Zoonotic Viruses Research Articles

Mosquito-independent milk-associated transmission of zoonotic Wesselsbron virus in sheep.

Wesselsbron virus (WSLV) is a zoonotic, mosquito-borne orthoflavivirus endemic to sub-Saharan Africa, causing abortions and stillbirths in small ruminants. The life cycle of WSLV involves Aedes mosquitoes and various wildlife and domestic animals. Seminal studies in the 1950s have shown the zoonotic potential of WSLV, notably in accidental infections of laboratory workers exposed to infected material. More recent epidemiological studies suggest the emergence of clade I WSLV strains in peri-domestic and rural areas of western and eastern Africa. The pathobiology of recent clade I WSLV strains is unknown and no virus isolate is available. To address these gaps, we generated a recombinant clade I WSLV SA999 infectious clone (rSA999) by reverse genetics. Subsequently, lactating ewes were inoculated intravenously with the WSLV rSA999 strain or the clade II SAH177 strain in insect-free biocontainment stables. Inoculated ewes developed fever, viremia, and showed high levels of viral RNA at mucosal surfaces, and elevated viral titers in milk. Milk production was reduced, which directly affected the growth of the lambs, particularly within the rSA999 group. The ewes with higher WSLV titers in their milk in each group transmitted the infection to their lambs, which developed fever, prolonged viremia, and virus secretion. All infected animals produced high antibody titers with cross-neutralizing activity against both WSLV strains. Histopathology and blood biochemistry analysis indicated liver damage associated with necrotizing hepatitis lesions and active viral replication in some cases, which was more pronounced in the rSA999 group. Notably, only the SAH177-infected animals exhibited lesions consistent with meningoencephalitis, suggesting that WSLV clade II strains are neurotropic and that clade I strain are more hepatotropic. These findings demonstrate a previously unrecognized mode of vector-free transmission of WSLV that raises significant concerns for public and animal health.

A Large-Scale Serological Survey in Pets From October 2020 Through June 2021 in France Shows Significantly Higher Exposure to SARS-CoV-2 in Cats Compared to Dogs.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has the potential to infect various animals, including domestic pets like dogs and cats. Many studies have documented infection in companion animals by molecular and serological methods. However, only a few have compared seroprevalence in cats and dogs from the general population, and these studies were limited by small sample sizes and collections over short periods. Our aim was to obtain a more accurate evaluation of seroprevalence in companion animals in France and to determine whether cats and dogs differ in their exposure to SARS-CoV-2. We conducted an extensive serological survey of SARS-CoV-2, collecting blood samples from 2036 cats and 3577 dogs during routine veterinary medical examinations across different regions of metropolitan France from October 2020 to June 2021. This period encompassed the peaks and onset of two waves, as well as the emergence of the first variants. A microsphere immunoassay targeting the receptor-binding domain and trimeric spike protein was used to detect anti-SARS-CoV-2 antibodies. A subset of 308 seropositive samples was tested for the presence of neutralising antibodies. We determined an overall seroprevalence of anti-SARS-CoV-2 antibodies of 7.1% (95% confidence interval [CI]: 6.4%-7.8%) among the sampled pets. Cats exhibited a significantly higher seroprevalence (9.3%; 95% CI: 8.1%-10.1%) compared to dogs (5.9%; 95% CI: 5.2%-6.8%). Among the subset of seropositive samples, 81 (26.3%; 95% CI: 21.5%-31.6%) displayed neutralizing antibodies. Furthermore, seroprevalence in both species was lower in older animals and was not associated with sex. Finally, unlike cats, seroprevalence in dogs was found to be correlated with the date of sampling. The large sample size enhances the reliability and statistical robustness of our estimates regarding pet exposure to SARS-CoV-2. This study on SARS-CoV-2 reaffirms the crucial importance of adopting a One Health approach incorporating domestic animals when managing an epidemic caused by a zoonotic virus.

Evidence of prostate cancer-linked virus zoonoses from biophysical genomic variations.

An ongoing double-blind examination of (mathematically) smooth functional dependences of population-based genomic distributions of single nucleotide polymorphisms (SNPs) on quantified environmental parameters has flagged a SNP that has been associated with prostate cancer for dependence on zoonotic viruses. The SNP rs13091518 is an intergenic variant near the gene/pseudo-gene COX6CP6 on chromosome 3. The risk T allele, which is the major allele in all homeostatic populations considered, clearly demonstrates a negative adaptive force of about -0.1 universal genomic energy units/zoonotic virus unit. This biophysical perspective has thus provided evidence for a causative relationship between zoonotic viruses and prostate cancer. Our findings are consistent with other studies that have found an association between several zoonotic viruses and prostate cancer. This result demonstrates the significance of an intergenic variant in the adaptive response to a viral zoonotic pathogen.

Gastrointestinal Shedding of Rubulaviruses from Egyptian Rousette Bats: Temporal Dynamics and Spillover Implications

Bats are recognized as reservoirs for diverse paramyxoviruses, some of which are closely related to known human pathogens or directly implicated in zoonotic transmission. The emergence of the zoonotic Sosuga virus (SOSV) from Egyptian rousette bats (ERBs), which caused an acute febrile illness in a reported human case in Africa, has increased the focus on the zoonotic potential of the Rubulavirinae subfamily. Previous studies identified human parainfluenza virus 2 (HPIV2)- and mumps (MuV)-related viruses in ERBs from South Africa, with HPIV2-related viruses restricted to gastrointestinal samples, an underexplored target for rubulavirus biosurveillance, suggesting that sample-type bias may have led to their oversight. To address this, we performed a longitudinal analysis of population-level fecal samples from an ERB maternity roost for rubulavirus RNA, employing a broadly reactive hemi-nested RT-PCR assay targeting the polymerase gene. We detected HPIV2- and MuV-related viruses in addition to numerous pararubulaviruses, highlighting significant viral diversity. Temporal analysis of three major clades revealed peaks in rubulavirus shedding that correlated with seasonal environmental changes and host reproductive cycles, although shedding patterns varied between clades. These findings identify specific periods of increased risk for the spillover of bat-associated rubulaviruses to humans, providing critical information for developing targeted mitigation strategies to minimize zoonotic transmission risk within the local community.

Transboundary Movement of Yezo Virus via Ticks on Migratory Birds, Japan, 2020-2021.

Migratory birds carry ticks harboring various pathogens, including the zoonotic Yezo virus. In Hokkaido, Japan, we collected ticks from migratory birds during 2020-2021. Eight of 385 pools, comprising 2,534 ticks, tested positive for Yezo virus RNA, suggesting Yezo virus might be spread through the flyways of migratory birds.

First Report of Influenza D Virus in Dairy Cattle in Pakistan

Influenza D virus (IDV) is a newly emerged zoonotic virus increasingly reported worldwide. Cattle are considered the main reservoir of IDV, although it was first isolated from pigs. IDV infects multiple animal species and contributes to the bovine respiratory disease complex (BRDC). To date, there has been no report on the presence and frequency of IDV among cattle herds in Pakistan. In this study, we collected nasal swabs from cattle and performed virological surveillance of IDV via qRT-PCR. Among 376 swab samples, IDV was detected in 9 samples (2.4%). Four dairy cattle farms were positive for IDV; two IDV-positive samples (two/nine, 22.2%) belonged to asymptomatic cattle, while seven IDV-positive samples (seven/nine, 77.8%) were from cattle showing respiratory clinical signs, including two with a recent history of abortion and mastitis. Partial sequences of the hemagglutinin–esterase-fusion gene of IDV were obtained from nine qRT-PCR-positive samples. Notably, all IDV strains in this study clustered within the D/OK lineages in phylogenetic analysis. A 98.8–99.6% genetic identity to its European and US counterparts indicates that the IDVs are closely related. The D/OK lineage of IDV was previously unreported in Pakistan. This is the first report of IDV in Pakistan. We confirmed that IDV is circulating among cattle herds in Pakistan. This study underscores the importance of virological surveillance to monitor the ecology of IDV for better animal and public health. The continued spread of IDV and its adaptation to various hosts necessitate further epidemiological studies.

Construction and evaluation of glycoprotein-based nucleic acid vaccines for Marburg virus.

Marburg virus (MARV) is a zoonotic virus that can infect humans and non-human primates (NHPs) and lead to a fatal Marburg hemorrhagic fever (MHF), while there is no approved vaccine or antiviral treatment for MHF. The nucleic acid vaccine has unique advantages, including fast and simple preparation, easy to follow the virus mutation situation, and less adverse reactions. Therefore, we constructed the DNA and mRNA candidate vaccines based on codon-optimized MARV glycoprotein sequence, and evaluated the immune effect in mice through ELISA, ELISpot, and Flow cytometry. After the second booster immunization, both of the candidate vaccines induced strong humoral immune response, enhanced T cell response, and elicited neutralizing antibodies. Notably, DNA candidate vaccine induced stronger humoral immune response, while mRNA candidate vaccine elicited higher levels of IFN-γ and IL-4. In addition, transcriptome analysis revealed that the candidate vaccines activated immune response related pathways. Our study shed new light on the nucleic acid vaccines for MARV and further confirmed the potential of nucleic acid vaccine for future MHF prevention and control.

Isolation and Propagation of Marburgviruses.

Marburgviruses (Marburg virus and Ravn virus) have caused ~20 outbreaks of human Marburg virus disease since their discovery in 1967. These zoonotic viruses are categorized as priority pathogens with no licensed vaccines or treatment options. The foundation for all experimental work including deciphering disease parameters and countermeasure development is a defined virus stock. This chapter provides a guide for the isolation and growth of marburgviruses in tissue culture.

Plotting the major proteins of borealpox virus

In an era marked by rapid environmental transformations, the viability of numerous species hinges crucially on their ability to navigate and adjust to shifting climatic conditions through migration. Yet, amidst this natural quest for survival, a consequential and often overlooked consequence emerges: the inadvertent transportation of a diverse array of parasites and pathogens across landscapes. This phenomenon poses a substantial and tangible threat to global health, particularly in the wake of recent outbreaks and pandemics fueled by zoonotic viruses, which leap from animals to humans. These viruses, originating in animals but capable of infecting humans, serve as poignant reminders of the intricate relationship between human and wildlife health, and the potential dangers of disregarding this delicate balance. In 2015, the borealpox virus (BRPV) [formerly Alaskapox virus (AKPV)], classified as an Orthopoxvirus, was first identified in a woman living near Fairbanks, Alaska. The BRPV causes borealpox disease. The first recorded fatality attributed to BRPV infection occurred in January 2024. Current evidence suggests that BRPV primarily targets small mammals, particularly red-backed voles and shrews, as evidenced by sampling efforts in the Fairbanks North Star Borough. However, it is likely that the virus is more widespread among Alaska’s small mammal populations, potentially leading to undiagnosed human infections. Additionally, domestic pets, such as cats and dogs, may also contribute to the transmission of the virus. To date, no instances of human-to-human transmission have been documented, but the lack of diagnostics and vaccines for BRPV remains a concerning gap. This paper aims to address this issue by reporting the structure and epitopes of the major proteins of BRPV. This data could serve as a foundation for the development of novel diagnostics and vaccines to combat BRPV, thereby mitigating its impact on both human and animal populations.

Molecular diagnostics using the QIAstat-Dx syndromic device for covering avian influenza pandemic preparedness

IntroductionA key factor in influenza pandemic preparedness is the ability to detect zoonotic influenza virus strains as they emerge in humans through spillover events, ideally before human-to-human transmission occurs. DesignIn this study, the utility of the QIAstat-Dx syndromic device for influenza surveillance was evaluated. Bioinformatic analysis was performed on all WHO-recommended influenza Candidate Vaccine Viruses (CVVs), including the common strains recommended for the 2023–2024 influenza vaccine composition in the northern hemisphere, and 16 different H5 highly pathogenic avian influenza virus (HPAIV) and two H9N2 low pathogenic avian influenza virus (LPAIV) strains. For laboratory validation, engineered gene fragments and real HPAIV and LPAIV samples were tested using the QIAstat-Dx Respiratory SARS-CoV-2 Panel. ResultsDuring the bioinformatic screening, common influenza strains were positive including influenza A subtypes, and all H5 HPAIV and LPAIV H9N2 were detected as Influenza A positive without subtype discrimination. In all cases, laboratory validation confirmed all bioinformatic results. ConclusionQIAstat-Dx can detect all tested potentially zoonotic influenza A virus strains, and discriminate them from human sesonal influenza A viruses, ensuring a correct diagnosis. Any tool available for surveillance and pandemic preparedness is essential for a rapid response to reduce healthcare costs and severity of future influenza pandemics.

Edible bird’s nest: N- and O-glycan analysis and synergistic anti-avian influenza virus activity with neuraminidase inhibitors

Zoonotic avian influenza viruses have continued to infect people on occasion. During treatment, antiviral resistant viruses have occasionally emerged, highlighting the need for a novel strategy for treating human illness. After pancreatin treatment, edible bird's nest (EBN), swiftlet saliva consumed for health purposes, possesses anti-avian viral activity by inhibiting receptor-binding hemagglutinin (HA) activity. Glycan analysis revealed an abundance of α2,3Neu5Ac decoy receptors in pancreatin-treated EBN. Fucosylated tri-α2,3Neu5Ac tri-antennary N-glycans (N-35) and di-α2,3Neu5Ac core 2 O-glycans (O-15) are predominant, accounting for 53.46% and 44.66% of total N- and O-glycan amounts, respectively. Isobologram analysis revealed that the treated EBN had a strong synergistic effect with either oseltamivir carboxylate or zanamivir, a competitive inhibitor of receptor-destroying neuraminidases (NAs), against the avian H5N1 virus. Taken together, EBN has the potential to be developed as a food-derived avian viral trap to prevent and decrease avian virus infection as well as in combination with a viral releasing-NA inhibitor to increase therapeutic potency, reduce toxicity, delay resistance development, and potentially prevent pandemic onset.

Unveiling the Role of TMPRSS2 in the Proteolytic Activation of Pandemic and Zoonotic Influenza Viruses and Coronaviruses in Human Airway Cells.

The zoonotic transmission of influenza A viruses (IAVs) and coronaviruses (CoVs) may result in severe disease. Cleavage of the surface glycoproteins hemagglutinin (HA) and spike protein (S), respectively, is essential for viral infectivity. The transmembrane serine protease 2 (TMPRSS2) is crucial for cleaving IAV HAs containing monobasic cleavage sites and severe acute respiratory syndrome (SARS)-CoV-2 S in human airway cells. Here, we analysed and compared the TMPRSS2-dependency of SARS-CoV, Middle East respiratory syndrome (MERS)-CoV, the 1918 pandemic H1N1 IAV and IAV H12, H13 and H17 subtypes in human airway cells. We used the peptide-conjugated morpholino oligomer (PPMO) T-ex5 to knockdown the expression of active TMPRSS2 and determine the impact on virus activation and replication in Calu-3 cells. The activation of H1N1/1918 and H13 relied on TMPRSS2, whereas recombinant IAVs carrying H12 or H17 were not affected by TMPRSS2 knockdown. MERS-CoV replication was strongly suppressed in T-ex5 treated cells, while SARS-CoV was less dependent on TMPRSS2. Our data underline the importance of TMPRSS2 for certain (potentially) pandemic respiratory viruses, including H1N1/1918 and MERS-CoV, in human airways, further suggesting a promising drug target. However, our findings also highlight that IAVs and CoVs differ in TMPRSS2 dependency and that other proteases are involved in virus activation.

Prevalence of Crimean-Congo Haemorrhagic Fever virus and Ganjam virus among livestock & ticks in Wayanad, Kerala.

The Western Ghat region of Kerala has abundant flora and domestic and wild animal species that provide an ideal ecological niche for the ticks. Kyasanur Forest Disease virus (KFDV), a zoonotic tick-borne virus causing Haemorrhagic fever, commonly known as monkey fever is prevalent in the area. The tick infestations have been documented in the majority of household animals in Wayanad and risks are further amplified as the majority of the animals reared, graze in the adjoining forest areas and these animals are often housed in and around farmer's dwellings. Therefore, the farmers are at high risk of contracting deadly tick-borne diseases, and surveillance in animals can act as an indicator of disease hotspots. Even though the tick-borne KFDV is endemic to the area, the surveillance data on other significant zoonotic tick-borne viruses such as CCHFV and GANV are scanty. Overall CCHFV seroprevalence of 2.33 was reported amongst livestock sampled. Species-wise percent seropositivity was 1.01 and 5.10 in cattle and goats, respectively. The study revealed the presence of ticks belonging to 3 genera viz. Rhipicephalus, Amblyomma, and Haemaphysalis. Despite the CCHFV seroprevalence, CCHFV and GANV could not be detected in ticks. Even though ticks were negative for the CCHFV genome, seroprevalence in adjoining taluks indicates the local virus circulation. Therefore serological as well as molecular investigation with a large number of samples collected at the peak of tick activity across the western ghat would help identify the potential hotspot for CCHFV.

Rapid Development of Small Rodent Animal Models for Infectious Disease Research Through Vectorized Receptor Molecule Expression.

The emergence and re-emergence of pathogens with pandemic potential has been a persistent issue throughout history. Recent decades have seen significant outbreaks of zoonotic viruses from members of the Coronaviridae, Filoviridae, Paramyxoviridae, Flaviviridae, and Togaviridae families, resulting in widespread infections. The continual emergence of zoonotic viral pathogens and associated infections highlights the need for prevention strategies and effective treatments. Central to this effort is the availability of suitable animal models, which are essential for understanding pathogenesis and assessing transmission dynamics. These animals are also critical for evaluating the safety and efficacy of novel vaccines or therapeutics and are essential in facilitating regulatory approval of new products. Rapid development of animal models is an integral aspect of pandemic response and preparedness; however, their establishment is fraught by several rate-limiting steps, including selection of a suitable species, the logistical challenges associated with sharing and disseminating transgenic animals (e.g., the time-intensive nature of breeding and maintaining colonies), the availability of technical expertise, as well as ethical and regulatory approvals. A method for the rapid development of relevant animal models that has recently gained traction, in large part due to the COVID-19 pandemic, is the use of gene therapy vectors to express human viral receptors in readily accessible laboratory animals to enable virus infection and development of clinical disease. These models can be developed rapidly on any genetic background, making mechanistic studies and accelerated evaluation of novel countermeasures possible. In this review, we will discuss important considerations for the effective development of animal models using viral vector approaches and review the current vector-based animal models for studying viral pathogenesis and evaluating prophylactic and therapeutic strategies, with an emphasis on models of SARS-CoV-2 infection based on the vectorized expression of human angiotensin-converting enzyme 2.

Application of a Sensitive Capture Sequencing Approach to Reservoir Surveillance Detects Novel Viruses in Zambian Wild Rodents.

We utilized a pan-viral capture sequencing assay, VirCapSeq-VERT, to assess viral diversity in rodents from the Eastern Province of Zambia as a model for pre-pandemic viral reservoir surveillance. We report rodent adeno-, parvo-, paramyxo-, and picornaviruses that represent novel species or isolates, including murine adenovirus 4, two additional species in the genus Chaphamaparvovirus, two paramyxoviruses distantly related to unclassified viruses in the genus Jeilongvirus, and the first Aichivirus A sequence identified from rodents in Africa. Our results emphasize the importance of rodents as a reservoir for potential zoonotic viruses.

A rapid and versatile reverse genetic approach and visualization animal models for emerging zoonotic pseudorabies virus

Pseudorabies virus (PRV), a member of the Alphaherpesvirinae subfamily and a causative pathogen of Aujeszky's disease, has a broad host range including domestic and wild animals. PRV has been reported as a causative agent in patients with acute encephalitis in 2021, which suggests PRV might be a novel animal-origin virus in terms of zoonotic spillover and spread potential. To manage current PRV epidemics in pigs and prepare for future pandemics in other species including humans. Fundamental techniques essential for procuring such knowledge on prevention and therapy of PRV. Here, PRV CD22 strain was isolated and phylogenetic analysis showed that PRV CD22 belongs to the current epidemic strains in China. PRV CD22 was highly lethal to mice and piglets in vivo. Moreover, a rapid and efficient system to generate recombinant PRV was constructed based on PRV CD22 genomic DNA fosmid library. Using this system, a recombinant PRV strain expressing engineered labeling protein was rescued for visualization of viral infection in mouse model. Our study allows the generation of PRV that can be used for downstream treatment analyses. Once experimental or surveillance samples are obtained, PRV can be generated and treated efficiently based on our study.

Discovering Lassa virus nucleoprotein inhibitors via in silico drug repositioning approach

Lassa fever, caused by the zoonotic Lassa virus (LASV), poses a significant health threat in Africa, leading to thousands of infections and deaths annually and has the potential to spread to other parts of the world. Despite the urgency for effective treatments, there are currently no approved drugs or vaccines for Lassa fever. LASV possesses a unique negative-sense RNA genome, and NP plays a crucial role in viral assembly and infection. Crystallographic analysis reveals distinct domains in NP, with the N-terminal domain involved in RNA binding and the C-terminal domain exhibiting exoribonuclease activity, suppressing type I interferon-mediated immune responses. This study explores the potential of repurposing existing FDA-approved drugs by targeting the N-terminal domain of LASV’s nucleoprotein (NP). Docking simulations and molecular dynamics experiments were conducted, revealing promising interactions between NP and widely used and well tolerated drugs such as metacycline, eltrombopag, glimepiride, lurasidone, paliperidone, prednisone, doxazosin, flavin mononucleotide, and pimozide. These drugs exhibited stable binding throughout 100 ns simulations, with interactions resembling those observed with the natural ligand, dTTP. Binding free energy calculations identified key amino acids, particularly Phe176 and Arg300, as crucial for drug-NP interactions. Notably, drugs like FMN, prednisone, metacycline, pimozide, and glimepiride displayed binding affinities comparable to dTTP, suggesting their potential as LASV inhibitors. The study underscores the importance of further experimental and clinical validation of these in silico findings. The identified drugs present promising candidates for potential treatments for Lassa fever, addressing the current gap in approved therapeutics for this life-threatening infectious disease.

PANoptosis Regulation in Reservoir Hosts of Zoonotic Viruses.

Zoonotic viruses originating from reservoir hosts, such as bats and birds, often cause severe illness and outbreaks amongst humans. Upon zoonotic virus transmission, infected cells mount innate immune responses that include the activation of programmed cell death pathways to recruit innate immune cells to the site of infection and eliminate viral replication niches. Different inflammatory and non-inflammatory cell death pathways, such as pyroptosis, apoptosis, necroptosis, and PANoptosis can undergo concurrent activation in humans leading to mortality and morbidity during zoonosis. While controlled activation of PANoptosis is vital for viral clearance during infection and restoring tissue homeostasis, uncontrolled PANoptosis activation results in immunopathology during zoonotic virus infections. Intriguingly, animal reservoirs of zoonotic viruses, such as bats and birds, appear to have a unique immune tolerance adaptation, allowing them to host viruses without succumbing to disease. The mechanisms facilitating high viral tolerance in bats and birds are poorly understood. In this perspective review, we discuss the regulation of PANoptotic pathways in bats and birds and indicate how they co-exist with viruses with mild clinical signs and no immunopathology. Understanding the PANoptotic machinery of bats and birds may thus assist us in devising strategies to contain zoonotic outbreaks amongst humans.

Ecological and Reproductive Cycles Drive Henipavirus Seroprevalence in the African Straw-Coloured Fruit Bat (Eidolon helvum).

Bats are known to host zoonotic viruses, including henipaviruses that cause high fatality rates in humans (Nipah virus and Hendra virus). However, the determinants of zoonotic spillover are generally unknown, as the ecological and demographic drivers of viral circulation in bats are difficult to ascertain without longitudinal data. Here we analyse serological data collected from African straw-coloured fruit bats (Eidolon helvum) in Ghana over the course of 2 years and across four sites, comprising three wild roosts and one captive colony. We focus on antibody affinity to five henipavirus antigens: Ghanaian bat henipavirus (GhV), Nipah virus (NiV), Hendra virus (HeV), Mojiang virus (MojV) and Cedar virus (CedV). In the wild roosts, we detected seasonal variations in henipavirus antibody binding, possibly associated with bat life-history cycles and migration patterns. In the captive colony, we identified increases in antibody affinity levels among pregnant bats, suggesting possible shifts in the immune system during pregnancy. These bats then pass maternal antibodies to their pups, which wane before antibody affinity levels rise later in life following initial infections and/or reactivation of latent infections. These results improve our understanding of the links between bat ecology and viral circulation, including for GhV, a locally-circulating African henipavirus.

Innate immune control of influenza virus interspecies adaptation via IFITM3

Influenza virus pandemics are caused by viruses from animal reservoirs that adapt to efficiently infect and replicate in human hosts. Here, we investigate whether Interferon-Induced Transmembrane Protein 3 (IFITM3), a host antiviral factor with known human deficiencies, plays a role in interspecies virus infection and adaptation. We find that IFITM3-deficient mice and human cells can be infected with low doses of avian influenza viruses that fail to infect WT counterparts, identifying a new role for IFITM3 in controlling the minimum infectious virus dose threshold. Remarkably, influenza viruses passaged through Ifitm3−/− mice exhibit enhanced host adaptation, a result that is distinct from viruses passaged in mice deficient for interferon signaling, which exhibit attenuation. Our data demonstrate that IFITM3 deficiency uniquely facilitates potentially zoonotic influenza virus infections and subsequent adaptation, implicating IFITM3 deficiencies in the human population as a vulnerability for emergence of new pandemic viruses.