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L11 I&I Viral respiratory pathogens

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tagsinfectionandimmunity, lecture
aliasesL11 I&I Viral respiratory pathogens

15 min read

Overview

This lecture surveys the viruses that cause human respiratory disease, why they remain so prevalent and keep generating new variants, and works through three case studies in depth: paramyxoviruses (particularly Respiratory Syncytial Virus and its link to childhood asthma), coronaviruses (from the mild common-cold strains through SARS, MERS and SARS-CoV-2), and influenza A (its structure, subtyping, and the two mechanisms, antigenic drift and antigenic shift, by which it changes). It closes with the clinical severity comparison between mild seasonal viruses and the novel, more dangerous ones, and with available vaccines and antivirals.

Respiratory Tract Anatomy and Symptoms

  • Respiratory disease arises from inflammation of the respiratory tract: nasal cavity, pharynx, larynx, trachea, bronchi, bronchioles, lungs (structures run top to bottom from nasal cavity to alveoli).
  • Upper respiratory tract structures (nasal cavity, pharynx, larynx, trachea) produce upper tract symptoms: stuffy/runny nose, sneezing, congestion from excess mucus production, dry or wet cough.
  • Lower respiratory tract structures (bronchi, bronchioles, lung) produce lower tract symptoms: chest cold (bronchitis), wheezing, pneumonia, Acute Respiratory Distress Syndrome (ARDS, breathing difficulty requiring oxygen support).
  • Infection with respiratory viruses causes many of these symptoms.

Classification of Human Respiratory Viruses

Six virus families cause human respiratory infection:

  • Adenoviruses (DNA genome), e.g. Type B, C and E
  • Coronaviruses, e.g. HCoV-229E, SARS 2.0
  • Orthomyxoviruses, e.g. Influenza virus A, B, and C
  • Paramyxoviruses, e.g. Parainfluenza virus, RSV
  • Picornaviruses, e.g. Rhinovirus
  • Parvovirus, e.g. Human Bocavirus

Why Respiratory Viruses Are So Prevalent and Continually Emerge

  • Viruses are part of the ecosystem: they infect multiple reservoir hosts (bats, birds) and clinical hosts (humans, other mammals such as dogs, cats, horses, seals).
  • Respiratory viruses are endemic in the human population and most active during winter.
  • Winter alternates between the Northern and Southern Hemisphere, which keeps respiratory viruses in circulation throughout the year and year after year.
  • Most respiratory viruses have an RNA genome; RNA polymerases lack proofreading capability, so RNA is prone to mutation, driving the emergence of new variants.
  • Vaccines and antiviral drugs have not been developed for all respiratory viruses, which should be a health priority.
  • The vaccines and antiviral drugs that do exist put selective pressure on viruses to continuously evolve, requiring constant research and development.

Paramyxoviruses and RSV

  • Paramyxoviruses have an RNA genome and cause common respiratory infections in infants and young children: parainfluenza virus, Respiratory Syncytial Virus (RSV), human metapneumovirus, mumps virus (swollen salivary glands), and measles virus (rashes on the body).
  • Vaccine available for mumps, measles, and RSV.
  • Particle structure: matrix protein (M) under a lipid bilayer; large RNA polymerase protein (L); phosphoprotein (P); nucleocapsid protein (NP); HN tetramer and F protein (trimer, with a fusion peptide) as surface proteins.
  • RSV specifically: major cause of lower respiratory tract infection in infants. By age 1, about 70% of infants have been infected; by age 2, almost all have. Symptoms range from common cold to bronchitis to pneumonia. Bronchitis is distinctly associated with RSV infection and increases the risk of wheezing and childhood asthma. RSV is a major cause of otitis media in infants (30-50%).
  • Two major antigenic types of RSV: A and B.
  • Two vaccines, Abrysvo and Arexvy, are available for adults aged 60 and over; no vaccine yet for children.
  • Passive immunization against RSV: maternal antibodies protect infants during the initial months of life; purified monoclonal antibodies (Synagis, Beyfortus) are also used. Otherwise, supportive care.
  • Histologically, RSV-infected respiratory epithelium shows syncytial cells (multinucleated giant cells), the feature the virus is named for.

RSV and the Development of Asthma

  • Asthma is a chronic condition of the bronchial airways that is easily inflamed by allergens; narrowing of the airways causes difficulty breathing, wheezing, and chest tightness. A normal bronchiole has an open lumen and thin lining, versus an asthmatic bronchiole with a narrowed lumen and thickened, inflamed lining.
  • RSV bronchitis causes airway inflammation, wheezing, and breathing difficulty, and can lead to the development of asthma later in life.
  • Retrospective and longitudinal studies (Wu and Hartert, 2011) indicate three contributing factors:
    1. Over-sensitization of the innate immune response to allergens
    2. Abnormalities in subsequent lung development and function
    3. Over-expression of nerve growth factors, leading to airway hyperactivity

Rhinoviruses

  • RNA genome.
  • The most commonly recovered infectious agent from people with mild upper respiratory tract illness; main cause of the common cold in humans.
  • Aggravate asthma.
  • More than 100 types known.
  • No vaccine available.

Coronaviruses Causing the Common Cold

  • RNA genome.
  • Cause 15-30% of all common colds in humans: HCoV-229E (1960), HCoV-OC43 (1960), HCoV-NL63 (2004), HCoV-HKU1 (2005).
  • No vaccine available for these.
  • Particle structure: M, N, E and S proteins around a single-stranded RNA (ssRNA) genome.

Genetic Recombination and the Emergence of Novel Coronaviruses

  • Genetic Recombination is the exchange of genetic material between two viral genomes. It occurs when two viruses infect the same host (e.g. a bat): the RNA polymerase switches template mid-replication (template switching), generating a recombinant genome that mixes material from both parent viruses.
  • SARS (Severe Acute Respiratory Syndrome): first discovered in 2003 in a 48-year-old man in Hanoi, who died from it. 8,096 cases and 774 deaths worldwide (Dec 2003, WHO). SARS “disappeared” and vaccine development stopped midway. It emerged in bats through genetic recombination between different coronaviruses, then passed bats to civets to humans.
  • SARS-CoV-2 (“SARS 2.0”): first discovered in 2019 in a 49-year-old woman and a 32-year-old and 61-year-old man. Causes Coronavirus Disease 2019 (COVID-19). Shares >85% genome identity with the 2003 SARS coronavirus; arose from a bat virus recombining with a pangolin virus before reaching humans. Pandemic with >770 million cases and >7 million deaths. At least 8 vaccines approved, with billions of doses administered.
  • MERS (Middle East Respiratory Syndrome): first identified in 2012 in a 60-year-old man in Saudi Arabia, who died from it. Also emerged in bats through genetic recombination between coronaviruses, passing bats to camels to humans. 2,494 cases across 27 countries, 858 deaths (Nov 2019, WHO). No vaccine yet.

COVID-19 Pathogenesis and Treatment

  • SARS-CoV-2 particles bind receptors on respiratory epithelial cells, triggering a Cytokine Storm: a surge of cytokines (including IL-10, IL-12, IL-6, IL-2, M-CSF, TNF-alpha, IP-10, MIP-1alpha, IL-13, IL-4, IL-1, VEGF, GM-CSF, IFN-gamma, G-CSF, MCP-1, IL-17) that radiates outward from the lungs.
  • This cytokine storm causes tissue damage in other organs, including the kidneys, heart, intestine, liver, blood vessels, and brain, producing severe COVID-19.
  • Anti-COVID-19 drugs:
    • Paxlovid: viral protease inhibitor, effective in reducing viral load
    • REGEN-COV: anti-Spike monoclonal antibodies, neutralize viral progeny
    • Remdesivir: nucleoside analogue, interferes with RNA replication, not very effective
    • Hydroxychloroquine: anti-malaria drug, no evidence of efficacy
    • Dexamethasone*: corticosteroid, reduces inflammation
    • Baricitinib*: rheumatoid arthritis drug, reduces inflammation
    • Tocilizumab*: anti-IL-6 monoclonal antibody, reduces inflammation
    • *approved only for hospitalized patients

Adenoviruses and Coxsackieviruses

  • Adenoviruses: DNA genome; about 49 antigenic types known to infect humans. In addition to the common cold, they cause gastrointestinal, urinary tract and eye infections, and an acute respiratory disease syndrome among young military recruits. A vaccine is available for the US military but not for the public.
  • Coxsackieviruses: RNA genome; two major groups, A and B. Cause herpangina, presenting as bumps or sores in the mouth. No vaccine available.

Influenza Virus: Types, Structure and Subtypes

  • Four influenza types: A, B, C, and D. Type A infects humans, other mammals, and birds. Types B and C infect humans; type D infects cattle and pigs.
  • Types A and B cause seasonal epidemics: annually billions of cases and about 650,000 deaths worldwide. In New Zealand, about 500 deaths and 800 hospitalizations occur annually. Type A has caused 4 pandemics (1918, 1957, 1968, 2009).
  • Transmission ecology: aquatic birds are the ultimate reservoir, transmitting to domestic poultry, pigs, horses, cattle, aquatic mammals, and humans.
  • Influenza A virus: RNA genome, segmented, negative-sense. Hemagglutinin (HA) and neuraminidase (NA) are the major antigens. Particle structure: HA and NA on the surface, M2 ion channel, M1 matrix protein under the lipid bilayer, NP (nucleocapsid protein), NEP, and the PB1/PB2/PA RNA polymerase complex bound to the segmented genome.
  • Influenza A is further subtyped by its HA and NA antigens: 16 HA and 9 NA subtypes are known, all found in aquatic birds. Subtypes H17N10, H18N11, and H9N2 are found in bats. Subtypes H1, H2, H3, H5, H7, and H9 are known to infect humans. The core issue is regular inter-species transmission.

Antigenic Drift and Antigenic Shift

  • Antigenic Drift: point mutations in a viral protein reduce its antigenicity, helping the virus escape existing antibody-mediated immunity. Occurs in HA and NA of both type A and type B influenza viruses, through small, sequential mutations. This is the main reason for recurring seasonal flu epidemics and the need for annual flu vaccination.
  • Antigenic Shift: a shift in antigenicity resulting from the exchange of genes between two viruses (genetic reassortment). Only seen with type A influenza viruses, and is the cause of flu pandemics. It occurs when two different influenza A viruses infect the same host, e.g. a pig: a human subtype and an avian subtype exchange genes, producing a novel hybrid subtype.

Avian Influenza and Disease Severity

  • Avian influenza A/H5N1: first identified in 1997 in Hong Kong. 18 people infected, 6 died. Transmits from infected poultry to humans; endemic in poultry, causing sporadic human infections. Mortality rate about 50%. Vaccine available.
  • Avian influenza A/H7N9: first identified in China in 2013. 3 people infected, all 3 died. Transmits from infected poultry to humans; continues to be active in China. Mortality rate about 30%. Vaccine available.
  • Respiratory disease caused by H5N1/H7N9 or SARS/MERS is clinically and pathologically distinct from mild seasonal infections, progressing from lower respiratory tract infection to pneumonia to ARDS.
    • Mild, more localized disease: H1N1, H3N2, HCoV-229E.
    • Severe disease: H5N1, SARS, MERS, plus diarrhoea specifically with SARS and kidney failure specifically with MERS.

Influenza Vaccines and Antiviral Drugs

  • Influenza vaccines are available but not universal: they are type- and subtype-specific. Because of antigenic drift, the vaccine must be reformulated every year.
  • Three classes of anti-influenza drugs are available:
    • Symmetrel: inhibits virus entry into host cells
    • Tamiflu: inhibits progeny virus release from host cells
    • Xofluza: inhibits the viral RNA polymerase
  • The challenge for all three is the emergence of drug resistance.

Self-test

  1. Distinguish the upper respiratory tract symptoms of viral infection from the lower respiratory tract symptoms, and name the anatomical structures associated with each.
  2. List the six virus families that cause human respiratory infection, with one example virus for each.
  3. Explain two reasons respiratory viruses stay endemic in the human population year-round despite being seasonal.
  4. Describe the mechanism by which the RNA genome of most respiratory viruses drives the emergence of new variants.
  5. List the paramyxoviruses that commonly infect infants and young children, and state which of them have an available vaccine.
  6. Describe the natural history of RSV infection in infants, including the proportion infected by age 1 and age 2, and the typical progression of symptoms.
  7. Distinguish the RSV prevention strategies available for adults from those available for infants.
  8. Describe the three factors that longitudinal studies link to RSV bronchitis leading to asthma later in life.
  9. Distinguish a normal bronchiole from an asthmatic bronchiole.
  10. Describe the steps by which genetic recombination generates a novel coronavirus, using bats as the example host.
  11. Distinguish SARS from MERS in terms of year discovered, intermediate host, and case/death numbers.
  12. Describe the origin of SARS-CoV-2, including its genome identity to the 2003 SARS coronavirus and its proposed intermediate host.
  13. Describe the steps from SARS-CoV-2 binding respiratory epithelial cell receptors to multi-organ tissue damage in severe COVID-19.
  14. For each of Paxlovid, REGEN-COV, Remdesivir and Dexamethasone, state its mechanism of action against COVID-19.
  15. Distinguish antigenic drift from antigenic shift in influenza, including which influenza types each affects and the clinical consequence of each.
  16. Describe the steps of antigenic shift using the example of a pig co-infected with human and avian influenza A subtypes.
  17. A patient presents with severe lower respiratory tract infection progressing to pneumonia, with diarrhoea. Which of the novel respiratory viruses covered does this best fit, and why?
  18. Distinguish avian influenza A/H5N1 from A/H7N9 in terms of year and location first identified, number infected and died, and mortality rate.
  19. Name the three classes of anti-influenza drug and the mechanism of each, and explain why the influenza vaccine must be reformulated annually.
  20. Explain why RSV, SARS-CoV-2, and influenza A illustrate three different routes by which respiratory viruses evade or overcome the host’s existing immunity (chronic epithelial damage/inflammation, cytokine-driven pathology, and antigenic change).

Answers

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