Sunday, March 30, 2025

Experimental Infection of Rats with Influenza A Viruses: Implications for Murine Rodents in Influenza A Virus Ecology

Credit CDC

#18,397

Over the years the idea that rats and other rodents could be potential hosts for novel flu viruses has come up a number of times (see 2016's The role of rodents in avian influenza outbreaks in poultry farms: a review), but until recently there has been little evidence to back up those concerns. 

A 2019 study out of Boston found RT-PCR evidence of IAV (Influenza A Virus) in 11% of 163 Norway rats (Rattus norvegicus) trapped and swabbed (note: half came from paw swabs, which may indicate contamination rather than infection). 

But 10 months ago, the USDA reported the detection of rodents (the House Mouse) to their Mammalian Wildlife with H5N1 for the first time, and since then deer mice and black rats have been added as well. 

Today rodents make up 129 of the 574 mammals (22%) on that list, although very little has been released about the circumstances of their discovery.  

The USDA's list is far from exhaustive, since many states have reported zero - or only a few - infections. Reporting is often limited by animals dying in remote and difficult to access places, or by animals that survive the infection. 

But it also seems likely that some states are looking harder for cases than others. 

While the susceptibility of cats (both wild and domestic) to HPAI H5N1 has been long known (see 2015's HPAI H5: Catch As Cats Can), the role that rodents may play in its ecology is less well understood. 

Two recent studies of note, however, include:
In addition to rodents, we've recently seen a number of studies showing that shrews, voles, and other small (often peridomestic) mammals are susceptible to novel flu (see Virology: Susceptibilities & Viral Shedding of Peridomestic Wildlife Infected with Clade 2.3.4.4b HPAI Virus (H5N1)) 

Last summer, in  Nature: Decoding the RNA Viromes in Shrew Lungs Along the Eastern Coast of China, we looked at a study that found a wide range of zoonotic viruses - including HPAI H5N6 - in shrews. Previously, in 2015's Taking HPAI To The Bank (Vole), we looked at that species' susceptibility to both H5N1 and H7N1.

Today we have a study which looks at the experimental infection of Sprague-Dawley rats with a variety of IAV subtypes, including H5Nx, H7N9, H9N2, H10N8 and the 2009 pandemic H1N1 (see chart below).  Not included: The North American Clade 2.3.4.4b H5N1 Virus.


Somewhat surprisingly, despite all of the viruses causing significant lung injury, none of the rats succumbed to the virus.  A trait that may enable rats to stealthily carry, and transmit, some strains of IAV (including H5N1).  

I've only included the link, Abstract, and a few excerpts from this study. Follow the link to read it in its entirety.  I'll have a postscript when you return.

Experimental Infection of Rats with Influenza A Viruses: Implications for Murine Rodents in Influenza A Virus Ecology

by  1, 1, 1, 1, 1,2,* and 1,2,*
Viruses 2025, 17(4), 495; https://doi.org/10.3390/v17040495 (registering DOI)
Submission received: 28 February 2025 / Revised: 25 March 2025 / Accepted: 27 March 2025 / Published: 29 March 2025
Abstract

Rattus norvegicus (brown rat), a widely distributed rodent and common biomedical model, is a known reservoir for many zoonotic pathogens but has not been traditionally recognized as a host for influenza A virus (IAV).
To evaluate their susceptibility, we intranasally inoculated Sprague-Dawley rats with various IAV subtypes, including H5Nx, H7N9, H9N2, H10N8 and the 2009 pandemic H1N1.
All strains productively infected the rats, inducing seroconversion without overt clinical signs. While replication efficiency varied, all viruses caused significant lung injury with a preferential tropism for the upper respiratory tract.
Investigation of receptor distribution revealed a predominance of α2,3-linked sialic acid (SA) in the nasal turbinates and trachea, whereas α2,6-linked SA was more abundant in the lungs. Notably, both receptor types coexisted throughout the respiratory tract, aligning with the observed tissue-specific replication patterns and broad viral infectivity.
These findings demonstrate that rats are permissive hosts for multiple IAV subtypes, challenging their exclusion from IAV ecology. The asymptomatic yet pathogenic nature of infection, combined with the global synanthropy of rats, underscores their potential role as cryptic reservoirs in viral maintenance and transmission. This study highlights the need for expanded surveillance of rodents in influenza ecology to mitigate zoonotic risks.

(SNIP)
Discussion

The role of rats and other rodents in influenza ecology remains understudied and controversial. This study provides compelling experimental evidence that SD rats, a representative model of the Rattus species, are susceptible to productive infection by diverse subtypes of contemporary IAVs that pose significant threats to both public health and agriculture. These include avian HPAI H5Nx (clades 1.0 and 2.3.4.4a, b, e, g, both human and avian isolates), H7N9 (HPAI and LPAI), H9N2, H10N8, and the mammalian-adapted pandemic 2009 H1N1 viruses (Table 1). 
Notably, these infections occurred without prior viral adaptation, challenging the conventional assumptions that rats are generally insusceptible and not natural hosts of IAV. Our findings, together with previous reports [11,12,13,14,15,16,17,37,38,39,40], underscore the need to reevaluate rodents as potential reservoirs, mechanical vectors, or bridging hosts in the zoonotic transmission of IAVs. 

The absence of overt clinical signs, despite robust viral replication, seroconversion, and histopathological evidence of lung injury (Figure 1, Figure 2, Figure 3, Figure 4 and Figure 5), positions rats as cryptic carriers capable of sustaining IAV infections undetected in natural settings.
A striking feature of IAV-infected SD rats is the dissociation between their subclinical manifestations and significant virological and immunological findings. Unlike mice and ferrets, which develop observable disease or mortality following experimental IAV challenge [32,33], rats exhibited only a statistically insignificant lower rate of weight gain compared to the control group (Figure 1) and no influenza-like symptoms, even when infected with HPAI H5 or H7N9 strains.

This asymptomatic phenotype resembles that of wild waterfowl, the natural reservoirs of IAV [4,5]. The absence of disease presentation and the induction of seroconversion in most rats suggests that rats may use effective immune mechanisms to limit systemic viral spread while allowing local replication in the upper respiratory tract (this study and [19,20,37]). This balance may facilitate viral infection without compromising host survival, positioning rats as potential stealth vectors in ecosystems where they interact with domestic animals, wildlife, and humans.
          (SNIP)
Conclusions

This study redefines Rattus norvegicus as a permissive host for multiple IAV subtypes prevalent in birds or humans and highlights its ability to sustain subclinical infections with potential ecological consequences. The convergence of broad viral susceptibility, synanthropic behavior, and dual SA receptor expression in the respiratory tracts positions rats as underrecognized players in influenza ecology.
While their role as “mixing vessels” remains speculative, the risk of environmental virus amplification and spillover to domestic animals or humans cannot be dismissed. Strengthening surveillance in rodent populations and integrating rats into One Health frameworks will be essential for mitigating zoonotic threats in an era of escalating avian influenza activity.
          (Continue . . .)


Not so very long ago, HPAI H5 was regarded ass pretty much just an avian virus, with occasional spillovers to humans, or to cats unlucky enough to be fed a diet of raw chicken. But 2021 - following a series of reassortment events - we began to see reports of numerous spillovers into a much wider range of mammals (see graphic below).
While surveillance, testing, and reporting of infected mammals remains severely (some would say, criminally) limited, the growing global impact of HPAI H5 on our shared environment these past few years is unmistakable (see  Nature Reviews: The Threat of Avian Influenza H5N1 Looms Over Global Biodiversity).


As the HPAI H5 virus continues to find new mammalian hosts it only increases the chances that it will find new evolutionary pathways that were unavailable to it when it was primarily a disease of birds. 
  
Where that leads us in anyone's guess, but the more entrenched the virus becomes in the environment, the fewer our options will become to deal with it. 
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