthrax → Occurs when airborne spores are inhaled → The spores are carried by phagocytes to lymph nodes where they germinate, producing bacilli that release toxins that cause hemorrhagic mediastinitis → Rapidly leads to shock and frequently death within 1 to 2 days Gastrointestinal anthrax → Usually contracted by eating undercooked meat contaminated with B. anthracis → Mortality is approximately 40% Pathogenesis B. anthracis produces potent toxins and an antiphagocytic Figure 25. Neisseria spp. in blood smear and gram stain. polyglutamyl capsule Retrieved from Dr. Gomez’s PPT (2024) Toxins → 2 A subunits: edema factor (EF), lethal factor (LF) Pertussis → 1 B subunit: protective antigen (PA) Also called Whooping cough PA binds to a cell surface >> A host protease removes a fragment of Caused by the gram-negative coccobacillus Bordetella pertussis the PA >> The remaining fragment self-associates to form a An acute, highly communicable illness heptamer >> 1-3 molecules of the EF/LF bind to a PA heptamer >> Characterized by paroxysms of violent coughing followed by a loud Complex is endocytosed into the host cell inspiratory "whoop" as the patient gasps for air PA is not toxic, but it serves to deliver the toxic EF and LF into cells → Infants < 1 year of age are at highest risk of death EF: ↑ cAMP → Children with pertussis can have coughing spells for up to 10 LF: destroys mitogen-activated protein kinase kinases (MAPKKs) weeks Pathogenesis B. pertussis → Colonizes the brush border of the bronchial epithelium → Invades macrophages → Contains a filamentous hemagglutinin that binds to carbohydrates on the surface of respiratory epithelial cells, as well as to CR3 (Mac-1) integrins on macrophages → Virulence factors of B. pertussis include pertussis toxin, adenylate cyclase toxin, dermonecrotic toxin, and tracheal cytotoxin ▪ Adenylate cyclase toxin enters host cells and converts ATP to supraphysiologic levels of cAMP ▪ Rise in cAMP inhibits the following: − Phagocytosis − Oxidative burst − Nitric oxide-mediated killing in neutrophils and macrophages − Formation of neutrophil extracellular traps Morphology Bordetella spp. cause a laryngotracheobronchitis that in severe cases features bronchial mucosal erosion, hyperemia, and copious Figure 23. Mechanism of anthrax toxins. Note that each cluster of B mucopurulent exudate subunits binds either the edema factor or the lethal factor, but not both (as Lymphocytosis is a common systemic laboratory feature in infants shown for simplicity). Retrieved from Robbins and Cotran (2024). with pertussis and is caused by the pertussis toxin Morphology → Pertussis causes an initial increased mobilization of lymphocytes → Anthrax lesions at any site are typified by necrosis and exudative from the lymphoid organs and then the lymphocytosis is inflammation rich in neutrophils and macrophages sustained by an inhibition of recirculation from blood to lymph → Presence of large, boxcar-shaped gram-positive extracellular → Increased lymphocytosis is associated with pulmonary bacteria in chains, hypertension, pneumonia, and death ▪ Seen using the Brown and Brenn stain or grown in culture → Small mature lymphocytes with deep nuclear clefts can → Inhalational anthrax causes: occasionally be observed in a peripheral smear as shown, and ▪ Numerous foci of hemorrhage in the mediastinum might serve as a diagnostic clue ▪ Hemorrhagic lymphadenitis of hilar & peribronchial lymph nodes In parallel with a striking peripheral lymphocytosis (up to 90%), there → Lymph nodes are expanded by edema and by macrophages is hypercellularity and enlargement of the mucosal lymph follicles containing phagocytosed apoptotic lymphocytes and peribronchial lymph nodes CM 109 Infectious Diseases 10 of 18  Tuberculosis Pathogenesis Infection by M. tuberculosis proceeds in steps, from initial infection of macrophages to a subsequent Th1 response that both contains the bacteria and causes tissue damage Entry into macrophages: M. tuberculosis enters macrophages by phagocytosis mediated by several receptors expressed on the phagocyte, including mannose-binding lectin and the type 3 complement receptor (CR3) Replication in macrophages: M. tuberculosis inhibits maturation of Figure 26. Bordetella spp. in infected individual and blood smear. the phagosome and blocks formation of the phagolysosome, Retrieved from Dr. Gomez’s PPT (2024) allowing the bacterium to replicate unchecked within the vesicle, protected from the microbicidal mechanisms of lysosomes Note: Information was directly taken from Dr. Gomez’s PPT (2024). → The bacterium blocks phagolysosome formation by recruiting a Whooping cough showing a haze of bacilli (arrows) entangled with host protein called coronin to the membrane of the phagosome the cells of bronchial epithelial cells ▪ Coronin activates the phosphatase calcineurin >> inhibition of The inset highlights the haze of bacilli by immunohistochemistry phagosome-lysosome fusion using a monoclonal antibody reactive to the lipo-oligosaccharide A → During the earliest stage of primary tuberculosis (> IFN-γ functions to mobilize an effective host → Occurs when organisms draining through lymphatics enter the