The most heavily studied animal coronavirus is murine hepatitis virus (MHV), which causes a variety of outcomes in mice, including respiratory, enteric, hepatic, and neurologic infections. These infections often serve as highly useful models of disease. For instance, MHV-1 causes severe respiratory disease in susceptible A/J and C3H/HeJ mice, A59 and MHV-3 induce severe hepatitis, while JHMV causes severe encephalitis. Interestingly, MHV-3 induces cellular injury through the activation of the coagulation cascade [ 68 ]. Most notably, A59 and attenuated versions of JHMV cause a chronic demyelinating disease that bears similarities to multiple sclerosis (MS), making MHV infection one of the best models for this debilitating human disease. Early studies suggested that demyelination was dependent on viral replication in oligodendrocytes in the brain and spinal cord [ 69 , 70 ]; however, more recent reports clearly demonstrate that the disease is immune-mediated. Irradiated mice or immunodeficient (lacking T and B cells) mice do not develop demyelination, but addition of virus-specific T cells restores the development of demyelination [ 71 , 72 ]. Additionally, demyelination is accompanied by a large influx of macrophages and microglia that can phagocytose infected myelin [ 73 ], although it is unknown what the signals are that direct immune cells to destroy myelin. Finally, MHV can be studied under BSL2 laboratory conditions, unlike SARS-CoV or MERS-CoV, which require a BSL3 laboratory, and provides a large number of suitable animal models. These factors make MHV an ideal model for studying the basics of viral replication in tissue culture cells as well as for studying the pathogenesis and immune response to coronaviruses.

Coronaviruses cause a large variety of diseases in animals, and their ability to cause severe disease in livestock and companion animals such as pigs, cows, chickens, dogs, and cats led to significant research on these viruses in the last half of the twentieth century. For instance, Transmissible Gastroenteritis Virus (TGEV) and Porcine Epidemic Diarrhea Virus (PEDV) cause severe gastroenteritis in young piglets, leading to significant morbidity, mortality, and ultimately economic losses. PEDV recently emerged in North America for the first time, causing significant losses of young piglets. Porcine hemagglutinating encephalomyelitis virus (PHEV) mostly leads to enteric infection but has the ability to infect the nervous system, causing encephalitis, vomiting, and wasting in pigs. Feline enteric coronavirus (FCoV) causes a mild or asymptomatic infection in domestic cats, but during persistent infection, mutation transforms the virus into a highly virulent strain of FCoV, Feline Infectious Peritonitis Virus (FIPV), that leads to development of a lethal disease called feline infectious peritonitis (FIP). FIP has wet and dry forms, with similarities to the human disease, sarcoidosis. FIPV is macrophage tropic and it is believed that it causes aberrant cytokine and/or chemokine expression and lymphocyte depletion, resulting in lethal disease [ 63 ]. However, additional research is needed to confirm this hypothesis. Bovine CoV, Rat CoV, and Infectious Bronchitis Virus (IBV) cause mild to severe respiratory tract infections in cattle, rats, and chickens, respectively. Bovine CoV causes significant losses in the cattle industry and also has spread to infect a variety of ruminants, including elk, deer, and camels. In addition to severe respiratory disease, the virus causes diarrhea (“winter dysentery” and “shipping fever”), all leading to weight loss, dehydration, decreased milk production, and depression [ 63 ]. Some strains of IBV, a γ-coronavirus, also affect the urogenital tract of chickens causing renal disease. Infection of the reproductive tract with IBV significantly diminishes egg production, causing substantial losses in the egg-production industry each year [ 63 ]. More recently, a novel coronavirus named SW1 has been identified in a deceased Beluga whale [ 64 ]. Large numbers of virus particles were identified in the liver of the deceased whale with respiratory disease and acute liver failure. Although, electron microscopic images were not sufficient to identify the virus as a coronavirus, sequencing of the liver tissue clearly identified the virus as a coronavirus. It was subsequently determined to be a γ-coronavirus based on phylogenetic analysis but it has not yet been verified experimentally that this virus is actually a causative agent of disease in whales. In addition, there has been intense interest in identifying novel bat CoVs, since these are the likely ancestors for SARS-CoV and MERS-CoV, and hundreds of novel bat coronaviruses have been identified over the past decade [ 65 ]. Finally, another novel family of nidoviruses, Mesoniviridae, has been recently identified as the first nidoviruses to exclusively infect insect hosts [ 66 , 67 ]. These viruses are highly divergent from other nidoviruses but are most closely related to the roniviruses. In size, they are ~20 kb, falling in between large and small nidoviruses. Interestingly, these viruses do not encode for an endoribonuclease, which is present in all other nidoviruses. These attributes suggest these viruses are the prototype of a new nidovirus family and may be a missing link in the transition from small to large nidoviruses.

5.2 Human Coronaviruses

Prior to the SARS-CoV outbreak, coronaviruses were only thought to cause mild, self-limiting respiratory infections in humans. Two of these human coronaviruses are α-coronaviruses, HCoV-229E and HCoV-NL63, while the other two are β-coronaviruses, HCoV-OC43 and HCoV-HKU1. HCoV-229E and HCoV-OC43 were isolated nearly 50 years ago [74, 75, 76], while HCoV-NL63 and HCoV-HKU1 have only recently been identified following the SARS-CoV outbreak [77, 78]. These viruses are endemic in the human populations, causing 15–30 % of respiratory tract infections each year. They cause more severe disease in neonates, the elderly, and in individuals with underlying illnesses, with a greater incidence of lower respiratory tract infection in these populations. HCoV-NL63 is also associated with acute laryngotracheitis (croup) [79]. One interesting aspect of these viruses is their differences in tolerance to genetic variability. HCoV-229E isolates from around the world have only minimal sequence divergence [80], while HCoV-OC43 isolates from the same location but isolated in different years show significant genetic variability [81]. This likely explains the inability of HCoV-229E to cross the species barrier to infect mice while HCoV-OC43 and the closely related bovine coronavirus, BCoV, are capable of infecting mice and several ruminant species. Based on the ability of MHV to cause demyelinating disease, it has been suggested that human CoVs may be involved in the development of multiple sclerosis (MS). However, no evidence to date suggests that human CoVs play a significant role in MS.

SARS-CoV, a group 2b β-coronavirus, was identified as the causative agent of the Severe Acute Respiratory Syndrome (SARS) outbreak that occurred in 2002–2003 in the Guangdong Province of China. It is the most severe human disease caused by any coronavirus. During the 2002–2003 outbreak approximately 8,098 cases occurred with 774 deaths, resulting in a mortality rate of 9 %. This rate was much higher in elderly individuals, with mortality rates approaching 50 % in individuals over 60 years of age. Furthermore, the outbreak resulted in the loss of nearly $40 billion dollars in economic activity, as the virus nearly shut down many activities in Southeast Asia and Toronto, Canada for several months. The outbreak began in a hotel in Hong Kong and ultimately spread to more than two dozen countries. During the epidemic, closely related viruses were isolated from several exotic animals including Himalayan palm civets and raccoon dogs [82]. However, it is widely accepted that SARS-CoV originated in bats as a large number of Chinese horseshoe bats contain sequences of SARS-related CoVs and contain serologic evidence for a prior infection with a related CoV [83, 84]. In fact, two novel bat SARS-related CoVs have been recently identified that are more similar to SARS-CoV than any other virus identified to date [85]. They were also found to use the same receptor as the human virus, angiotensin converting enzyme 2 (ACE2), providing further evidence that SARS-CoV originated in bats. Although some human individuals within wet animal markets had serologic evidence of SARS-CoV infection prior to the outbreak, these individuals had no apparent symptoms [82]. Thus, it is likely that a closely related virus circulated in the wet animal markets for several years before a series of factors facilitated its spread into the larger population.

Transmission of SARS-CoV was relatively inefficient, as it only spread through direct contact with infected individuals after the onset of illness. Thus, the outbreak was largely contained within households and healthcare settings [86], except in a few cases of superspreading events where one individual was able to infect multiple contacts due to an enhanced development of high viral burdens or ability to aerosolize virus. As a result of the relatively inefficient transmission of SARS-CoV, the outbreak was controllable through the use of quarantining. Only a small number of SARS cases occurred after the outbreak was controlled in June 2003.

SARS-CoV primarily infects epithelial cells within the lung. The virus is capable of entering macrophages and dendritic cells but only leads to an abortive infection [87, 88]. Despite this, infection of these cell types may be important in inducing pro-inflammatory cytokines that may contribute to disease [89]. In fact, many cytokines and chemokines are produced by these cell types and are elevated in the serum of SARS-CoV infected patients [90]. The exact mechanism of lung injury and cause of severe disease in humans remains undetermined. Viral titers seem to diminish when severe disease develops in both humans and in several animal models of the disease. Furthermore, animals infected with rodent-adapted SARS-CoV strains show similar clinical features to the human disease, including an age-dependent increase in disease severity [91]. These animals also show increased levels of proinflammatory cytokines and reduced T-cell responses, suggesting a possible immunopathological mechanism of disease [92, 93].

While the SARS-CoV epidemic was controlled in 2003 and the virus has not since returned, a novel human CoV emerged in the Middle East in 2012. This virus, named Middle East Respiratory Syndrome-CoV (MERS-CoV), was found to be the causative agent in a series of highly pathogenic respiratory tract infections in Saudi Arabia and other countries in the Middle East [94]. Based on the high mortality rate of ~50 % in the early stages of the outbreak, it was feared the virus would lead to a very serious outbreak. However, the outbreak did not accelerate in 2013, although sporadic cases continued throughout the rest of the year. In April 2014, a spike of over 200 cases and almost 40 deaths occurred, prompting fears that the virus had mutated and was more capable of human-to-human transmission. More likely, the increased number of cases resulted from improved detection and reporting methods combined with a seasonal increase in birthing camels. As of August 27th, 2014 there have been a total of 855 cases of MERS-CoV, with 333 deaths and a case fatality rate of nearly 40 %, according to the European Center for Disease Prevention and Control.

MERS-CoV is a group 2c β-coronavirus highly related to two previously identified bat coronaviruses, HKU4 and HKU5 [95]. It is believed that the virus originated from bats, but likely had an intermediate host as humans rarely come in contact with bat secreta. Serological studies have identified MERS-CoV antibodies in dromedary camels in the Middle East [96], and cell lines from camels have been found to be permissive for MERS-CoV replication [97] providing evidence that dromedary camels may be the natural host. More convincing evidence for this comes from recent studies identifying nearly identical MERS-CoVs in both camels and human cases in nearby proximities in Saudi Arabia [98, 99]. In one of these studies the human case had direct contact with an infected camel and the virus isolated from this patient was identical to the virus isolated from the camel [99]. At the present time it remains to be determined how many MERS-CoV cases can be attributed to an intermediate host as opposed to human-to-human transmission. It has also been postulated that human-to-camel spread contributed to the outbreak.

MERS-CoV utilizes Dipeptidyl peptidase 4 (DPP4) as its receptor [100]. The virus is only able to use the receptor from certain species such as bats, humans, camels, rabbits, and horses to establish infection. Unfortunately for researchers, the virus is unable to infect mouse cells due to differences in the structure of DPP4, making it difficult to evaluate potential vaccines or antivirals. Recently, a small animal model for MERS-CoV has been developed using an Adenoviral vector to introduce the human DPP4 gene into mouse lungs [101]. This unique system makes it possible to test therapeutic interventions and novel vaccines for MERS-CoV in any animal sensitive to adenoviral transductions.