Chapter 19 Upper Respiratory Tract Infections and select toxins from ch. 20 LRTI

Question 1

What does heterophile positive mean, and which upper respiratory tract-infecting virus expresses this quality?

Answer 1

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)

Question 2

What cancers are associated with EBV?

Answer 2

• Burkitt’s lymphoma
• B cell lymphomas
• nasopharyngeal carcinoma

Question 3

What is the pathogenesis of EBV?

Answer 3

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

Question 4

What are the four key categories of symptoms of EBV?

Answer 4

1. central: fatigue, malaise, loss of appetite, headache
2. tonsils: red, swollen, white patches
3. swollen lymph nodes
4. hepatosplenomegaly due to excessive B cell proliferation

Question 5

What would the physical exam (ENT) of someone with infectious mononucleosis caused by EBV look like?

Answer 5

The tonsils and uvula are swollen and covered in white exudate. There are petechiae on the soft palate.

Question 6

What are the cytopathic effects of cytomegalovirus (CMV)?

Answer 6

“huge cells” with nuclei containing inclusion bodies, masses of viral proteins and nuclear capsids

Question 7

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?

Answer 7

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)

Question 8

What causes “heterophile-negative” infectious mononucleosis?

Answer 8

cytomegalovirus

Question 9

What are the main symptoms of CMV, and how do they compare to those of EBV?

Answer 9

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

Question 10

Which group of S. pyogenes was pointed out as an important human pathogen and what diseases can it cause?

Answer 10

Group A Streptococci (beta-hemolytic)
can cause pharyngitis, scarlet fever, toxic shock, acute rheumatic fever, glomerulonephritis, impetigo, cellulitis, necrotizing fasciitis

Question 11

Describe the different hemolytic classifications of Streptococci and the principle behind this bacterial test.

Answer 11

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

Question 12

How does molecular mimicry play a role in GAS autoimmunity?

Answer 12

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

Question 13

Describe the two types of infections caused by GAS.

Answer 13

Suppurative infections – direct damage by the organism and secreted enzymes
Non-suppurative infections – late manifestations caused by autoimmune response

Question 14

How does Streptococcus pyogenes spread and multiply at the onset of infection, and later in prolonged infection?

Answer 14

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

Question 15

Describe the structure of rhinovirus

Answer 15

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

Question 16

Compare enveloped and non-enveloped viruses

Answer 16

Non-enveloped viruses can survive in the environment for relatively long period of time, whereas an enveloped virus would succumb to dehydration.

Question 17

How is rhinovirus transmitted?

Answer 17

respiratory droplets

Question 18

How does the optimum growing condition of rhinovirus affect its infectivity?

Answer 18

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

Question 19

Describe the epidemiology of rhinovirus

Answer 19

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

Question 20

How does HRV increase susceptibility to bacterial infections and other complications?

Answer 20

(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

Question 21

What is the treatment, prevention, and control of rhinovirus?

Answer 21

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

Question 22

Which species, genus and family of viruses does coxsackievirus belong to?

Answer 22

Species: Human enterovirus (A, B, C, D)
Genus: Enterovirus
Family: picornaviridae

Question 23

Describe the diseases associated with coxsackie virus.

Answer 23

-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)

Question 24

Describe the structure of the Human Herpes Virus family.

Answer 24

-large genome, linear dsDNA, enveloped viruses, icosahedral capsid, tegument “matrix”

Question 25

What is tegument?

Answer 25

= viral “matrix” – space between nucleocapsid & envelope, contains proteins & enzymes for viral DNA replication after infection

Question 26

Describe the replication qualities of the Human Herpes Virus family.

Answer 26

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

Question 27

What kind of infections do members of the Human Herpes Virus cause?

Answer 27

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.

Question 28

What are the steps of viral infection of a cell described for Herpes Family replication?

Answer 28

1. attachment 2. penetration 3. uncoating 4. synthesis 5. assembly 6. release

Question 29

What kind of latency do HSV-1, -2, and VZV have, and where does this mean that site of latency is?

Answer 29

Neurotropic, latent in neurons (HSV-1 in trigeminal ganglia, HSV-2 in lumbar or sacral ganglia, and VZV or cranial or thoracic ganglia)

Question 30

What kind of latency does cytomegalovirus have, and where does this mean that site of latency is?

Answer 30

lymphotropic, latent in monocytes, (myeloid stem cells) and T cells

Question 31

What kind of latency does Epstein-Barr virus have, and where does this mean that site of latency is?

Answer 31

lymphotropic, latent in B cells

Question 32

What causes the re-activation of a latent Hepres Family virus?

Answer 32

stress signal and lower T cell activity

Question 33

What is the incubation period and duration of EBV?

Answer 33

symptoms appear ~14-60 days after contracting and remain ~30-60 days

Question 34

What type of reaction may be seen in an EBV-infected individual if she is prescribed ampicillin for sore throat?

Answer 34

(transient) erythematous rash, type II reaction

Question 35

What is the treatment for EBV infection?

Answer 35

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.

Question 36

How is CMV treated and controlled?

Answer 36

``` 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)

Question 37

How are Streptococci classified?

Answer 37

1. Serological - Lancefield Classification - into serogroups using antibodies to group specific cell wall carbohydrates/CAPSULE ANTIGENS 2. Hemolysis patterns - (in blood agar) – alpha, beta and gamma 3. Clinical – pyogenic, oral, skin, [enteric – Enterococcus] - Catalase negative (as opposed to Staphylococci) - Facultative anaerobes - Complex nutritional requirements (blood or serum enriched medium)

Question 38

What are the virulence factors of Streptococcus pyogenes (GAS)?

Answer 38

-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

Question 39

What causes scarlet fever?

Answer 39

complication og pharyngitis due to streptococcal pyrogenic toxin (SPEs)- superantigen

Question 40

Describe the structure of the mumps virus

Answer 40

Paramyxoviridae structure: - enveloped virus with negative-sense, ssRNA in a helical nucleocapsid - single HN glycoprotein and F (fusion) protein - only one serotype

Question 41

How come mumps and measles are contracted only once in a lifetime?

Answer 41

only one serotype

Question 42

Describe the replication of single stranded negative-sense RNA genomes

Answer 42

``` 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 ```

Question 43

What are the symptoms of mumps infections?

Answer 43

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%)

Question 44

What is the treatment for mumps?

Answer 44

MMR live attenuated vaccine is the only means of prevention | -no antivirals

Question 45

What is the structure of Haemophilus influenzae?

Answer 45

Gram-negative, coccobacilli (pleiomorphic)

Question 46

What are the virulence factors of Haemophilus influenzae?

Answer 46

IgA protease Hib capsule LOS mediate symptoms, antigenic variation of LOS residues

Question 47

What are the types of H. influenzae and what diseases do they cause?

Answer 47

1. Capsulated: Serotyped into 6 different types (a-f) based on their biochemically different capsules - Hib->Bacteria, meningitis (<5yo), epiglottitis 2. Non-capsulated H. influenzae or non-typeable H. influenzae (NTHi), no serotype. - pneumonia-> elderly with underlying COPD

Question 48

What part of Hib is a target for vaccines and why?

Answer 48

Polyribsoylribitol phosphate (PRP) capsule is the major virulence vaccine of Hib, sugar residues on capsule induces T-independent response

Question 49

What is the pathogenesis of Haemophilus?

Answer 49

1. Attach with adhesins 2. IgA protease facilitates colonization (Hib and NTHi) 3. Form biofilm 4. Change surface molecules in response to oxygen levels 5. Avoid phagocytosis due to capsule PRP (Hib) - Avoid Macrophage killing 6. Extensive superoxide and NO detoxification mechanisms impaired ciliary function -> damaged respiratory epithelium (LOS-induced tissue destruction)

Question 50

What is the growth form(s) of Candida?

Answer 50

dimorphic: 1. filamentous: grows as multinucleate, branching hyphae, forming mycelium (infectious form- can punch through tissues) 2. yeast: grows as ovoid or spherical single cells that mutiply by budding and division

Question 51

How is a Candida infection fought off, and what predisposes one to such an infection?

Answer 51

T-cell mediated immunity is important for skin and mucosal resistance - infection associated with: - diabetes - T cell deficiency - neutropenia

Question 52

What is the clinical presentation of chronic mucocutaneous candidiasis and how is is treated?

Answer 52

onychomycosis and oral thrush treated with amphotericin B and fluconazole

Question 53

What is structure of Viridans Streptococci such as Streptococcus mutans?

Answer 53

Gram-positive cocci in chains, alpha-hemolytic

Question 54

What diseases do Viridans Streptocci cause, and how?

Answer 54

-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)

Question 55

What is the pathogenesis of Anctinomycosis?

Answer 55

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