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Influenza viruses, since time immemorial, have been the major respiratory pathogen known to infect a wide variety of animals, birds and reptiles with established lineages. They belong to the family Orthomyxoviridae and cause acute respiratory illness often during local outbreaks or seasonal epidemics and occasionally during pandemics. Recent studies have identified a new genus within the Orthomyxoviridae family. This newly identified pathogen, D/swine/Oklahoma/1334/2011 (D/OK), first identified in pigs with influenza-like illness was classified as the influenza D virus (IDV) which is distantly related to the previously characterized human influenza C virus. Several other back-to-back studies soon suggested cattle as the natural reservoir and possible involvement of IDV in the bovine respiratory disease complex was established. Not much is known about its likelihood to cause disease in humans, but it definitely poses a potential threat as an emerging pathogen in cattle-workers. Here, we review the evolution, epidemiology, virology and pathobiology of influenza D virus and the possibility of transmission among various hosts and potential to cause human disease.

The global anxiety and a significant threat to public health due to the current COVID-19 pandemic reiterate the need for active surveillance for the zoonotic virus diseases of pandemic potential. Influenza virus due to its wide host range and zoonotic potential poses such a significant threat to public health. Swine serve as a “mixing vessel” for influenza virus reassortment and evolution which as a result may facilitate the emergence of new strains or subtypes of zoonotic potential. In this context, the currently available scientific data hold a high significance to unravel influenza virus epidemiology and evolution. With this objective, the current systematic review summarizes the original research articles and case reports of all the four types of influenza viruses reported in swine populations worldwide. A total of 281 articles were found eligible through screening of PubMed and Google Scholar databases and hence were included in this systematic review. The highest number of research articles (n = 107) were reported from Asia, followed by Americas (n = 97), Europe (n = 55), Africa (n = 18), and Australia (n = 4). The H1N1, H1N2, H3N2, and A(H1N1)pdm09 viruses were the most common influenza A virus subtypes reported in swine in most countries across the globe, however, few strains of influenza B, C, and D viruses were also reported in certain countries. Multiple reports of the avian influenza virus strains documented in the last two decades in swine in China, the United States, Canada, South Korea, Nigeria, and Egypt provided the evidence of interspecies transmission of influenza viruses from birds to swine. Inter-species transmission of equine influenza virus H3N8 from horse to swine in China expanded the genetic diversity of swine influenza viruses. Additionally, numerous reports of the double and triple-reassortant strains which emerged due to reassortments among avian, human, and swine strains within swine further increased the genetic diversity of swine influenza viruses. These findings are alarming hence active surveillance should be in place to prevent future influenza pandemics.

Reverse genetics systems for influenza C virus encounter challenges due to the inefficient production of infectious virus particles. In the present study, we explored the underlying cause by assessing the efficiency of generating influenza C virus-like particles (C-VLPs) containing specific virus RNA (vRNA) segments. Using 293T cells transfected with plasmids encoding GFP- and DsRed2-vRNAs (each flanked by the non-coding regions of Segments 5 and 6, respectively), along with plasmids expressing virus proteins, we observed that C-VLPs containing a single vRNA segment were generated efficiently. However, the simultaneous packaging of two vRNA segments into a single C-VLP was less frequent, as demonstrated by flow cytometry and reverse-transcription PCR analyses. Statistical evaluations revealed a decreased efficiency of incorporating multiple vRNA segments into single particles, which likely contributes to the reduced production of infectious virus particles in reverse genetics systems. These findings highlight a critical limitation in the vRNA incorporation mechanism of influenza C virus, contrasting with that of influenza A virus. Hence, further studies are required to elucidate specific vRNA packaging signals and optimize vRNA expression levels to improve the production of infectious influenza C virus particles.

Influenza viruses are important pathogens causing respiratory disease in humans and animals. In contrast to influenza A virus (IAV) that can infect a wide range of animal species, other influenza viruses, including influenza B virus (IBV), influenza C virus (ICV), and influenza D virus (IDV) have a limited host range. Swine can be infected with all four different genera of influenza viruses. IAV infection of pigs causes the well-known swine influenza that poses significant threats to human and animal health. However, influenza virus infection of pigs with IBV, ICV, and IDV are not well-characterized. Herein, we compared pathogenicity of IBV and IDV using intratracheal and intranasal infection of pigs, which are IAV seropositive, and commingled naïve pigs with the infected animals to determine their transmissibility. Both viruses caused fever and some lung lesions, replicated in the lungs of infected pigs, but only IDV transmitted to the contact animals. Although IBV and IDV displayed differing levels of replication in the respiratory tract of infected pigs, no significant differences in pathogenicity of both viruses were observed. These results indicate that both IBV and IDV can replicate, and are pathogenic in pigs.

Influenza C virus (ICV) is a common yet under-recognized cause of acute respiratory illness. ICV seropositivity has been found to be as high as 90% by 7–10 years of age, suggesting that most people are exposed to ICV at least once during childhood. Due to difficulty detecting ICV by cell culture, epidemiologic studies of ICV likely have underestimated the burden of ICV infection and disease. Recent development of highly sensitive RT-PCR has facilitated epidemiologic studies that provide further insights into the prevalence, seasonality, and course of ICV infection. In this review, we summarize the epidemiology and clinical characteristics of ICV.

The emergence and spread of antiviral-resistant influenza viruses are of great concern. To minimize the public health risk, it is important to monitor antiviral susceptibilities of influenza viruses. Analyses of the antiviral susceptibilities of influenza A and B viruses have been conducted globally; however, those of influenza C and D viruses are limited. Here, we determined the susceptibilities of influenza C viruses representing all six lineages (C/Taylor, C/Yamagata, C/Sao Paulo, C/Aichi, C/Kanagawa, and C/Mississippi) and influenza D viruses representing four lineages (D/OK, D/660, D/Yama2016, and D/Yama2019) to RNA polymerase inhibitors (baloxavir and favipiravir) by using a focus reduction assay. All viruses tested were susceptible to both drugs. We then performed a genetic analysis to check for amino acid substitutions associated with baloxavir and favipiravir resistance and found that none of the viruses tested possessed these substitutions. Use of the focus reduction assay with the genotypic assay has proven valuable for monitoring the antiviral susceptibilities of influenza C and D viruses as well as influenza A and B viruses. Antiviral susceptibility monitoring of all influenza virus types should continue in order to assess the public health risks posed by these viruses.

Influenza C virus (ICV) was discovered in 1947 and detected in humans, with natural infections occurring periodically. However, early studies on ICV were challenging in diagnosis because the virus is difficult to culture. As a result, the disease burden and pathogenicity of ICV have been underestimated. Recent studies using molecular biological techniques such as real-time polymerase chain reaction have provided further insights into prevalence, seasonality, genomic diversity, and evolution. In addition, the possibility of interspecies transmission was suggested based on the high similarity between the nucleotide sequence of ICV confirmed to infect animals and the sequence of ICV isolated from humans. In this review, we summarize current data on the epidemiology and clinical features, viral genome analysis, and animal studies of ICV.

Viral cross-species transmission is recognized to be a major threat to both human and animal health, however detailed information on determinants underlying virus host tropism and susceptibility is missing. Influenza C and D viruses (ICV, IDV) are two respiratory viruses that share up to 50% genetic similarity, and both employ 9-O-acetylated sialic acids to enter a host cell. While ICV infections are mainly restricted to humans, IDV possesses a much broader host tropism and has shown to have a zoonotic potential. This suggests that additional virus–host interactions play an important role in the distinct host spectrum of ICV and IDV. In this study, we aimed to characterize the innate immune response of the respiratory epithelium of biologically relevant host species during influenza virus infection to identify possible determinants involved in viral cross-species transmission. To this end, we performed a detailed characterization of ICV and IDV infection in primary airway epithelial cell (AEC) cultures from human, porcine, and bovine origin. We monitored virus replication kinetics, cellular and host tropism, as well as the host transcriptional response over time at distinct ambient temperatures. We observed that both ICV and IDV predominantly infect ciliated cells, independently from host and temperature. Interestingly, temperature had a profound influence on ICV replication in both porcine and bovine AEC cultures, while IDV replicated efficiently irrespective of temperature and host. Detailed time-resolved transcriptome analysis revealed both species-specific and species uniform host responses and highlighted 34 innate immune-related genes with clear virus-specific and temperature-dependent profiles. These data provide the first comprehensive insights into important common and species-specific virus-host dynamics underlying the distinct host tropism of ICV and IDV, as well as possible determinants involved in viral cross-species transmission.

Homology-dependent RNA silencing occurs in many eukaryotic cells. We reported recently that nodaviral infection triggers an RNA silencing-based antiviral response (RSAR) in Drosophila, which is capable of a rapid virus clearance in the absence of expression of a virus-encoded suppressor. Here, we present further evidence to show that the Drosophila RSAR is mediated by the RNA interference (RNAi) pathway, as the viral suppressor of RSAR inhibits experimental RNAi initiated by exogenous double-stranded RNA and RSAR requires the RNAi machinery. We demonstrate that RNAi also functions as a natural antiviral immunity in mosquito cells. We further show that vaccinia virus and human influenza A, B, and C viruses each encode an essential protein that suppresses RSAR in Drosophila. The vaccinia and influenza viral suppressors, E3L and NS1, are distinct double-stranded RNA-binding proteins and essential for pathogenesis by inhibiting the mammalian IFN-regulated innate antiviral response. We found that the double-stranded RNA-binding domain of NS1, implicated in innate immunity suppression, is both essential and sufficient for RSAR suppression. These findings provide evidence that mammalian virus proteins can inhibit RNA silencing, implicating this mechanism as a nucleic acid-based antiviral immunity in mammalian cells.