Influenza Virus Lecture Notes

Classification and Introduction to Influenza Viruses

Differentiation Based on Internal Proteins: Influenza viruses are categorized into types based on their internal proteins, specifically the nucleoprotein (N) and matrix proteins (M). * Influenza A: Found in many species. Responsible for seasonal epidemics and global pandemics. * Influenza B: Found primarily in humans. Responsible for seasonal epidemics. * Influenza C: Causes relatively mild respiratory illness and is generally not considered a significant medical concern.

Comparative Clinical Features: Flu vs. Common Cold

General Comparison: Influenza (Flu) is frequently confused with the common cold; however, flu symptoms typically manifest more rapidly and are significantly more severe.
Infection Process: * 1. An infected individual coughs or sneezes, releasing microscopic droplets containing the virus into the air. * 2. The virus enters the respiratory tract of a new host. * 3. The virus binds to host cells and releases its genetic information. * 4. As the virus begins to replicate, the respiratory tract becomes swollen and inflamed. Symptoms emerge as the virus potentially moves into the bloodstream.
Symptom Differentiation: * Onset: Cold onset is slow; Flu onset is sudden. * Body Temperature: Cold involves low or no fever and no chills; Flu involves high fever (exceeding $102^{\circ}\text{F}$ ) and chills. * Headache: Rare in colds; characteristic and achy in the flu. * Muscles: Fine in colds; achy in the flu. * Fatigue: Mild in colds; severe in the flu, potentially lasting $2$ to $3$ weeks. * Nose: Runny and sneezing are common in colds; stuffiness occurs only sometimes in the flu. * Throat: Characteristically sore in colds; sore only sometimes in the flu. * Chest/Respiratory: Colds involve mild to hacking coughs; Flu involves dry coughs that can become severe. * Appetite: Normal in colds; decreased in the flu.

Structural Composition of the Influenza Virus

Key Components: * Helical Nucleocapsid: Composed of RNA plus the NP protein (nucleoprotein). * Polymerase Complex: Essential for viral replication. * Lipid Bilayer Membrane: The outer envelope of the virus. * M1 Protein: Located just beneath the lipid bilayer.
Surface Antigens: * HA (Hemagglutinin): Involved in cell attachment and entry. * NA (Neuraminidase): An enzyme involved in the release of new viral particles from infected cells.
Sub-typing: While Type A, B, and C are determined by NP and M1 proteins, specific sub-types (e.g., H1N1) are determined by the HA and NA surface proteins.

Viral Replication Cycle

Step-by-Step Mechanism: * Adherence: Viral HA protein binds to host cell receptors. * Entry: The virus enters via a coated vesicle and moves into an endosome. * Uncoating: The viral envelope and capsid are removed, releasing genetic material. * Replication, Transcription, & Translation: * Viral RNA moves into the nucleus of the host cell. * mRNA is synthesized and translated by host machinery. * Synthesis of internal proteins (NP, NS1) and envelope proteins (HA, NA) occurs. * Envelope proteins are processed through the Endoplasmic Reticulum and Golgi apparatus. * Assembly and Packaging: New viral components are organized at the host cell membrane. * Maturation and Budding: The virus matures and buds from the host cell membrane. * Release: Viral neuraminidase (NA) facilitates the release of the newly formed virus from the infected cell.

Modes of Transmission

Human-to-Human: Occurs via air droplets or by touching contaminated surfaces/areas (hands).
Cross-Species Transmission: * Humans can transmit to or receive from other humans. * Transmission can occur between Birds and Pigs. * Transmission can occur between Pigs and Humans. * Direct transmission from Birds to Humans has been documented.

Pathogenesis and Viral Evasion

Step 1: Adherence and Invasion: * The Viral HA protein is mandatory for cell attachment. * To successfully invade cells, the HA protein must be cleaved by human proteases. * Avirulent/Mild Strains: HA is cleaved only by proteases found in the throat and lungs, restricting the infection to those areas. * Highly Virulent Strains (e.g., H5N1): HA can be cleaved by a wide variety of proteases throughout the body, allowing the virus to spread systemically.
Disease Progression: * Aerosol inoculation leads to replication in the respiratory tract. * This causes desquamation of mucus-secreting and ciliated cells. * The resulting "Influenza syndrome" involves interferon induction and T-cell responses. * Potential outcomes include Primary viral pneumonia or secondary bacterial infections leading to pneumonia.
Step 2: Evasion Mechanisms: * Antigenic Drift: Minor changes or point mutations in the viral RNA. Because RNA polymerase/transcriptase lacks proof-reading capabilities, mutations accumulate, leading to small changes in surface antigens. * Antigenic Shift: Major changes in viral surface antigens. This occurs through major mutations or "genetic reassortment" when two different viruses infect the same host cell and reassemble. This often leads to new viral subtypes and potential pandemics. * Mixing Vessel: An animal (usually a pig) concurrently infected with human and animal flu viruses, allowing for genetic exchange.

Clinical Symptoms and Complications

Adult Symptoms: Rapid onset of fever, malaise, myalgias, sore throat, and a nonproductive (dry) cough.
Child Symptoms: Similar to adults but with higher fever, gastrointestinal symptoms (abdominal pain, vomiting), otitis media, myositis, and more frequent croup.
Major Complications: * Respiratory: Primary viral pneumonia and secondary bacterial pneumonia. * Systemic: Myositis and cardiac involvement. * Neurologic Syndromes: Guillain-Barr syndrome, Encephalopathy, Encephalitis, and Reye's syndrome.

Laboratory Diagnosis, Treatment, and Prevention

Laboratory Diagnosis: Utilizes Molecular methods and Serology.
Treatment and Control Modes: * Self-recovery (rest and fluids). * Good hygiene practices. * Anti-viral Drugs: * Influenza A only (prevent uncoating): Amantadine (Symmetrel) and Rimantadine (Flumadine). * Influenza A & B (prevent NA activity): Zanamivir (Relenza) and Oseltamivir (Tamiflu).
Prevention (Vaccines): * Vaccines contain predicted yearly strains of Influenza A and B. * Killed/Inactivated Vaccines: Administered via injection into the upper arm. * Live Attenuated Vaccines: Administered via nasal spray. * Effectiveness: Vaccines take approximately $14$ days to become effective. Failure to prevent illness may result from being infected by a different strain or being exposed before the $14$ -day window.

H5N1 (Avian Influenza)

Nature: Known as "Bird Flu." Shorebirds are natural carriers in the wild.
Transmission Cycle: * Natural Cycle: Waterfowl are infected via shared water sources; shorebirds carry it. * Pandemic Cycle: Domestic birds act as intermediate hosts, infected through nasal or fecal contact. Hogs can also be infected by both human and avian strains, increasing mutation risks. * Human Risk: Humans are rarely infected by unaltered strains, but mutated forms pose a realistic risk of a pandemic through human-to-human spread.
Historical Major Pandemics: * Spanish Flu ( $1918$ ): H1N1 strain; killed over $50$ million people worldwide (approx. $500,000$ in the USA). * Asian Flu ( $1957$ ): H2N2 strain; approx. $70,000$ deaths in the USA. * Hong Kong Flu ( $1968$ ): H3N2 strain; approx. $34,000$ deaths in the USA.

H1N1 (Swine Flu) and the 2009 Pandemic

Definitions: Not all H1N1 viruses are "swine flu"; some seasonal strains are H1N1. Swine flu refers specifically to strains evolved from viruses that caused flu in pigs.
Novel H1N1: Labeled "novel" because it was a completely new strain never before seen. It is a reassortment of four strains: one human, one avian, and two swine.
The 2009 Outbreak: * Officially declared a pandemic by the WHO on June 11, 2009 (the first of the $21^{st}$ century). * Reported in $74$ countries with over $182,166$ cases and $1,799$ deaths.
Genetics: Six genes from North American viruses (triple mixture of human, pig, avian) and two genes from Eurasian swine viruses. Human immunity is limited due to this unique mixture.
Vaccination (2009 Monovalent): * Recommended as a single dose for people $6$ months and older. * Pandemic H1N1 vaccines do not protect against seasonal flu.