REVIEW published: 06 September 2018 doi: 10.3389/fmicb.2018.01941 A Comprehensive Review on Equine Influenza Virus: Etiology, Epidemiology, Pathobiology, Advances in Developing Diagnostics, Vaccines, and Control Strategies Raj K. Singh 1, Kuldeep Dhama 2*, Kumaragurubaran Karthik 3, Rekha Khandia 4, Ashok Munjal 4, Sandip K. Khurana 5, Sandip Chakraborty 6, Yashpal S. Malik 7, Nitin Virmani 5, Rajendra Singh 2, Bhupendra N. Tripathi 5, Muhammad Munir 8 and Johannes H. van der Kolk 9* 1 ICAR-Indian Veterinary Research Institute, Bareilly, India, 2 Division of Pathology, ICAR-Indian Veterinary Research Institute, Bareilly, India, 3 Central University Laboratory, Tamil Nadu Veterinary and Animal Sciences University, Chennai, India, 4 Department of Biochemistry and Genetics, Barkatullah University, Bhopal, India, 5 National Research Centre on Equines, Edited by: Hisar, India, 6 Department of Veterinary Microbiology, College of Veterinary Sciences and Animal Husbandry, West Tripura, Akio Adachi, India, 7 Division of Biological Standardization, ICAR-Indian Veterinary Research Institute, Bareilly, India, 8 Division of Biomedical Kansai Medical University, Japan and Life Sciences, Lancaster University, Lancaster, United Kingdom, 9 Division of Clinical Veterinary Medicine, Swiss Institute Reviewed by: for Equine Medicine (ISME), Vetsuisse Faculty, University of Bern and Agroscope, Bern, Switzerland Luis Carlos Villamil-Jiménez, Independent Researcher, Columbia Eric Claassen, Among all the emerging and re-emerging animal diseases, influenza group is the VU University Amsterdam, prototype member associated with severe respiratory infections in wide host species. Netherlands Kevin L. Legge, Wherein, Equine influenza (EI) is the main cause of respiratory illness in equines across University of Iowa, United States globe and is caused by equine influenza A virus (EIV-A) which has impacted the equine *Correspondence: industry internationally due to high morbidity and marginal morality. The virus transmits Kuldeep Dhama easily by direct contact and inhalation making its spread global and leaving only limited [email protected] Johannes H. van der Kolk areas untouched. Hitherto reports confirm that this virus crosses the species barriers johannes.vanderkolk@ and found to affect canines and few other animal species (cat and camel). EIV is vetsuisse.unibe.ch continuously evolving with changes at the amino acid level wreaking the control program Specialty section: a tedious task. Until now, no natural EI origin infections have been reported explicitly in This article was submitted to humans. Recent advances in the diagnostics have led to efficient surveillance and rapid Virology, a section of the journal detection of EIV infections at the onset of outbreaks. Incessant surveillance programs Frontiers in Microbiology will aid in opting a better control strategy for this virus by updating the circulating Received: 07 March 2018 vaccine strains. Recurrent vaccination failures against this virus due to antigenic drift and Accepted: 31 July 2018 shift have been disappointing, however better understanding of the virus pathogenesis Published: 06 September 2018 would make it easier to design effective vaccines predominantly targeting the conserved Citation: Singh RK, Dhama K, Karthik K, epitopes (HA glycoprotein). Additionally, the cold adapted and canarypox vectored Khandia R, Munjal A, Khurana SK, vaccines are proving effective in ceasing the severity of disease. Furthermore, better Chakraborty S, Malik YS, Virmani N, understanding of its genetics and molecular biology will help in estimating the rate Singh R, Tripathi BN, Munir M and van der Kolk JH (2018) A Comprehensive of evolution and occurrence of pandemics in future. Here, we highlight the advances Review on Equine Influenza Virus: occurred in understanding the etiology, epidemiology and pathobiology of EIV and a Etiology, Epidemiology, Pathobiology, Advances in Developing Diagnostics, special focus is on designing and developing effective diagnostics, vaccines and control Vaccines, and Control Strategies. strategies for mitigating the emerging menace by EIV. Front. Microbiol. 9:1941. doi: 10.3389/fmicb.2018.01941 Keywords: equine, influenza virus, epidemiology, pathogenesis, diagnosis, vaccine, prevention, control Frontiers in Microbiology | www.frontiersin.org 1 September 2018 | Volume 9 | Article 1941 Singh et al. Equine Influenza Virus—An Update INTRODUCTION isolation from specimens. Although, zoonotic implications of EIV have not yet been fully elucidated, nevertheless, the virus Equine influenza (EI) is an extremely contagious disease of horses can pose a threat to laboratory personnel (Alexander and Brown, (including wild horses), which is caused by Influenza A viruses. 2000; OIE, 2008). Since detection of EIV in dogs, it is presumed These viruses are known for high rates of transmission in a that this virus can re-assort (H3N8) with human influenza virus wide variety of animal species. Equine influenza virus (EIV), and might lead to the emergence of novel strains (Na et al., the causative agent of EI, is considered to be one of the most 2016). important viral respiratory pathogens of equines. The disease Although vaccination is the most useful prophylactic strategy; is characterized by flu-like symptoms affecting predominantly continuous genetic evolution of the virus demands genetic the respiratory tract (Wilson, 1993; Slater and Hannant, 2000; characterization of currently circulating EIVs for the selection van Maanen and Cullinane, 2002; Newton and Mumford, 2005; of a candidate vaccine strain. As vaccine failures occur in Cullinane et al., 2006; Landolt et al., 2007; OIE, 2008; Stack et al., several parts of the world there is need for a better vaccine 2013; Kapoor and Dhama, 2014; Yin et al., 2014). The presence of to completely eradicate equine influenza (Kinsley et al., 2016). influenza infections has been suggested in horses since the time of Hence, understanding of the molecular mechanisms involved Hippocrates and Absyrtus, the latter being a Greek veterinarian, with its cross-species transmission is of prime importance to described a disease resembling influenza in 412 BC and 433 devise any prophylactic and control strategy (Holland, 2003; AD, respectively. In 1872, an outbreak of influenza occurred Smyth, 2007; Joseph et al., 2017). throughout the North America and affected large population of The present review comprehensively describes EIV and horses resulting in crippled transportation of goods, unloading of the disease it causes, epidemiology, transmission, pathogenesis ships and stoppage of almost all essential services (Law, 1874). In and pathology, advances in diagnosis, vaccine development India, one of the largest EI outbreak occurred in 1987 affecting and appropriate prevention, and control strategies to be more than 27,000 equines and causing death of several hundred adapted. (Uppal et al., 1989). In Australia during 2007, an EI outbreak infected ∼10,000 equines despite keeping strict preventive and control measures. The disease was restricted after great efforts at ETIOLOGY the colossal cost of about one billion Australian dollars (Cowled et al., 2009). Based on the matrix and nucleoprotein genes of influenza viruses, Equine influenza is mainly caused by two subtypes of they have been classified as type A, B, C, and D. Type A viruses influenza A viruses namely H7N7 (first isolated in the year 1956) mainly infect animals and humans while type B and C viruses and H3N8 (first isolated in the year 1963; Sovinova et al., 1958; infect only humans. A close relative of Type C virus, Type D was Waddel et al., 1963). Previously, H7N7 was considered as the first reported in the year 2011 from swine and later identified major cause of epidemics whereas latter H3N8 strain is mainly from cattle, sheep, and goats (Ferguson et al., 2016). Sero- responsible for outbreaks across the globe (Mathew et al., 2010; surveys showed that type D antibodies were found in humans Bryant et al., 2011; Alves Beuttemmüller et al., 2016). Genetic and equines also (Nedland et al., 2018). AIV is considered as an analysis has revealed close relatedness of H3N8 strains of EI with ancestor to all other influenza viruses of mammalian and non- avian influenza virus (AIV), which may indicate co-existence of mammalian species. H7N7 and H3N8, the major subtypes of EIV, influenza viruses in aves and equines (Cullinane and Newton, were previously referred as equine 1 and 2 viruses, respectively 2013). Notably, EIV has been seen to infect unusual host, dogs (Daly et al., 2011; Chambers, 2014; Sreenivasan et al., 2018). (Kirkland et al., 2010; Wang et al., 2017). Although, before 2004, EIV is a segmented RNA virus with 80–120nm in diameter canines were considered resistant to influenza virus infection, the and is classified under the family Orthomyxoviridae belonging recent epidemic of influenza in canines came as a surprise (Gibbs to the genus Influenza A (Timoney, 1996). Influenza A viruses and Anderson, 2010). Interspecies transmission of the virus possess eight single segmented negative sense RNA strands and has been reported in racing greyhounds in the USA where the are sub-typed based on the two surface glycoproteins that make isolated virus showed close relatedness to H3N8 virus (Crawford 45% of the mass of this virus, namely hemagglutinin (HA) et al., 2005). Further studies confirmed that though this virus was and neuraminidase (NA) (Webby et al., 2007; Cullinane and earlier considered to be confined to the equine host exclusively, Newton,