Tuesday, August 13, 2024

Nature: Adaptation Potential of H3N8 Canine Influenza Virus in Human Respiratory Cells

 

Dogs as `mixing vessels' for influenza

#18,239


While HPAI H5N1 is currently garnering most of the flu headlines, it is far from the only influenza virus with pandemic potential.  The CDC's IRAT lists the Texas H5N1 virus as #8 in their list of 25 zoonotic flu threats, but even that list is missing some potential contenders. 

While avian H5 or H7 viruses are thought capable of producing more severe pandemics, they may be far less likely to emerge than an H1, H2, or H3 subtype (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?).
The CDC's IRAT places the EA H1N1 `G4' swine-origin virus well ahead of H5N1 both in terms of likelihood of emerging, and impact. Of course, these assessments are subject to change.


While it is currently not part of the IRAT list, one of the viruses we continue to watch is Canine H3N8, which jumped from horses to dogs in Florida 20 years ago, and has spread globally since then.   

There are other (non-canine) versions of this subtype, as well (avian, equine, etc.)

A relative recent entry in the zoonotic sweepstakes, avian H3N8 infected two children (1 severely, infecting the family dog and cat as well) in China in 2022, and reportedly killed a woman in Guangdong province (1000 km to the south) in March of last year.

H3N8 is of particular interested because:
  • about 60 years ago H3N8 jumped unexpectedly to horses, supplanting the old equine H7N7 virus, and subsequently jumped from horses to dogs in 2004
  • in 2011 avian H3N8 was found in marine mammals (harbor seals), and 2012’s mBio: A Mammalian Adapted H3N8 In Seals, provided evidence that this virus had recently adapted to bind to alpha 2,6 receptor cells, the type found in the human upper respiratory tract.
Over the past couple of years we've seen a steady stream of cautionary reports (primarily) by Chinese researchers, warning of the zoonotic potential of H3N8. A few recent examples include:
Cell: Airborne Transmission of Human-isolated Avian H3N8 Influenza Virus Between Ferrets

A Novel Triple Reassortment H3N8 Avian Influenza Virus: Characteristics, Pathogenicity, and Transmissibility

EID Dispatch: Replication of Novel Zoonotic-Like Influenza A(H3N8) Virus in Ex Vivo Human Bronchus and Lung

All of which brings us to a new study, published in Nature, where researchers from the University of Tokyo report that the Canine H3N8 virus - after successive passages through human alveolar cells - acquires HA and NA mutations that allow it to replicate efficiently in human lung tissue. 

Due to its lengthy, and technical nature, I've only posted the link, abstract, and a brief excerpt.  Follow the link to read it in its entirety.  I'll have a bit more when you return.

Adaptation potential of H3N8 canine influenza virus in human respiratory cells
Wataru Sekine, Haruhiko Kamiki, Hiroho Ishida, Hiromichi Matsugo, Kosuke Ohira, Kaixin Li, Misa Katayama, Akiko Takenaka-Uema, Shin Murakami & Taisuke Horimoto

Scientific Reports volume 14, Article number: 18750 (2024)  

Abstract

In 2004, the equine-origin H3N8 canine influenza virus (CIV) first caused an outbreak with lethal cases in racing greyhounds in Florida, USA, and then spread to domestic dogs nationwide. Although transmission of this canine virus to humans has not been reported, it is important to evaluate its zoonotic potential because of the high contact opportunities between companion dogs and humans. 

To gain insight into the interspecies transmissibility of H3N8 CIV, we tested its adaptability to human respiratory A549 cells through successive passages. We found that CIV acquired high growth properties in these cells mainly through mutations in surface glycoproteins, such as hemagglutinin (HA) and neuraminidase (NA). 

Our reverse genetics approach revealed that HA2-K82E, HA2-R163K, and NA-S18L mutations were responsible for the increased growth of CIV in human cells. Molecular analyses revealed that both HA2 mutations altered the optimum pH for HA membrane fusion activity and that the NA mutation changed the HA-NA functional balance. 

These findings suggest that H3N8 CIV could evolve into a human pathogen with pandemic potential through a small number of mutations, thereby posing a threat to public health in the future.

          (SNIP)

In this study, we found that H3N8 CIV acquires high growth capacity in human cells by altering membrane fusion activity through mutation of the HA stalk region and HA-NA functional balance through mutation of the NA transmembrane region. The mutated amino acids detected in HA2 and NA of A549 cell-adapted viruses (HA2-82E, -163K, and NA-18L) were not found in any H3N8 human isolates19 or recent seasonal H3N2 viruses in the database. 

Nonetheless, these findings reveal that the H3N8 CIV has the potential to mutate into a virus infecting human respiratory organs through a few mutations in surface glycoproteins.

We previously reported that H7N2 feline IAV could adapt to A549 cells by altering the membrane fusion activity and HA-NA functional balance48 and H3N2 CIV could adapt to feline cells by altering the membrane fusion activity49. These results suggest that interspecies transmission of AIVs between mammals can be achieved more easily by a few mutations in surface glycoproteins, compared with the transmission of avian IAVs to humans, which requires a number of mutations in various genes involved in reassortment with human IAVs. 

Notably, a recent report showed that H3N2 CIVs, first transmitted from avian to dogs around 2006, have evolved to possess human-type receptor specificity, increased HA stability, and replication ability in human airway epithelial cells, suggesting their potential to become human pathogens50.

Therefore, more attention should be paid to canine IAVs, including H3N8 CIVs, in addition to avian IAVs, for risk assessment using the global surveillance system for pandemic preparedness. 

(Continue . . . )


This study references a report on Canine H3N2, which we looked at last year (see Increased Public Health Threat of Avian-origin H3N2 Influenza Virus During Evolution in Dogs (Revisited)).

Canine H3N2 first appeared in South Korea in 2007, and analysis showed that the HA and NA genes of the A/canine/Korea/01/2007 (H3N2) isolate were closely related to those identified in 2003 from chickens and doves in South Korea.

Canine H3N2 arrived to the United States in 2015 (see CDC Statement On H3N2 Canine Influenza In Chicago Region) and has since spread nationally. In 2017, the CDC added Canine H3N2 to their IRAT (Influenza Risk Assessment Tool) list of novel flu viruses with zoonotic potential.

H3N2: [A/canine/Illinois/12191/2015]

The H3N2 canine influenza virus is an avian flu virus that adapted to infect dogs. This virus is different from human seasonal H3N2 viruses. Canine influenza A H3N2 virus was first detected in dogs in South Korea in 2007 and has since been reported in China and Thailand. It was first detected in dogs in the United States in April 2015. H3N2 canine influenza has reportedly infected some cats as well as dogs. There have been no reports of human cases.

Summary:  The average summary risk score for the virus to achieve sustained human-to-human transmission was low risk (less than 4). The average summary risk score for the virus to significantly impact public health if it were to achieve sustained human-to-human transmission was in the low risk range (less than 4).

Since then, we've seen sporadic reports (mostly out of China) on a variety of reassortant H3Nx viruses, including:



Follow up reports on these, and other studies out of China, are often slow in coming. But it is obvious that many Chinese scientists are taking a hard look at the pandemic potential of H3Nx viruses. 

A reminder that while H5N1 has our attention, we could always be hit by something out of left field. 

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