Flu B viruses: why not H-something-N-something?

Influenza A(H1N1) virus particles
Source: CDC Public Health Image Library.

The world of influenza (Flu) is filled with many strange things. One of these is why we label the influenza A (FluA) viruses with an “H” (short for the name of the gene, haemagglutinin, which produces the HA protein) and “N” (neuraminidase, NA) system, but not the other flu viruses. Let’s step through what we know of FluB and other Flu viruses, and see if we can find a reason for why we use “lineages” and strains but not “H-something-N-something”.

A generalised influenza virus particle schematic

Influenza B virus vary, but not a lot

The FluA/H3N2 tree is very lean. It has a trunk but few branches; its genotypes don’t hang around over time, they instead get replaced by the next one.
Bedford et al.[4]

Like the FluA H1N1, H3N2, H5N1, H5N6 …and so on…viruses, FluB viruses have an eight gene genome.

But FluB viruses have never caused a pandemic. They also mutate at slower rates than FluA viruses.[3]

This is why FluB illnesses are seen in a high proportion of young people – us oldies still have immunity left from earlier illnesses.

You can find out more about clades in Flu, genes, clades and H3N2

FluAs used to be transient – FluBs hang around

FluA/H3N2 evolves more rapidly than the FluB, but, at least until recent years, each newly emerged genotype tended to drop away and be replaced by new genotypes better able to avoid host immunity.[4] There does seem to be more longevity among A/H3N2 viruses that have emerged in recent years.

FluB viruses do experience change within their two lineages, and they often exchange certain gene segments [7], but then the genotypes tend to hang around beyond their spawning season, at least more than FluA/H3N2 used to.[6]

FluA/H1N1 and the two FluB lineages have more horizontal branching in their trees; genotypes hang around for longer mutating to avoid host immunity but mostly still sticking around. Bedford et al.[5]

FluB viruses infect mainly humans but, they have been used to infect lab animals during experimental studies.[24] They’ve also been found in seals where they may serve as an animal reservoir.[8,9] There was also a report with limited data, of a flu-like virus found in a snake of the Bothrops genus.[10]

FluAs are party viruses

FluA viruses are far more promiscuous; they can be found replicating in the guts of their natural reservoir, aquatic birds (ducks, shorebirds and gulls) but also in seals, pigs, dogs, bats (H17N10 and H18N11[15,16]), whales, mink and in us humans of course. This widespread distribution is facilitated by the many and genetically distinct HA (18 different proteins) and NA (11) proteins among the FluA viruses. Some H and N combinations are limited by biology, to particular animals.[23]

Humanity’s recent seasonal flu friends and their discovery over time.

When a mummy and a daddy virus love each other very much

FluA viruses – even the seasonal ones – can generate new “child” viruses if two or more “parent” viruses infect the same cell. But cellular co-infection is just the start of making a new virus.[22] A new set of genes must be compatible to co-exist in a single virus particle. Then this new genome needs to be able to produce proteins that can work together, assemble into virus particles, escape the cell, infect a new cell and so on.[11]

Turns out, FluA viruses can also mix one portion of one gene into another gene through a process of genetic recombination, producing genes with changed function.[20] This may not be an option among FluB viruses.[21]

It’s the same cell being infected by two – or more – compatible flu viruses that bring with it the risk of a new and distinct child flu virus emergence.

FluB genotypes can be clustered into two relatively similar groups

FluB viruses are currently assigned to two separate antigenic groups, the Victoria lineage (comprising mulitple clades thanks to reassortment between clades) and the Yamagata lineage (two main clades of distinct genomes.[3,6] The FluB lineages were identified and named in the late 1980s and they were initially defined by differences in the way their member viruses reacted to the same antisera.

AN ANTISERUM. An anti-virus (or other pathogen) antibody-rich blood serum usually collected from an animal that was previsouly inoculated with a virus (or other pathogen) and which has mounted an immune reposnse to antigens on that virus in order to fight off that virus and protect agains future disease

However, these differences may be created by only one or two dozen amino acids in the haemagglutinin gene.[3] There just aren’t the same genetically diverse range of different HA and NA genes – and resulting proteins – that we see among the FluAs.

The World Health Organization noted in 1980 that:

There is no provision for describing distinct subtypes of influenza B and C viruses. The existence of antigenic variation among influnza B strains is well established but the available information shows that a division into subtypes is not warranted.

A revision of the system of nomenclature for
influenza viruses: a WHO Memorandum* [17]

SIDENOTE. It’s also interesting that FluA and FluB viruses don’t seem to mix and match their genes to make new virus strains and genotypes. This is because they have evolved some significant differences – evolutionary bottlenecks – that make it difficult for any such intracellular marriage to bear progeny.[18] These bottlenecks might also reduce the likelihood of the emergence of certain FluA viruses as well.[19]

Strains, genotypes, subtypes, drift, shift …ARRGGHH!! 🤯

What about the other flu viruses?

Yep. There are influenza C viruses (FluC) and influenza D viruses (FluD) as well. We don’t hear much about them, because they are either rare causes of serious disease or just don’t cause human outbreaks.

Influenza C virus

These viruses only have a seven gene genome, lacking a distinct neuraminidase gene. The FluC two-for-one equivalent, the haemagglutinin-esterase (HE) gene, doesn’t mutate as fast as other flu viruses, so FluC viruses are more antigenically stable than FluA viruses. FluC genotypes can also reassort with other FluC genotypes during coinfections.[13,26,27]

So while multiple antigenic variants do exist among FluC genotypes, they aren’t as diverse or numerous as those seen among the FluA viruses. FluCs are considered to have only a single subtype (monosubtypic) and evolve much more slowly than the FluAs.[14,25,] The viruses still grouped into several genetic lineages though.[27]

FluC viruses are not frequently found in humans with acute respiratory illnesses but when they are, they usually cause mild to moderate illness, although hospitalizations do occur in association with FluC infection.[28,29]. Despite relatively few studies, humans are known to be infected during childhood,[28] and virus-specific antibodies develop in most children by ten years of age.[30, 31] Adults are immune so FluC, like FluB, is a disease of childhood.

FluC viruses have been identified in pigs, and can infect and transmit between pigs under experimental conditions, but humans are the reservoir species.[32, 2]

Despite early infection and some genetic and antigenic variation, the limited host range, lack of an NA gene and seemingly long-lasting immunity generated during childhood mean that these viruses don’t have specific H and N numbering.

Influenza D virus

FluD viruses also have a seven gene genome that lacks an NA gene. They were first identified causing illness in pigs in 2011.[34] FluD viruses can infect and be transmitted by ferrets under experimental conditions.[32,34]

Cattle are more often found with antibodies than pigs and they may be a reservoir of FluD.[33] Sheep and goats are infected [35] but FluD has not been found to cause outbreaks in humans.[12] FluD hasn’t been found to circulate in humans but it has the potential to do so.[34,37]

In further good news for humans, FluC and FluD viruses don’t seem capable of reassorting their gene segments between each other – despite some genetic similarities.[36] And like FluC, FluD viruses seem slower to evolve than the FluAs.[33] Like FluB, FluD viruses can be grouped into two antigenically and genetically distinct lineages which share most of their genes.[38]

Once again with limited human threat and limited findings elsewhere, no H or N system of naming has been applied.

Conclusion

So the main reason why FluA has all the cool H something N something names is that they actually have distinct H and N gene segments and because they are just so darn evolvey. They vary, they swap genes and they exist in a wide and highly mobile range of hosts.

Sound off in the comment section below if you have anything to add or any questions.

Reference

  1. Influenza B viruses: not to be discounted
    https://www.ncbi.nlm.nih.gov/pubmed/26357957
  2. Interspecies transmission of influenza C virus between humans and pigs
  3. Cocirculation of Two Distinct Evolutionary Lineages of Influenza Type B Virus since 1983
  4. Canalization of the evolutionary trajectory of the human influenza virus
  5. Integrating influenza antigenic dynamics with molecular evolution
  6. Genome-wide evolutionary dynamics of influenza B viruses on a global scale
  7. Reassortment between Influenza B Lineages and the Emergence of a Coadapted PB1–PB2–HA Gene Complex
  8. Recurring Influenza B Virus Infections in Seals
  9. Influenza B Virus in Seals
  10. Identification and characterization of influenza virus isolated from Brazilian snakes
  11. Natural co-infection of influenza A/H3N2 and A/H1N1pdm09 viruses resulting in a reassortant A/H3N2 virus
  12. Serological evidence for the presence of influenza D virus in small ruminants
  13. Full genome analysis and characterization of influenza C virus identified in Eastern India
  14. Antigenic Relationship Between Influenza C Viruses
  15. New world bats harbor diverse influenza A viruses
  16. Bat-derived influenza-like viruses H17N10 and H18N11
  17. A revision of the system of nomenclature for influenza viruses: a WHO Memorandum*
  18. Influenza A and B Virus Intertypic Reassortment through Compatible Viral Packaging Signals
  19. H5N8 and H7N9 packaging signals constrain HA reassortment with a seasonal H3N2 influenza A virus
  20. Nonhomologous Recombination between the Hemagglutinin Gene and the Nucleoprotein Gene of an Influenza Virus
  21. Homologous recombination is unlikely to play a major role in influenza B virus evolution
  22. Implications of segment mismatch for influenza A virus evolution
  23. Influenza Hemagglutinin and Neuraminidase: Yin–Yang Proteins Coevolving to Thwart Immunity
  24. Mucosal Immunity against Neuraminidase Prevents Influenza B Virus Transmission in Guinea Pigs
  25. Isolation of a Novel Swine Influenza Virus from Oklahoma in 2011 Which Is Distantly Related to Human Influenza C Viruses
  26. Frequent reassortment among influenza C viruses
  27. Evolution of the haemagglutinin-esterase gene of influenza C virus
    https://www.microbiologyresearch.org/content/journal/jgv/10.1099/0022-1317-77-4-673#tab2
  28. Clinical features of influenza C virus infection in children
    https://academic.oup.com/jid/article/193/9/1229/1012555
  29. Study of Influenza C Virus Infection in France
    https://www.ncbi.nlm.nih.gov/pubmed/18551600
  30. A clinical, epidemiologic, serologic, and virologic study of influenza C virus infection
    https://www.ncbi.nlm.nih.gov/pubmed/7425764
  31. Human antibody to influenza C virus: its age-related distribution and distinction from receptor analogs
    https://iai.asm.org/content/30/2/500
  32. Isolation of Influenza C Virus from Pigs and Experimental Infection of Pigs with Influenza C Virus
  33. Novel Influenza D virus: Epidemiology, pathology, evolution and biological characteristics
    https://www.ncbi.nlm.nih.gov/pubmed/28812422
  34. Isolation of a Novel Swine Influenza Virus from Oklahoma in 2011 Which Is Distantly Related to Human Influenza C Viruses
    https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003176
  35. Serological evidence for the presence of influenza D virus in small ruminants
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618254/
  36. Characterization of a Novel Influenza Virus in Cattle and Swine: Proposal for a New Genus in the Orthomyxoviridae Family
    https://mbio.asm.org/content/5/2/e00031-14
  37. Detection of influenza C virus but not influenza D virus in Scottish respiratory samples
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710576/
  38. Cocirculation of Two Distinct Genetic and Antigenic Lineages of Proposed Influenza D Virus in Cattle
    https://www.ncbi.nlm.nih.gov/pubmed/25355894
  39. Genetic diversity and evolution of the influenza C virus
    https://link.springer.com/article/10.1134/S1022795412070149

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