The millions of Norway rats inhabit New York City (NYC) are reservoirs of the SARS-CoV-2 Virus

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Millions of Norway rats (Rattus norvegicus) inhabit New York City (NYC), presenting the potential for transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from humans to rats.

The study findings were published in peer reviewed journal: mBio.
https://journals.asm.org/doi/10.1128/mbio.03621-22

Both the serological and molecular data from this study suggest that the rats from NYC were exposed to SARS-CoV-2.

Of the tested rats, 16.5% were seropositive, which was higher than the seropositivity rates described in previous reports (11, 12).

In addition, 5.1% of these samples were qRT-PCR-positive to SARS-CoV-2, and partial genomes were recovered from all samples which were qRT-PCR-positive for SARS-CoV-2.

Genomic analyses suggest that the viruses detected from the collected Norway rats were associated with the B-lineage virus, which was predominant in NYC during the early stages of the pandemic. We speculate that these B-lineage viruses are enzootic in rat populations after being introduced to the NYC rat populations during the early stages of the pandemic, or that rats could have been exposed to the B-lineage viruses present in unknown sources.

This is supported by a recent study reporting that the Wuhan-Hu-1-like virus can infect SD rats (17), although an earlier study showed that the prototype Wuhan-Hu-1-like SARS-CoV-2 could not infect SD rats (6). Such a discrepancy may be due to additional mutations in the challenge Wuhan-Hu-1-like strains or genetic variations in the SD rats used in these studies.

Thus, further surveillance is needed to understand the virological prevalence in NYC rats, particularly for several emerging variants with high infectivity among rats, including those that circulated in NYC during the past 2 years of the COVID-19 pandemic.

A number of studies have suggested that fragments of SARS-CoV-2 genomes were identified in sewage water systems, and that the prevalence of SARS-CoV-2 in sewage water systems coincides with outbreaks in resident human populations (18). However, no evidence has shown that SARS-CoV-2 viruses in sewage water are infectious (19), suggesting that sewage rats may have been exposed to the virus through airborne transmission, e.g., overlapping living spaces with humans or indirect transmission from unknown fomites, e.g., contaminated human food waste.

In a recent study, Zeiss et al. (13) showed that approximately one-quarter of naive rats shed SDAV, another rat respiratory betacoronavirus, following fomite exposure in a controlled laboratory setting. Notably, previously exposed seropositive rats became reinfected with SDAV at similar rates following fomite exposure 114 to 165 days later, indicating that immunity is temporary.

In our study, 2 of 4 rats (Rats 2 and 19) were both seropositive and viral RNA-positive, implying that previously exposed seropositive animals may still contract and shed SARS-CoV-2, consistent with prior studies demonstrating breakthrough infections in humans who were previously exposed to SARS-CoV-2 or rats exposed to SDAV (13, 20, 21).

Further studies need to evaluate whether rats with prior exposure to SARS-CoV-2 can be reinfected with the same SARS-CoV-2 or a different SARS-CoV-2 variant and whether these breakthrough infections, if present, could facilitate SARS-CoV-2 virus enzoosis in the NYC rat populations.

Although our limited sample size of wild Norway rats revealed detection of only B-lineage viruses, we used animal models to further demonstrate that, in addition to the Alpha and Beta variants which have been previously reported (6–9), Delta and Omicron variants can also cause infections in SD rats.

The tested variants also replicated to high levels in both the upper and lower respiratory tracts of rats, although they did not cause any bodyweight loss or other clinical signs. Of the three variants, Delta replicated the most efficiently, while the Omicron variant replicated the least efficiently compared to both Alpha and Delta, although this difference did not reach a statistically significant level between Omicron and Alpha.

This finding is consistent with earlier reports that Omicron replicated less efficiently and caused less lung pathology in wild-type or human ACE2 transgenic mice or hamsters compared to other variants (22, 23).

Structural modeling showed that all three variants Alpha, Delta, and Omicron have enhanced binding to SD rat ACE2 compared to the prototype Wuhan-Hu-1-like virus. In light of the biochemical data that Alpha and Delta RBDs bind to rat ACE2 equally well (15), the differences in the replication efficiency that we detected among the three viruses could be due to factors other than receptor binding affinity.

It is also interesting to note that many RBD mutations observed in the three variants, such as N501Y in Alpha and L452R/T478K in Delta, interact with ACE2 residues which vary between humans and rats/mice (Fig. 4E). Therefore, rats likely play an important role in the evolution of Alpha, Delta, Omicron variants, which has the potential to result in the emergence of new variants in rats that are naive to the human population and may contain properties harmful to humans.

As an example of this occurrence, Zhang et al. (16) proposed that mice could be associated with the emergence of Omicron variants.
In addition to receptor binding, a number of other studies suggested that other structural and nonstructural proteins may play critical roles in viral replication in vitro and the host tropism of SARS-CoV-2 viruses.

Syed et al. (24) showed that, despite envelope protein substitutions inhibiting virus assembly, Omicron has an overall higher assembly efficiency than the original SARS-CoV-2, similar to Delta. Bojkova et al. (25, 26) showed that the Omicron variant is less effective in antagonizing the interferon response and has higher sensitivity in interferon treatment than the Delta variant, which may be associated with the substitutions on NSP3, NSP12, NSP13, nucleocapsid, and ORF3 proteins.

Interestingly, Omicron did not adapt any observed amino acid substitutions throughout the course of a virus challenge in SD rats, whereas Alpha and Delta did for spike, nucleoprotein, NSP6, and NSP13. The roles of these amino acid substitutions in virus fitness needs to be further studied.

In summary, we found that the rats in the NYC sewage system have been exposed to SARS-CoV-2, and that the Delta and Omicron variants can infect rats in addition to the Alpha and Beta variants. Our findings highlight the potential risk of secondary zoonotic transmission from rats and the need for further monitoring of SARS-CoV-2 in wild rat populations.

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