Common Viral Pathogens - Influenza

Question 1

Basic structures, important proteins and their roles in pathogenesis - influenza

Answer 1

RNA virus w/ segmented genome. Surrounded by lipid envelope w/ lining of matrix proteins on inner side.

Hemagglutinin (H) and Neuraminidase (N) glycoproteins -> surface proteins, combinations determine strains of flu.

3 types of virus:
Type A and B circulate in the population.
Type A cause epidemics and pandemics and infect both humans and other animals.
Type C fu is mild.

Question 2

Transmission and prevention of influenza

Answer 2

Transmitted primarily by respiratory route (droplet and small particle aerosols) or contact w/ contamination of hands of inanimate objects (fomites)

Incubation period 1-3 days

Question 3

Vaccine strategies - influenza

Answer 3

Seasonal influenza vaccine:

Inactivated Vaccine (IM-IV) intramuscular or intradermal. Trivalent or quadrivalent and killed, for ppl 6 months and older. (Quadrivalent is a second B-virus)

Live attenuated influenza vaccine (LAIV) -> delivered intranasally via small, needle free syringe that delivers mist into the nose. For ppl 2 yrs – 49 yrs. Only quadrivalent. Not for babies, not for pregnant/immunocompromised.

Both are reformulated annually to provide against anticipated strains for that year.

Two A trains and one B strain selected for the trivalent, and additional B selected for quadrivalent. (Based on what is circulating through Southern hemisphere at the time)

70-90% effective well-matched years.

Question 4

Signs and symptoms of the influenza

Answer 4

In babies, often septic-like. Apnea may occur, lethalgy, decreased eating and mottling.

In children and adolescents, its classic: high fever, chills, malaise, and other symptoms.

In adults u should just know.

Question 5

Treatment of influenza

Answer 5

1. ) Matrix protein inhibitors for subtype A viruses – Amantadine, Rimantadine (almost ALL A strains are resistant)
2. ) Neuroaminidase Inhibitors – effective for both subtypes A and B. Oseltamivir (Tamiflu) Zanamivir, Peramivir (only IV medication)

Subtypes that are resistant to amantadine/rimantidine are susceptible to oseltamivir and zanamivir. Also need to distinguish between pandemic swine flu and regular swine flu because regular swine flu is resistant to oseltamivir.

Question 6

Basic Structures, Important Proteins and Roles in pathogenesis of RSV

Answer 6

Paramyxoviridae family
Single stranded, non-segmented RNA virus

F protein: fusion of viral envelope to host cell, or infected cells to each other (syncytia)

G protein: initial binding of virus to host cells

Two subtypes, A and B.
A causes worse diseases generally, but they can circulate at the same time. Get drift over time like influenza.

Question 7

How does RSV cause disease?

Answer 7

Invades conjuctiva/ nasopharynx, replicates in nasopharynx/epithelium, spreads to lower respiratory tract through inhalation

3-5 days incubation time

Causes severe damage to epithelium and bronchiolar ciliary apparatus. Results in collection of fluid in the bronchioles and and alveoli.

Emphysema of the airway, constriction of bronchioles of smooth muscle. Hypoxia, hyper expansion by mucous plugging.

Question 8

Transmission and Prevention of RSV

Answer 8

Annual (winter and spring). Spreads by large droplets, lives on surfaces for 1 hour, 40-60% attack rate on children under 2.

Question 9

Vaccine strategies for RSV

Answer 9

Antibody/immune protection is incomplete for infection (so there are reoccurent infections) but previous infection may prevent more severe disease.

RSV immunoprophylaxis with Palivizumab – human pooled antibody w/ high RSV titers, shown to decrease in disease severity of hospitalization. Once monthly IM injection during RSV season for high risk children.

Tried a formalin-inactivated RSV vaccine in 1960s but it did not protect and caused worse disease. ☹

Question 10

Signs and Symptoms of RSV

Answer 10

Clinical Features: respiratory distress, wheeze/rhonchi, hypoxia, copious secretions: Bronchiolitis

Question 11

Basic structures, important proteins, and roles in pathogenesis of ebola

Answer 11

Enveloped, (-) strand RNA, replicated in the cytoplasm

7 structural proteins and 2 non-structural proteins.

Virions are polyploidy – multiple genomes strung together (filamentous shape)

Structures: Viral membrane, RNA, Glycoprotein (also in secreted form, attachment/entry. IMPORTANT FOR PATHOGENICITY)

Matrix Proteins VP40 and VP24.

VP40 – main part of virion, structure, stability and assembly, budding.
VP24 – assembly, budding, nucleocapsid assembly, immune defense.

VP30 and nucleoproteins – forn nucleocapsid

Polymerase complex (VP35 and L) – function in replication RNA dependent RNA polymerase.

Question 12

How does ebola cause disease?

Answer 12

Enters body through mucosal surfaces or cuts to the skin
Only needs a few virions for infection
Ebola initially enters phagocytic cells, sends signals for more cells to come, infects THOSE cells, and spreads effectively when cells go to lymph noes.

Replicates very efficiently, induces massive cytokine storm, induce DIC, can infect many other cells/organs such as endothelial cells, liver spleen, and lungs.

When infects paranchymal cells, get significant cell destruction/necrosis.

W/ infection of endothelial cells, get leakage of fluids, severe fluid loss, hypovolemic shock, organ failure.

PEOPLE DIE FROM HYPOVOLEMIA and/or ORGAN FAILURE!

Question 13

Transmission and prevention of ebola

Answer 13

Infection outbreak is result from spillover events from animal reservoirs w/ human to human transmission. Often in bats, monkeys, dear, sometimes humans. Reservoir is the fruit bat.

Immunity: after infected, believed that they are protected from future infections. Antibody response to surface glycoprotein is associated w/ better survival.

Question 14

Signs and symptoms of Ebola

Answer 14

Symptoms of Ebola are non-specific – GI, fever, fatigue/weakness; very similar to other illness which are common (malaria, typhoid, dysentery)

People develop significant 3rd spacing, loose a lot of fluids through capillary leak, vomiting and diarrhea (can loose 5-10 liters/day)

Question 15

Treatment of ebola

Answer 15

Management is symptomatic – no actual treatments.

Can be found in many body flue and lasts longer than symptoms. Older age= worse outcome.

Treatments:
Antibodies from Ebola survivals -> ? does this work?

Vaccines – in phase I/II of study.

Drugs: Favipiravir and brincidofovir – both under investigation -> Zmapp – given to several US patients – monoclonal antibody against 3 targets on the GP

Question 16

How does ebola evade the human immune system?

Answer 16

Glycoprotein on surface masks antibody binding sites, parts exposed to immune system against which we make antibodies are highly variable/dispensable

Physically blocks the MHC to block triggering immune system

Glycoprotein (secreted) – act as decoys, antibodies aren’t good at neutralizing the virus.

V35 and VP24 – interfere w/ cell’s interferon production. Immune system becomes dysregulated bc overwhelmed.

Question 17

Antigenic drift (flu)

Answer 17

Antigenic drift refers to a gradual change in the virus that occurs through a slow series of mutations, substitutions of deletions in amino acids constituting the hemagglutinin or neuraminidase surface antigens. This occurs only after a viral strain has become established in humans, this is an adaptation to the development of host antibodies. New strains prevail for 2 to 5 years and are then replaced. Ongoing antigenic drift causes ongoing reformulation off influenza vaccine.

Question 18

Antigenic shift (flu)

Answer 18

Antigenic shift occurs when type A influenza with a COMPLETELY NOVEL hemagluttinin or neuraminidase is introduced into humans. The new gene segment usually acquired from other host species like bird or swine. Then, gene reassortment can occur when two or more influenza viruses infect a single human or animal. (since it has segmented genome, some segments can swap…) Less common than antigenic drift but MUCH MORE DRAMATIC OUTCOME.

Question 19

H1N1 -> what happened there?

Answer 19

Swine flu – reasserts in swine and then infects humans.
Recent pandemic was swine flu -> H1N1 strain.

Preferentially infects the lower respiratory tract.

FLAARDS (involved multi-organ failure) -> didn’t infect older people because a flu of the 1970’s got some memory T-cells.

Question 20

H5N1 -> what happened there?

Answer 20

Bird flu – avian influenza. Type A influenza virus, all 16 hemagglutinin and 9 neuraminidase types infect wild birds, but they are usually asymptomatic and have mild disease.

They fly! Domestic poultry have 2 types of disease – low pathogenic avian influenza and highly pathogenic avian influence (death like100%, current outbreak of H5N1)

Luckily this hasn’t been easily transmissible in humans but it did kill lots of livestock.

Question 21

Name the conditions that must be met for when an influenza pandemic is coming

Answer 21

1. ) Emergence of new influenza subtypes
2. ) Virus must infect humans and cause serious illness
3. ) Virus must have sustained human-to-human transmission and spread easily among humans.