The more often the virus infects mammals, the greater the risk. It’s a numbers game.
Scavengers
In vast areas of wilderness, most infections are not noticed by humans. The list of mammals with H5N1 infections is diverse, but the most common terrestrial mammals are opportunistic scavengers like foxes, skunks and raccoons. Bears and mountain lions may are probably over-represented due to their size. The number of mammals infected in the wilderness of the USA alone is probably orders of magnitude higher than the 200 identified cases. Large meta studies about wild mammals until 2024 can be found here and here.
Scavenging provides an opportunity for H5N1 to be transmitted back and forth between mammals and birds.
Incidentally the most worrying virus variant detected so far, although not peer-reviewed, was found in a bird with a preference for scavenging, the Red Tailed Hawk.
The species that scavenges frequently amongst the Buteo hawks is the Red-tailed Hawk. Like other hawks, Red-tailed Hawks are smaller than eagles, so they only usually eat smaller pieces of carrion – typically found along roadsides.
One isolate, A/Red Tailed Hawk/ON/FAV-0473-4/2022, efficiently transmitted by direct contact between ferrets, resulting in lethal outcomes.
Here, we performed molecular and serological screening of over 500 dead wild carnivores and sequencing of RNA positive materials. We show virological evidence for HPAI H5 virus infection in 0.8%, 1.4%, and 9.9% of animals tested in 2020, 2021, and 2022 respectively, with the highest proportion of positives in foxes, polecats and stone martens. (...) Serological evidence for infection was detected in 20% of the study population.
In total, 563 dead animals were submitted for HPAI viral RNA testing between 2020 and 2022. Of those, 174 animals were found dead and 389 were euthanized. The majority of euthanized animals (n = 375) were stone martens that had been trapped and euthanized in a meadow bird protection pilot.
A total of seven (almost) complete HPAI H5 virus genome sequences from infected animals were obtained: five from foxes, one from a polecat and one from a stone marten. All viruses were HPAI H5N1 viruses that belong to clade 2.3.4.4b. Of these, three sequences from foxes (3/7; 43%) contained the E627 K substitution in the PB2 open reading frame. Substitution T271A was found in the PB2 open reading frame of the virus sequence from the polecat.
This study shows that the exposure and number of HPAI H5 virus infections between 2020 and 2022 in wild carnivores was much higher than previous reports suggested. Our serology studies demonstrated that significant proportions of foxes and stone martens that were found dead had antibodies against HPAI H5 virus. The same animal species also tested positive for HPAI H5, with 29% of dead foxes and 24% of dead polecats testing RNA positive.
Also, the observed numbers of foxes, polecats and stone martens with antibodies against HPAI H5 virus with trauma as the most likely cause of death, suggests that infections may not always lead to severe disease. The observations in our study are different from the currently available body of evidence, describing ante mortem neurological signs in most of the cases of positive animals that were found dead. (...) So, infections with clade 2.3.4.4b HPAI H5 viruses likely do not always result in severe neuropathy or death, and disease presentation may even differ between different viruses within clade 2.3.4.4b, further complicating surveillance and risk assessment.
The risk of infection was identified mainly as predation
(or feeding) upon infected birds or contact with avian species. Evidence of mammal-to-mammal
transmission in the wild is only circumstantial and yet to be confirmed
Although there is the need for high vigilance,
zoonotic pathogens must overcome a hierarchical series of barriers to cause spillover
infections in humans (Plowright et al., 2017). Zoonotic infections do not immediately mean
pandemic. The ability to infect humans does not mean ability to sustain transmission among
humans, e.g. airborne transmission. During the last HPAI H5N1 panzootic, no adaptations
specific to humans were found in the human cases, but only mammalian mutations that might
have a moderate activity in humans (e.g.E627K) (EFSA, ECDC and EURL, 2023). Current
H5N1 strains may not replicate efficiently in human cells due to sensitivity to human reception
factors, although the mammalian adaptations found might suggest potential mammal-to-
mammal transmission risks. The factors to be evaluated to assess pandemic potential involve
replication in mammalian hosts (adaptation of the polymerase e.g. PB2 E627K mutation),
overcoming human restriction factors (Cimiski et al., 2021), hemagglutinin receptor binding
adaptations, and pH stability of hemagglutinin (Long et al., 2019). Indeed, in the transmission
from bird-to-bird or bird-to-mammal through environmental contamination (i.e. faecal-oral
cycle) emerges as a crucial factor, surpassing primary contact importance (Breban et al.,
2009; Rohani et al., 2009)
Rodents
Rodents like mice and rats are everywhere and numerous. Due to their size and tendency to hide underground they are difficult to observe. They also tend to die in their underground nests when feeling sick. Rodents are suspected as mechanical vector, introducing H5N1 sticking to fur or paws to poultry barns. A study has also shown that a H5N1 variant with the relatively common PB2-E627K mutation can be transmitted between mice through direct contact and with lethal outcome.
As this post shows, it could take many weeks to detect an H5N1 outbreak in humans, even with relatively close surveillance. How long would it take to detect an outbreak in mice or rats? What makes rodents dangerous is that they are elusive and nobody cares about them.
What about the animals that we don’t see so easily, like rats or mice? What’s happening? The large species we now know get infected easily. But the small species, we don’t even know.
But the in between steps of how avian flu travels from wild birds into poultry barns is a mystery.
"There's actually evidence in the scientific literature that mice and other small rodents can actually carry the virus. Maybe not as a biological vector, but as a mechanical one," says Dr. Brian McCluskey, the chief epidemiologist for the USDA's Animal and Plant Health Inspection Service. McCluskey says a mouse might enter a poultry barn with contaminated material in its fur or on its paws.
Rodents can be abundant around poultry houses, share their habitat with waterfowl and can readily enter poultry houses. Survival of AIV from waterfowl in poultry house surroundings and on the coat of rodents suggests that rodents are likely to act as mechanical vector. AIVs can replicate in rodents without adaptation, resulting in high viral titres in lungs and nasal turbinates, virus presence in nasal washes and saliva, and transmission to naïve contact animals. Therefore, active AIV shedding by infected rodents may play a role in transmission to poultry.
However, in modern industrial poultry farms without a free-range system, close contact with wild birds is unlikely and strict biosecurity measures are in place to reduce most indirect transmission routes. It was therefore remarkable that outbreaks of HPAIV H5N8 in Germany, the Netherlands and the United Kingdom in 2014–2015 occurred on modern farms with indoor poultry housing and that no outdoor production sites were affected. This suggests that intermediate factors may be involved in the transmission of AIV from wild birds to commercial poultry.
During the initial outbreak of HPAIV H5N1 in Hong Kong in 1997, dogs, cats, rats and mice living around poultry markets were screened for infection. Virus was not isolated from these animals, but haemagglutination inhibiting activity was detected in some rat sera. (...) However, care must be taken when applying serological tests, as these are often not specifically validated for the species examined and may not provide consistent results between assays and laboratories .
In this study we show that selected H7N1 and H5N1 HPAI viruses can be transmitted from mouse-to-mouse by direct contact, and that in experimentally infected animals they exhibit a different pattern of replication and transmission. Our results can be considered as a starting point for transmission experiments involving other influenza A viruses with α 2-3 receptor affinity in order to better understand the viral factors influencing transmissibility of these viruses in selected mammalian species.
More recently, the presence and distribution of human influenza virus receptors (α 2-6 SA receptors) in mice has also been revisited and preliminary data indicate the presence of both α 2-3 and α 2-6 SA receptors in the respiratory tract of BALB/c mice. Consequently, mice are potentially suitable for studying influenza virus infection, transmission and reassortment in non-avian species.
These viruses were chosen according to the presence or absence of the amino acid Lys in position 627PB2, which is known to play an important part in viral replication and pathogenicity in mice. (...) Four to six-week old female BALB/c mice were divided into two different groups of 10 each. Ten mice (group G1) were infected intranasally with 50 μL of a suspension containing 10 LD50 of each virus. Twenty-four hours p.i. the infected animals were moved into a clean cage. This cage already hosted 10 sentinel mice (group G2).
Among G2Tk/05 sentinel mice, 4 out of 10 died, without evident clinical signs or changes in body weight, with viral RNA detected in multiple organs. Two out of six sentinels sacrificed on day 20 p.c. showed viral RNA in the brain and the spleen. (...) None of G2Mal/835 mice died spontaneously. Viral RNA was detected only in the trachea/lung of a sentinel sacrificed on day 10 p.c., and was confirmed by virus isolation.
Unfortunately for property owners, it is very common for rats to die in their nests, especially when the death is due to poison. If a rat feels unwell, it is unlikely to have the energy to go out and search for food. Instead, it will just die in its nest.
Rats may also go to their nest on purpose when they feel sick or close to death because it is comfortable and relaxing there.
Also, avian influenza infections in rodents have been described, but so far rarely any monitoring or field research is targeting them.
The U.S. Department of Agriculture reported that H5N1 has been found in 11 house mice in New Mexico. Farms in the state have reported H5N1 outbreaks in cows, so it’s possible that the mice consumed unpasteurized milk from infected cows and became infected themselves. But that means the virus is inching closer to contact with people, since most people are more likely to encounter house mice than dairy cattle. “Any house, any home, any lodging or campground could bring humans in close contact with mice,” says Doron.
The animals showed signs of illness starting on day 1, including ruffled fur and lethargy. All the animals survived until day 4, when they were euthanized to determine virus titers in multiple organs. (...) Detection of virus in the mammary glands of two mice was consistent with the high virus load in the milk of lactating cows, even though these mice were not lactating. Collectively, our data indicate that HPAI A(H5N1) virus in untreated milk can infect susceptible animals that consume it.
In its latest updates, the US Department of Agriculture (USDA) Animal and Plant Health Inspection Service (APHIS) reported 36 more H5N1 avian flu detections in house mice, all in the same New Mexico county, as well as four more virus detections in domestic cats.
On June 4, APHIS first reported H5N1 detections in house mice from New Mexico's Roosevelt County, and today it reported 36 more from the same location, raising the total to 47. Collection dates for the latest detections range from May 6 to May 12.
We detected highly pathogenic avian influenza A(H5N1) virus in wild rats collected from a rural area in Giza, Egypt, near poultry farms, markets, and backyard flocks. Sequence and phylogenetic analyses indicated that the virus from the rats belonged to clade 2.3.4.4b, which has been the predominant virus genotype circulating in Egypt and worldwide since 2021-2022.
Seals and Sea Lions
Globally, the center of attention have been mass mortality events of seals and sea lions, which outnumber other species with over 10.000 reported cases.
>> Seals and Sea Lions
The highest numbers of reported mortalities in association with the HPAI H5
outbreak include marine mammal species, such as South American sea lions (Otaria byronia)
(~32,000) and southern elephant seals (Mirounga leonina) (~17,000) (...)
Feral Cat and Dog Populations
Feral cats and dogs could act as a reservoir for H5N1. Cats are much more susceptible to H5N1 than dogs. Free roaming domestic cats could get infected from strays and feral cats. They could then bring the virus into human households.
>> Cats and Dogs
Of the 701 stray cats examined, 83 were found to have antibodies to the bird flu virus. Some of the stray cats examined had mild symptoms of illness, but not specific to bird flu. Eating contaminated dead birds is a plausible route of infection for these stray cats. An analysis into different risk factors showed that stray cats originating from nature reserves had, on average, more frequent antibodies against the bird flu virus stray cats from other habitats, such as a livestock farm, holiday park or industrial area.
In domestic cats, 4 of the 814 blood samples examined had antibodies to the avian flu virus. The blood samples from the domestic cats were sent to the Faculty for blood testing for various reasons. These were therefore not part of the castration project, but were added to this part of the study as a control group. Among the domestic cats, there was an overrepresentation of cats from urban areas in the Randstad, and it is not known whether these cats went outside and thus may have had contact with (wild) birds. With the new study in domestic cats that go outdoors, the faculty aims to gain more insight into this. The study is expected to be completed by mid-2024.
