Chapter 19 Upper Respiratory Tract Infections and select toxins from ch. 20 LRTI Flashcards
What does heterophile positive mean, and which upper respiratory tract-infecting virus expresses this quality?
EBV activates B cells, causing secretion of a “heterophile” antibody, which recognizes non-specific antigens across species. If heterophile Ab is present, the agglutination will occur when patient serum is mixed with horse RBC (in Monospot test)
What cancers are associated with EBV?
- Burkitt’s lymphoma
- B cell lymphomas
- nasopharyngeal carcinoma
What is the pathogenesis of EBV?
Symptoms result from
infection of lymphocytes, inappropriate immune response
“War between T cells and B cells”- increased EBV-specific CD8+ CTLs and increased EBV-transformed B cells
Lymphocytosis and malaise are due to T-cell activation and proliferation, which have an atypical appearance
-Downey cells = 70% of WBC, Amount of cytoplasm increases greatly
What are the four key categories of symptoms of EBV?
- central: fatigue, malaise, loss of appetite, headache
- tonsils: red, swollen, white patches
- swollen lymph nodes
- hepatosplenomegaly due to excessive B cell proliferation
What would the physical exam (ENT) of someone with infectious mononucleosis caused by EBV look like?
The tonsils and uvula are swollen and covered in white exudate. There are petechiae on the soft palate.
What are the cytopathic effects of cytomegalovirus (CMV)?
“huge cells” with nuclei containing inclusion bodies, masses of viral proteins and nuclear capsids
What is the epidemiology of CMV? How much of the population is seropositive? What is the form of transmission? What are the triggers for re-activation?
Sero-positive Population
~35% children
~50% adult (latent carriers, 80% for ethnic minorities)
Transmission
CMV may be acquired from blood, tissue, and most body secretions
Neonate
Transplacental transmission, intrauterine infections, cervical secretions
Baby or Child
Body secretions: breast milk, saliva, tears, urine
Adult
Sexual transmission (semen), blood transfusion, organ graft
Triggers for re-activation:
Immunocompromised (AIDS, transplantation) – CMV is an opportunistic pathogen in immunocompromised patients
Pregnancy
Immunosuppressive drug therapies (anti-TNF, steroids)
What causes “heterophile-negative” infectious mononucleosis?
cytomegalovirus
What are the main symptoms of CMV, and how do they compare to those of EBV?
central: fatigue, malaise, loss of appetite, headache
tonsils: red, swollen, white patches; less prominent cervical lymphadenopathy than EBV, but otherwise indistiguishable
spleen: enlarged, abdominal pain, hepatosplenomegaly due to excessive monocyte proliferation
Which group of S. pyogenes was pointed out as an important human pathogen and what diseases can it cause?
Group A Streptococci (beta-hemolytic)
can cause pharyngitis, scarlet fever, toxic shock, acute rheumatic fever, glomerulonephritis, impetigo, cellulitis, necrotizing fasciitis
Describe the different hemolytic classifications of Streptococci and the principle behind this bacterial test.
Bacteria are cultured on blood agar, which they lyse because they require iron in the Fe(II) state like RBCs. They are classified based on the color of the agar after the hemolysis.
- alpha-hemolytic: green, partial hemolyis
- beta-hemolytic: clear, complete hemolysis
- gamma-hemolytic: stays red, no hemolysis
How does molecular mimicry play a role in GAS autoimmunity?
M protein resembles proteins of the heart and kidney, cross-reacts with self-tissues, causing Type II HSR.
- > acute rheumatic fever (carditis, chorea, polyarthritis, subcutaneous nodules, erythema marginatum)
- > acute post-streptococcal glomerulonephritis
Describe the two types of infections caused by GAS.
Suppurative infections – direct damage by the organism and secreted enzymes
Non-suppurative infections – late manifestations caused by autoimmune response
How does Streptococcus pyogenes spread and multiply at the onset of infection, and later in prolonged infection?
At the onset of infection, M protein prevents phagocytosis & Complement activation
Forms a dense fibrillar barrier on the bacterial surface
Binds to fibrinogen
Binds to Factor H, interfering with C3b deposition
Later in prolonged infection, M protein-specific antibodies promote opsonization and protect against subsequent infection
BUT, with > 100 M protein antigens/strains, protective immunity is limited to only those GAS strains that have been seen already
Describe the structure of rhinovirus
small, non-enveloped, icosahedral virus with positive sense ssRNA
Belongs to enterovirus family
Unlike other enteroviruses, rhinoviruses are unable to replicate in the GI tract
Acid labile
> 100 serotypes and antigenic drift occurs - the reason we cannot make vaccines
Viruses change amino acid sequences on outside surface, continually changing, difficult to immunize against
Major receptor – ICAM-1
Compare enveloped and non-enveloped viruses
Non-enveloped viruses can survive in the environment for relatively long period of time, whereas an enveloped virus would succumb to dehydration.
How is rhinovirus transmitted?
respiratory droplets
How does the optimum growing condition of rhinovirus affect its infectivity?
Grow best at 33C, cooler environment of nasal mucosa
-have failed to adapt/replicate efficient within normal body temp of 37C, keeps them from spreading to other parts of the body
Describe the epidemiology of rhinovirus
Responsible for ½ of URT infections
Common cold is not a serious disease
Highly infectious- One virion can initiate the infection
Transmitted by
Aerosols – direct person to person contact
Fomites (hands or contaminated inanimate objects) table tops in offices-
“Hand to Nose transmission”
-Many different serotypes during a specific cold season so one person may have back-to-back cold due to back-to-back infections
-Antigenic drift - development of new strains
How does HRV increase susceptibility to bacterial infections and other complications?
(1) HRVs disrupt epithelial cell barrier function by the dissociation of zona occludens 1 (ZO-1) from the tight junction complex via the increased generation of reactive oxygen species (ROS), thereby facilitating the transmigration of bacteria (28). (2) HRVs promote Staphylococcus aureus internalization into non-fully permissive cultured pneumocytes via the increased release of IL-6 and IL-8 and expression of intercellular adhesion molecule 1 (ICAM-1) on neighboring uninfected cells (175). (3) HRVs stimulate Streptococcus pneumoniae adhesion to human tracheal epithelial cells by inducing the surface expression of platelet-activating factor receptor (PAFR) via NF-κβ expression (173) and to nasal epithelial cells via increased gene and protein expression levels of fibronectin, PAFR, and carcinoembryonic antigen-related cell adhesion molecule. (4) Compared to non-HRV-activated macrophages, HRV-activated macrophages demonstrate reduced levels of secretion of TNF-α and IL-8 when exposed to bacterial Toll-like receptors (TLRs) (lipopolysaccharide and lipoteichoic acid) (176). SP-1, promoter-specific transcription factor 1.
secondary complications: -sinusitis and otitis media (bacterial infections)
- LRTI
- asthma exacerbation
What is the treatment, prevention, and control of rhinovirus?
No effective antivirals
Treatments for symptoms
Saline nasal spray
Antipyretics
Decongestants
Interferons – limit progression of disease, but not for long term use (if immunocompromised, not common)
Handwashing and disinfection are best to interrupt spread
Which species, genus and family of viruses does coxsackievirus belong to?
Species: Human enterovirus (A, B, C, D)
Genus: Enterovirus
Family: picornaviridae
Describe the diseases associated with coxsackie virus.
-Herpangina (associated with Coxackie A)
Common childhood illness
Small, blister-like ulcers on the roof of the mouth and in the back of the throat
May also cause a sudden fever, sore throat, headache, neck pain, pain on swallowing, anorexia, vomiting
-Hand, Foot-and-Mouth Disease: Fever, lesion on mouth and tongue FIRST.
Then appears on the hands & feet 1-2 days later
-Acute hemorrhagic conjunctivitis- an extremely contagious ocular disease
(pain, edema, photophobia, foreign body sensation, fever, malaise, headache)
Describe the structure of the Human Herpes Virus family.
-large genome, linear dsDNA, enveloped viruses, icosahedral capsid, tegument “matrix”
What is tegument?
= viral “matrix” – space between nucleocapsid & envelope, contains proteins & enzymes for viral DNA replication after infection
Describe the replication qualities of the Human Herpes Virus family.
HHV genome encodes viral DNA polymerase
Replication in nucleus
1. Virion assembly in nucleus, ER, and Golgi apparatus
Virus release through exocytosis or lysis
2. cell-to-cell release enables infections without exposing virus to extracellular environment
What kind of infections do members of the Human Herpes Virus cause?
Establish lytic, persistent, and latent infections
Entry of viral DNA results in :
Active infection targets one cell type. Lysis of infected cells and CMI (CD8+ and NK cells) to infected cells are responsible for symptoms.
Latent infection targets another cell type and is associated with asymptomatic carriage.
What are the steps of viral infection of a cell described for Herpes Family replication?
- attachment
- penetration
- uncoating
- synthesis
- assembly
- release
What kind of latency do HSV-1, -2, and VZV have, and where does this mean that site of latency is?
Neurotropic, latent in neurons (HSV-1 in trigeminal ganglia, HSV-2 in lumbar or sacral ganglia, and VZV or cranial or thoracic ganglia)
What kind of latency does cytomegalovirus have, and where does this mean that site of latency is?
lymphotropic, latent in monocytes, (myeloid stem cells) and T cells
What kind of latency does Epstein-Barr virus have, and where does this mean that site of latency is?
lymphotropic, latent in B cells
What causes the re-activation of a latent Hepres Family virus?
stress signal and lower T cell activity
What is the incubation period and duration of EBV?
symptoms appear ~14-60 days after contracting and remain ~30-60 days
What type of reaction may be seen in an EBV-infected individual if she is prescribed ampicillin for sore throat?
(transient) erythematous rash, type II reaction
What is the treatment for EBV infection?
EBV is treated with supportive care
Acyclovir: reduces tonsillar swelling but is not effective during EBV latency
The goal with these patients is to boost their immune system with EBV specific CTL cells.
How is CMV treated and controlled?
Prevention: -Safe sex -Screening of blood/organ donors and pregnant mothers Treatment: Immunoglobulin for pneumonia
If immunocompromised or BM or solid organ transplant pt: Ganciclovir (GCV*) or Valganciclovir (VGCV) (pro-drug, longer half-life)– synthetic analog of 2’-deoxyguanosine (relies on viral protein kinase UL97)
[NOT acyclovir, which relies on thymidine kinase for activation]
For both, activation based on viral protein (drug will not affect non-infected cell)
How are Streptococci classified?
- Serological - Lancefield Classification - into serogroups using antibodies to group specific cell wall carbohydrates/CAPSULE ANTIGENS
- Hemolysis patterns - (in blood agar) – alpha, beta and gamma
- Clinical – pyogenic, oral, skin, [enteric – Enterococcus]
- Catalase negative (as opposed to Staphylococci)
- Facultative anaerobes
- Complex nutritional requirements (blood or serum enriched medium)
What are the virulence factors of Streptococcus pyogenes (GAS)?
-surface structures:
Lipoteichoic acid (LTA): role in mucosal colonization through adhesion to tissue surfaces
Hyaluronic acid capsule
Degradative enzymes (hyaluronidase, streptokinase)
Facilitate invasion into tissues
Toxins (streptolysins S & O; pyrogenic exotoxins)
Avoidance of opsonization and phagocytosis
-Hyaluronic acid capsule – a poor immunogen and interferes with phagocytosis
-C5a peptidase (prevents early clearance from body)
M protein – hair-like projections on the cell wall
major virulence factor, type specific, binds to Factor H, an inhibitor of complement C3b activation, anti-phagocytic (binds to fibrinogen), forms dense fibrillar barrier on bacterial surface
What causes scarlet fever?
complication og pharyngitis due to streptococcal pyrogenic toxin (SPEs)- superantigen
Describe the structure of the mumps virus
Paramyxoviridae structure:
- enveloped virus with negative-sense, ssRNA in a helical nucleocapsid
- single HN glycoprotein and F (fusion) protein
- only one serotype
How come mumps and measles are contracted only once in a lifetime?
only one serotype
Describe the replication of single stranded negative-sense RNA genomes
The RNA polymerase is carried into the cell. Transcription, protein synthesis, and replication of the genome all occur in the host cell's cytoplasm. The genome is transcribed into individual messenger RNAs (mRNAs) and a full-length positive-sense RNA template. The mRNAs (individual) are then translated by the host cell protein synthesis machinery Positive sense (full length) RNA copy of the genome is used to make negative sense RNA genome
What are the symptoms of mumps infections?
Mumps infections are often asymptomatic.
Acute benign viral parotitis (painful swelling of the salivary glands).
Parotitis is almost always bilateral and accompanied by fever.
-Other glands can be infected
Orchitis – testicles (in rare cases, may cause sterility)
Pancreatitis & thyroiditis
Meningoencephalitis- rare though serious
Mumps virus involves the CNS in approximately 50% of patients; exhibit mild meningitis (10%)
What is the treatment for mumps?
MMR live attenuated vaccine is the only means of prevention
-no antivirals
What is the structure of Haemophilus influenzae?
Gram-negative, coccobacilli (pleiomorphic)
What are the virulence factors of Haemophilus influenzae?
IgA protease
Hib capsule
LOS mediate symptoms, antigenic variation of LOS residues
What are the types of H. influenzae and what diseases do they cause?
- Capsulated: Serotyped into 6 different types (a-f) based on their biochemically different capsules
- Hib->Bacteria, meningitis (<5yo), epiglottitis - Non-capsulated H. influenzae or non-typeable H. influenzae (NTHi), no serotype.
- pneumonia-> elderly with underlying COPD
What part of Hib is a target for vaccines and why?
Polyribsoylribitol phosphate (PRP) capsule is the major virulence vaccine of Hib, sugar residues on capsule induces T-independent response
What is the pathogenesis of Haemophilus?
- Attach with adhesins
- IgA protease facilitates colonization (Hib and NTHi)
- Form biofilm
- Change surface molecules in response to oxygen levels
- Avoid phagocytosis due to capsule PRP (Hib)
- Avoid Macrophage killing - Extensive superoxide and NO detoxification mechanisms
impaired ciliary function -> damaged respiratory epithelium (LOS-induced tissue destruction)
What is the growth form(s) of Candida?
dimorphic:
- filamentous: grows as multinucleate, branching hyphae, forming mycelium (infectious form- can punch through tissues)
- yeast: grows as ovoid or spherical single cells that mutiply by budding and division
How is a Candida infection fought off, and what predisposes one to such an infection?
T-cell mediated immunity is important for skin and mucosal resistance
- infection associated with:
- diabetes
- T cell deficiency
- neutropenia
What is the clinical presentation of chronic mucocutaneous candidiasis and how is is treated?
onychomycosis and oral thrush
treated with amphotericin B and fluconazole
What is structure of Viridans Streptococci such as Streptococcus mutans?
Gram-positive cocci in chains, alpha-hemolytic
What diseases do Viridans Streptocci cause, and how?
-Dental caries- S. mutans dextran-mediated adherence glue the oral flora onto teeth, forming plaque & causing dental caries
-Complication of dental procedure:
Native valve subacute bacterial endocarditis
Enter bloodstream following dental procedures (e.g., tooth extraction)
Preexisting valve abnormality; fibrin and platelets allow for bacterial adhesion
Malaise, fatigue, fever, murmur, anorexia, night sweats, weight loss etc.
(biofilm and plaque protect bacteria from environment)
What is the pathogenesis of Anctinomycosis?
Chronic granulomatous lesions that become suppurative & form abscesses
Low virulence potential - A break in the mucosal barrier is a pre-requisite for infection (OPPORTUNISTIC)
Resistance to ROS prevents killing by PMNs
Bacteria form anoxic abscess, which further protects replicating bacteria
